RARE DISEASE
Diffuse alveolar hemorrhage
Diffuse alveolar hemorrhage
Diffuse alveolar hemorrhage
Drug discovery
2
drugs
With orphan designations
Overview
Diffuse alveolar hemorrhage (DAH) is a life-threatening syndrome marked by intra-alveolar bleeding, often secondary to autoimmune disorders (e.g., vasculitis, systemic lupus erythematosus), coagulation defects, infections, or toxins. Clinical hallmarks include dyspnea, hemoptysis, anemia, and diffuse pulmonary infiltrates. Diagnosis requires bronchoscopy with bronchoalveolar lavage showing progressively bloody fluid. Treatment focuses on immunosuppression (corticosteroids, cyclophosphamide, rituximab) for autoimmune causes, supportive respiratory care, and addressing underlying etiologies. Mortality remains high (20–50%), particularly with shock, renal failure, or delayed intervention [1][2][5][14].
Therapies
High-dose corticosteroids (e.g., methylprednisolone) and immunosuppressants (cyclophosphamide, rituximab) [1][3][5].
Plasma exchange for Goodpasture syndrome or severe vasculitis [1][11].
Recombinant factor VIIa or antifibrinolytics in refractory cases; invasive ventilation for respiratory failure [3][7][11].
Categories: rare respiratory diseases
Research Papers
643 drug discovery papers about Diffuse alveolar hemorrhage, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
643 drug discovery papers about Diffuse alveolar hemorrhage, with 3 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-12 | Diffuse Alveolar Hemorrhage Following Trauma: A Diagnostic Dilemma With Rapid Steroid Response.
Diffuse alveolar hemorrhage (DAH) is a rare but potentially life-threatening pulmonary condition that, while classically linked to autoimmune disorders, can occur in the setting of trauma. We report the case of a 20-year-old male who sustained polytrauma following a road traffic accident and initially had a normal chest radiograph. On the fourth day of hospitalization, he developed acute hypoxemia with new bilateral alveolar infiltrates; high-resolution computed tomography revealed diffuse ground-glass opacities with septal thickening. Bronchoalveolar lavage demonstrated progressively hemorrhagic return across aliquots, confirming DAH. Autoimmune markers were largely negative, and in the absence of systemic features, a multifactorial etiology involving trauma-related injury and anticoagulant use was considered. High-dose intravenous corticosteroids produced rapid clinical and radiological recovery. This case underscores the importance of considering DAH in trauma patients presenting with unexplained hypoxemia and bilateral infiltrates, even without hemoptysis, where early bronchoscopy and prompt treatment can be lifesaving.
2026-08-01 | Diffuse alveolar hemorrhage in ANCA-associated vasculitis: Current evidence and multimodal treatment approaches.
Diffuse alveolar hemorrhage (DAH) is a rare but life-threatening complication of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with management largely extrapolated from broader AAV and ARDS literature. We conducted a review of studies published between 2000 and 2025 evaluating treatments and outcomes in AAV-associated DAH, synthesizing evidence across immunosuppressive, plasmapheresis, hemostatic, respiratory and hemodynamic, and infection prevention strategies. Glucocorticoids combined with rituximab or cyclophosphamide induce remission in most patients, although optimal steroid tapering and comparative efficacy in severe, ventilated DAH remain uncertain. Avacopan improves sustained remission and renal recovery in severe AAV and appears to be a feasible steroid-sparing adjunct in early DAH series. Large randomized trials demonstrate no survival benefit of plasma exchange. Local hemostatic therapies may provide rapid bleeding control, but evidence is limited. Respiratory outcomes are driven by hypoxemia severity and need for invasive ventilation or extracorporeal support. Lastly, infection prevention measures are strongly supported.
2026-07-28 | MEK/ERK Mediated Diffuse Alveolar Hemorrhage in Murine Lupus 2261092
Abstract Introduction About 3% of patients with lupus develop severe diffuse alveolar hemorrhage (DAH) with pulmonary vasculitis. C57BL/6 (B6) mice with pristane-induced lupus also develop DAH, but BALB/c mice are resistant. DAH is independent of Toll-like receptor signaling and other inflammatory pathways. This study examined the role of the MEK1/2 pathway Methods B6 and BALB/c mice were treated with pristane with or without inhibitors of MEK1/2 (trametinib/GSK1120212 [GSK]), ERK1/2 (SCH772984 [SCH]), JNK, or p38. Effects on lung hemorrhage and hemostasis were determined Results GSK and SCH abolished DAH, whereas JNK and p38 inhibitors were ineffective. Apoptotic cells were present in lung samples from pristane-treated mice but not in mice receiving pristane and GSK, and endothelial dysfunction was normalized. Expression of the ERK1/2-regulated transcription factor early growth response 1 increased in pristane-treated B6, but not BALB/c, mice and was normalized by GSK. Pristane also increased expression of the anticoagulant genes Tfpi and Thbd in B6 mice. The ratio of Tfpi to tissue factor (F3) to Tfpi increased in B6 (but not BALB/c) mice and was normalized by GSK. Circulating thrombomodulin protein levels increased in B6 mice and returned to normal after GSK treatment. Consistent with augmented endothelial anticoagulant activity, pristane treatment increased tail bleeding in B6 mice. Conclusion Pristane treatment promotes lung endothelial injury and DAH in B6 mice by activating the MEK1/2-ERK1/2 pathway and impairing hemostasis. The hereditary factors determining susceptibility to lung injury and bleeding in pristane-induced lupus are relevant to the pathophysiology of life-threatening DAH in systemic lupus erythematosus and may help to optimize therapy. Funding Source NIH, University of Florida Gatorade fund Topic Categories Therapeutic Approaches to Autoimmunity (THER)
2026-07-26 | A case report of pregnancy complicated by diffuse alveolar hemorrhage: An unexpected link to untreated Graves' disease.
Diffuse Alveolar Hemorrhage (DAH) is a life-threatening condition characterized by widespread bleeding within the alveoli, often resulting from pulmonary capillaritis, bland pulmonary hemorrhage, or diffuse alveolar damage. It presents with hemoptysis, dyspnea, hypoxemia, and anemia, and can lead to respiratory failure. This case report highlights a rare instance of DAH in a pregnant woman with untreated Graves' disease, emphasizing the importance of considering uncommon etiologies in the absence of typical triggers. A 36-year-old pregnant woman at 37 weeks of gestation presented with hemoptysis and dyspnea. Initial evaluations, including pulmonary CT angiography, ruled out pulmonary embolism but revealed bilateral diffuse alveolar involvement. Bronchoscopy confirmed DAH, with serologic tests indicating hyperthyroidism due to Graves' disease. The patient was treated with pulse methylprednisolone and later methimazole, leading to symptom resolution. She delivered a healthy baby at 40 weeks via uncomplicated vaginal delivery. DAH during pregnancy is rare, and its association with untreated Graves' disease is exceptionally uncommon. In this case, untreated Graves' disease may have contributed to left ventricular diastolic dysfunction, exerting shear stress on pulmonary vasculature and potentially resulting in DAH. The absence of coagulopathy, environmental exposures, or autoantibodies supported this conclusion. This case underscores the need to consider thyroid disorders in the differential diagnosis of bland pulmonary hemorrhage, particularly when other causes are excluded. Early identification and management of underlying causes can significantly improve maternal and fetal outcomes. This report highlights the importance of exploring rare etiologies in cases of DAH, especially in pregnant patients, to ensure timely and effective intervention.
2026-07-10 | Idiopathic Pulmonary Hemosiderosis: A Comprehensive Review of Pathophysiology, Diagnostic Paradigms, and Management Strategies in the Context of Diffuse Alveolar Hemorrhage
Idiopathic pulmonary hemosiderosis (IPH) represents a rare, potentially life-threatening pulmonary syndrome characterized by recurrent episodes of diffuse alveolar hemorrhage (DAH) in the absence of an identifiable underlying etiology. As a diagnosis of strict exclusion within the broader spectrum of DAH, IPH poses substantial diagnostic and therapeutic challenges to clinicians across multiple specialties. This comprehensive review synthesizes current evidence regarding the etiopathogenesis, epidemiology, clinical presentation, diagnostic evaluation, and management of IPH, with particular emphasis on its conceptualization as an immune-mediated disorder and its integration within the contemporary classification of children's interstitial lung disease (chILD). The pathogenesis of IPH remains incompletely elucidated; however, accumulating evidence supports a fundamentally immune-dysregulatory mechanism, with autoantibodies detectable in a significant proportion of patients and well-documented associations with autoimmune conditions, most notably celiac disease, which defines the clinically significant Lane–Hamilton syndrome. The clinical presentation is remarkably heterogeneous, ranging from acute respiratory failure and massive hemoptysis to isolated iron-deficiency anemia without overt pulmonary symptoms, particularly in pediatric populations. Diagnosis requires systematic exclusion of vasculitic, infectious, cardiac, coagulopathic, and toxicologic etiologies through a structured approach encompassing serologic evaluation, bronchoalveolar lavage, high-resolution computed tomography, and, when indicated, lung biopsy demonstrating bland alveolar hemorrhage without capillaritis. Management is predicated upon immunosuppressive therapy, with systemic corticosteroids serving as the cornerstone, augmented by steroid-sparing agents in refractory or relapsing disease, and supplemented by strict gluten-free dietary intervention in patients with coexistent celiac disease. Prognosis has improved substantially in the modern immunosuppressive era, although significant morbidity persists, with relapse rates approaching 60% and progressive pulmonary fibrosis representing a major long-term complication. An interprofessional, collaborative approach involving pulmonology, rheumatology, gastroenterology, and supportive care services is essential to optimize diagnostic accuracy, therapeutic adherence, and longitudinal outcomes in this challenging patient population.
antibodies
2026-06-30 | Unilateral diffuse alveolar haemorrhage as an atypical presentation of PR3-ANCA-associated vasculitis: A case report.
Diffuse alveolar haemorrhage (DAH) is a life-threatening pulmonary manifestation of small-vessel vasculitis, most commonly associated with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Unilateral DAH has been infrequently reported and may pose diagnostic challenges, as its radiological presentation can mimic pneumonia, pulmonary oedema, or localized haemorrhage. This atypical presentation may delay recognition of the underlying vasculitis and appropriate immunosuppressive therapy. We present a case of a woman in her thirties with previously diagnosed PR3-ANCA-associated vasculitis who presented with acute worsening of dyspnea (mMRC grade IV) and hemoptysis. Radiological assessments revealed extensive right-sided ground-glass opacities with areas of consolidation and minimal left lower lobe involvement. Bronchoscopy with sequential bronchoalveolar lavage (BAL) showed progressively haemorrhagic aliquots consistent with DAH. Laboratory investigations revealed anemia (Hb 7.1 mg/dL) and elevated serum creatinine (5.02 mg/dL). The patient developed type I respiratory failure requiring mechanical ventilation and hemodialysis. She was treated with pulse intravenous methylprednisolone followed by rituximab therapy, along with trimethoprim-sulfamethoxazole prophylaxis. The patient improved clinically, radiologically, and biochemically and was discharged on supplemental oxygen.
2026-05-29 | Alveolar dysregulation of host response in pneumonia and ARDS: implications for immune modulation and infection.
Respiratory failure due to pneumonia and acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality in the intensive care unit. The alveolar compartment plays a central role in both pathogen clearance and tissue injury, yet its biology is poorly captured by systemic measurements. Growing evidence shows that dysregulation of alveolar host responses drives disease progression, shapes susceptibility to secondary infections, and influences recovery. Community-, hospital-, and ventilator-associated pneumonia differ in microbial drivers and host responses, but all share a pattern of localized inflammation. In most cases, pathogens are rapidly controlled following antimicrobial treatment, while alveolar inflammation persists. This persistence likely reflects self-reinforcing cycles between epithelial injury, neutrophil activity, and monocyte-macrophage dysfunction. Mechanical ventilation further disrupts local defenses, promoting microbial overgrowth and ventilator-associated pneumonia.In ARDS, diffuse alveolar damage initiates an early influx of neutrophils and monocyte-derived macrophages. Although peripheral blood has been used to identify systemic inflammatory subphenotypes, molecular signatures in the alveolar compartment often differ and may provide complementary biological information. Patients may diverge into distinct alveolar immune trajectories, ranging from sustained alveolar hyperinflammation to immune exhaustion. These divergent trajectories influence downstream repair, determining whether patients achieve epithelial recovery or develop fibrotic remodeling.Alveolar immune dysregulation also creates a permissive niche for viral and fungal pathogens. Pulmonary reactivation of herpes simplex virus or cytomegalovirus and fungal infections with Aspergillus frequently occur in critically ill patients and may reflect impaired local host defense. These processes are associated with prolonged mechanical ventilation and illustrate how impaired alveolar defenses may sustain injury and propagate complications. Pneumonia and ARDS share common pathways of alveolar immune dysregulation that are not adequately captured by systemic profiling alone. Integrating systemic and alveolar immune assessment, including their concordance and discordance, may improve patient stratification, facilitate identification of treatable traits, and support the development of more personalized, compartment-informed therapeutic strategies, including both immunomodulatory and pathogen-directed interventions. A more refined understanding of compartment-specific host responses will be key to advancing these approaches.
2026-05-01 | A33-41 Libman-Sacks vs. Infective Endocarditis: A Case of Diagnostic Uncertainty in a Patient With Diffuse Alveolar Hemorrhage
Abstract Introduction Libman-Sacks endocarditis is noninfectious endocarditis marked by sterile platelet thrombi on heart valves. It is a rare cardiac manifestation of systemic lupus erythematosus (SLE). Differentiating its vegetations from culture-negative infective endocarditis (IE) is difficult, especially in patients with risk factors for both, as seen in our case. Case Presentation A 51-year-old female with type 2 diabetes mellitus, hypertension, and end-stage renal disease on peritoneal dialysis was recently treated with antibiotics for multifocal pneumonia. Six days post-discharge, she presented with dyspnea, cough, hemoptysis, fever, and hypoxia. Chest CT revealed diffuse ground-glass opacities and pulmonary edema. Transthoracic echocardiography (TTE) showed a large (39 × 10 mm), mobile vegetation on the posterior mitral leaflet with moderate mitral regurgitation. Autoimmune serologies were positive for ANA, anti-dsDNA, lupus anticoagulant, anticardiolipin, and β2-glycoprotein antibodies. The initial bronchoscopy was not favorable for diffuse alveolar hemorrhage (DAH), and blood cultures were negative. A prior kidney biopsy (2021) showed diabetic glomerulosclerosis with resolved immune complex glomerulonephritis. Given the vegetation’s size and mobility, lack of clinical SLE features, elevated WBC, CRP, and procalcitonin, and negative DAH, a multidisciplinary team favored culture-negative IE over Libman-Sacks. Empiric vancomycin and ceftriaxone were initiated. The hospital course was complicated by embolic strokes and DRESS syndrome. Antibiotics were stopped, high-dose prednisone and anticoagulation were started. Repeat TTE showed smaller vegetation and improved mitral regurgitation. She was discharged in stable condition. Ten days later, she returned with hypoxic respiratory failure from DAH (confirmed on bronchoscopy), hemorrhagic toe bullae, and anterior tibial artery occlusion. Lupus flare or catastrophic antiphospholipid syndrome (CAPS) was suspected. She improved with plasmapheresis, rituximab, and corticosteroids, and was discharged on immunosuppressants and warfarin. Discussion and Conclusion Several factors help differentiate Libman-Sacks from IE. Libman-Sacks is more commonly associated with high prevalence of antiphospholipid antibodies but a lower prevalence of SLE-specific autoantibodies. IE typically presents with high WBC, markedly elevated CRP, and procalcitonin, whereas Libman-Sacks may show low WBC and strongly positive antiphospholipid antibodies. Valvular pathology also differs: Libman-Sacks shows small to medium vegetations on either or both sides of the leaflets, while IE typically has large, irregular masses on the valve cusps, often extending to the cords. Our patient’s inflammatory markers and valve findings favored infection initially. This case highlights the diagnostic challenge in patients with risk factors for both. Early multidisciplinary evaluation is essential in guiding management. This abstract is funded by: None
2026-05-01 | A35-09 The Unexpected Hemorrhage: Acute Diffuse Alveolar Hemorrhage Leading to Diagnosis of Eosinophilic Granulomatosis With Polyangiitis Diagnosis
Abstract Introduction Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare vasculitis affecting small- to medium-sized vessels, mainly in adults with asthma, chronic rhinosinusitis (often with nasal polyps), and peripheral eosinophilia. Incidence is ∼2 per million person-years and prevalence 30-35 per million, complicating diagnosis. Patients develop worsening asthma, sinonasal disease, and migratory pulmonary infiltrates; one-third are myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive. Serious complications include neuropathy, cardiac issues, and diffuse alveolar hemorrhage (DAH), which pose significant morbidity. We report a case of EGPA presenting with bronchoscopically confirmed DAH in a young woman, whose persistent asthma and sinonasal polyposis initially masked the vasculitis. Case A 29-year-old woman with severe persistent asthma and nasal polyps presented for elective bronchoscopy for cough and scant hemoptysis. For nine months, she developed worsening dyspnea and recurrent asthma/sinusitis exacerbations despite escalating inhaled therapy and repeated antibiotics and steroids. On admission, vitals were stable, and labs showed leukocytosis (14.32 × 10³/µL) with a normal eosinophil count—likely suppressed by prednisone 60mg started the day prior. Of note, outpatient lab showed peripheral eosinophilia (2,610/µL; 20%). Bronchoscopy showed progressively bloodier bronchoalveolar lavage fluid, consistent with DAH. The differential contained 70% eosinophils. Biopsy revealed chronic inflammation with increased eosinophils and focal granulation tissue. Serology was positive for p-ANCA with MPO specificity; IgE was elevated. Prior outpatient data supported vasculitic, type-2-driven airway disease: CT chest with peribronchovascular ground-glass nodules [Figure 1]; severe obstructive physiology with air trapping, diffuse sinonasal polyposis; and peripheral eosinophilia. The patient was started on pulse-dose intravenous glucocorticoids followed by taper and initiation of mepolizumab, then underwent sinus surgery with improvement. Follow-up with otolaryngology, rheumatology, and pulmonology was arranged. Discussion Our patient presented with hemoptysis alongside severe persistent asthma and chronic rhinosinusitis of unclear cause. EGPA involves two immune processes: a type-2, interleukin-5-driven eosinophilic pathway, and an ANCA-mediated vasculitis. She exemplifies this: refractory asthma with nasal polyps reflects the eosinophil/Th2 axis, while hemoptysis with DAH indicates vasculitic injury. Careful review of her history and testing led her pulmonologist to suspect EGPA and pursue bronchoscopy, which confirmed DAH with eosinophil predominance. Since EGPA often mimics difficult asthma and sinus disease, high clinical suspicion enabled timely glucocorticoids and IL-5-pathway biologic therapy, per guidelines. A coordinated multidisciplinary approach moved care beyond inhaler escalation to vasculitis-directed treatment, underscoring the need for vigilant reassessment when asthma therapies fail and continued work to refine EGPA diagnostic pathways for earlier, targeted management. This abstract is funded by: None
2026-05-01 | B105-11 The Clinical Course Of Pediatric Diffuse Alveolar Hemorrhage Syndrome, Through A Long-term Observation
Abstract Background Previous studies have reported that up to 50% of patients with diffuse alveolar hemorrhage (DAH) die within 2.5 years after onset. However, its clinical subtypes and disease course remain poorly defined. Some reviews have suggested that DAH often follows a ‘relapse-remission’ pattern, while a ‘progressive’ course is less common, though these claims lack detailed description or empirical evidence. This study retrospectively analyzed the long-term outcomes of children with DAH at our center to delineate patterns of clinical progression. Methods Retrospective analysis of 82 pediatric DAH patients (2010-2024) with ≥1 year follow-up at our institution. Results A total of 82 children were enrolled (male:female = 1:2.56). The median age at onset was 3 years (range: 0.3-12.4), and 67 (81.7%) were ≤6 years old. The median interval from onset to diagnosis was 3 months (range: 1 day-7 years).Follow-up ranged from 13 months to 13 years 8 months. Seventy-eight patients (95.1%) experienced relapse, with a median of 4 episodes (range: 1-17). Ten relapsed once, 61 relapsed 2-10 times, and 7 relapsed ≥10 times. Four patients remained relapse-free during follow-up (maximum 9 years 9 months). The median interval from initial treatment to first relapse was 8 months (range: 2-36); 59 patients (75.6%) relapsed within one year, including 13 (22%) in month 7.Based on clinical course, two major types were identified:1.Monocyclic type (25.6%, 21/82): remission after initial treatment with no or ≤2 relapses, showing a single-peak pattern with acute hemorrhagic and stable phases.2.Multicyclic type (74.4%, 61/82): ≥2 relapses after initial treatment, comprising acute hemorrhagic, absorption, chronic persistent, remission, or subsequent relapse phases. Subtypes included:Relapsing-remitting (39%, 32/82): recovery or minimal residual changes between relapses.Relapsing-progressive(31.7%, 26/82): progressive course or residual impairment after each relapse.Relapsing-secondary progressive (3.6%, 3/82): irreversible progression after later relapse, leading to severe respiratory dysfunction or death. Conclusions To our knowledge, this represents the first evidence-based characterization of clinical course patterns in pediatric diffuse alveolar hemorrhage (DAH). Two clinical courses patterns were identified: monocyclic and multicyclic. Approximately one-third of children exhibited a monocyclic course with favorable outcomes, while most demonstrated multicyclic courses, predominantly of the relapsing-remitting or relapsing-progressive types. Our findings indicate that the majority of patients were able to lead normal lives despite experiencing relapses over many years. Clinicians should recognize that recurrent relapses may represent an intrinsic feature of the disease rather than treatment failure. This abstract is funded by: None
proteins
2026-06-08 | The Role of Macrophage M1/M2 Polarization Imbalance in the Pathogenesis of Immune Associated Diffuse Alveolar Hemorrhage: Evidence From the Study of Human Clinical Specimens.
An imbalance in M1/M2 macrophage polarization has been shown to play a critical role in the pathogenesis of diffuse alveolar hemorrhage (DAH) in mouse models. However, its contribution to immune-associated DAH in humans remains unclear. This study aimed to investigate the role of macrophage M1/M2 polarization imbalance in the pathogenesis of immune-associated DAH in children. A total of 24 children with immune-associated DAH (DAH group) and 13 children with acute airway foreign body or mild benign airway stenosis (control group) were enrolled. Bronchoalveolar lavage fluid (BALF) was obtained via bronchoscopy, and supernatant was isolated by centrifugation. Cytokine levels in BALF supernatant were measured using a cytometric bead array. Monocyte-derived macrophages (MDMs) were stimulated in vitro with BALF supernatant. The mRNA expression levels of M1 markers (IL-1β, TNF-α, IL-6, TGM2) and M2 markers (CD163, MRC1) were quantified using real-time PCR. Protein expression of surface markers (CD14, CD80, CD86, CD163, CD206) was analyzed by flow cytometry. (1) Levels of MCP-1, IL-6 and IL-8 in BALF supernatant were significantly higher in the DAH group than those in the control group. (2) MDMs stimulated with BALF supernatant from the DAH group showed significantly elevated mRNA expression of IL-1β and IL-6 and significantly reduced expression of MRC1 compared to those stimulated with control supernatant. (3) Flow cytometry revealed significantly higher CD86 expression and significantly lower CD163 and CD206 expression in MDMs treated with DAH group BALF supernatant. This study provides evidence that macrophage M1/M2 polarization imbalance contributes to the pathogenesis of immune-associated DAH in humans, highlighting a potential target for immunomodulatory therapy.
2026-02-02 | Liraglutide prevents lupus-associated diffuse alveolar hemorrhage via inhibiting lymphocyte infiltration and promoting macrophage M2 polarization.
This study aimed to explore the prophylactic and therapeutic role of liraglutide for lupus-associated diffuse alveolar hemorrhage (DAH). A lupus-associated DAH model was established in 6-8-week-old female C57BL/6 mice via intraperitoneal injection of 0.5 mL pristane. Mice were randomized to receive daily intraperitoneal injections of either saline or liraglutide (2 mg/kg/day), starting either 14 days before or on the day of pristane injection, and continuing until 14 days post-injection. Body weight and blood glucose were monitored. Serum levels of anti-dsDNA, ANA, total IgM and IgG were quantified using ELISA. Lung tissues were collected for histopathological analysis with H&E and Prussian blue staining, respectively, characterization of different types of immune cells infiltration with flow cytometry (t-SNE for subset dimensionality reduction) and immunofluorescence, and quantification of protein levels with Western blot. Liraglutide significantly alleviated pulmonary hemorrhage, as evidenced by reduced lung wet weight, incidence of lung hemorrhage, pulmonary hemosiderin-laden macrophages, and total serum IgG, without affecting body weight or glucose. Mechanistically, liraglutide treatment reduced pulmonary infiltration of multiple T and B lymphocyte subsets (e.g., CD4+, CD8+, B220+), while concurrently increasing alveolar macrophages and promoting M2 macrophage polarization. The phenotypic shift was demonstrated by increased M2 cell numbers, elevated CD206 expression, and downregulation of M1 marker CD86 and upregulation of M2 marker CD163 as confirmed at the protein level. Liraglutide treatment effectively ameliorates lupus-associated DAH, potentially through modulation of T cells, B cells, and macrophages polarization, offering a novel prophylactic and therapeutic strategy for this fatal complication of lupus.
2025-09-30 | Diffuse alveolar hemorrhage in a child with mild hemophilia A who underwent bone marrow transplantation for thalassemia: a case report
Diffuse alveolar hemorrhage (DAH) is a relatively rare complication of bone marrow transplantation (BMT) associated with a high risk of mortality. It generally occurs in the early post-transplant phase during severe thrombocytopenia; however, since most thrombocytopenic cases do not develop DAH, cofactors are at play. Here, we discuss the case of a 4-year-old male child with mild asymptomatic hemophilia A discovered on routine evaluation pre-BMT, who developed DAH after a fully matched sibling BMT for HbE/Beta-thalassemia. The patient presented on day +21 post-BMT with sudden onset of cough followed one day later by hemoptysis. He had received FVIII supplementation with PTT normalization and FVIII levels of 28%. A chest CT scan showed interstitial lung disease with areas of ground glass bilaterally, mainly in the lower lobes. A radiological diagnosis of DAH was made, and the child was treated with additional FVIII concentrate (Advate), blow-by oxygen supplementation, red blood cells transfusion, platelet transfusion, methylprednisolone, tranexamic acid, and antioxidants (vitamin C and E). He responded well and recovered in a few days. Mild hemophilia associated with DAH post-BMT has never been reported before, however, it should be considered as a potentially treatable cause of DAH after BMT. FVIII levels should be part of the routine workup of children developing DAH post-transplantation. In the presence of thrombocytopenia, high FVIII levels of >30-40% might be required to prevent/treat DAH.
2025-09-28 | Management and outcome of immune-mediated diffuse alveolar hemorrhage: a single centre case series
The standard treatment of immune-mediated diffuse alveolar hemorrhage (IM-DAH) encompasses immunosuppression with glucocorticoids (GC) and either cyclophosphamide (CYC) or rituximab (RTX). The role of intravenous immunoglobulin (IVIg) and plasma exchange (PLEX) remains controversial. We conducted a single-centre retrospective observational study on patients admitted with IM-DAH to evaluate treatment approaches and outcomes. Twelve episodes were identified in ten patients. All episodes were treated with GC and nine with CYC. IVIg was administered as first-line and/or bridging therapy in three cases with concomitant infections or high infection risk. PLEX was used in six episodes. IVIg and PLEX were primarily used as add-on therapies or when other immunosuppression was not recommended. After one year, nine patients survived. The combination of GC and CYC was the most common treatment regimen. While the role of PLEX and IVIg is not well established, they may be beneficial as second-line or as add-on therapies in selected cases.
2024-08-27 | Quantitative proteomic analysis and replacement therapy identifies haptoglobin as a therapeutic target in a murine model of SLE-associated diffuse alveolar hemorrhage.
Diffuse alveolar hemorrhage (DAH) is a catastrophic clinical syndrome and one of the manifestations of pulmonary involvement in systemic lupus erythematosus (SLE), which is characterized by hemoptysis, diffuse pulmonary infiltrates, and respiratory failure. However, the treatment options for DAH remain limited, and DAH-related studies are needed to explore more effective therapeutic directions for better disease management and improved prognosis. This study utilized the pristane-induced DAH murine model to mimic the pathological process of DAH in patients with SLE. Proteomic analysis was conducted to detect differentially expressed proteins (DEPs) in the plasma of surviving and non-surviving mice, followed by an analysis of biological functions and pathways. The most significant DEP was then confirmed in the plasma of SLE patients with or without DAH and DAH murine model with or without fatal outcomes. Finally, the therapeutic value of haptoglobin (Hp) replacement was validated in a DAH murine model through lung histopathology, RT-qPCR, and survival analysis. This study identified 178 DEPs, with 118 upregulated and 60 downregulated DEPs in the non-survival group. Within a set of notable Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, complement and coagulation cascades emerged as the most prominent pathway associated with the process of DAH. Later, the most significant DEP, haptoglobin (Hp), was confirmed to exhibit a significant decrease in the plasma of individuals with SLE-DAH and DAH murine model with poor outcomes by the ELISA test. Finally, compared with the control group, the severity of DAH in the Hp treatment group was alleviated significantly, as manifested by the decreased levels of pro-inflammatory cytokines (IL-6 and TNF-α), increased levels of anti-inflammatory cytokines (IL-10 and TGF-β), and decreased mortality. A reduction in plasma Hp levels was observed in SLE-DAH, and the replacement therapy with Hp could alleviate pulmonary hemorrhage and reduce mortality in DAH mice. This study identified Hp as a potential biomarker for its clinical diagnosis and a direction for treatment.
cell therapies
2024-11-19 | Trained mesenchymal stromal cell-based therapy HXB-319 for treating diffuse alveolar hemorrhage in a pristane-induced murine model.
Mesenchymal stromal cells (MSCs) can modulate immune responses and suppress inflammation in autoimmune diseases. Although their safety has been established in clinical trials, the efficacy of MSCs is inconsistent due to variability in potency among different preparations and limited specificity in targeting mechanisms driving autoimmune diseases. We utilized high-dimensional design of experiments methodology to identify factor combinations that modulate gene expression by MSCs to mitigate inflammation. This led to a novel MSC-based cell therapy, HXB-319. Its anti-inflammatory properties were validated in vitro by flow cytometry, RT-PCR, and mass spectrophotometry. To evaluate in vivo efficacy, we treated a diffuse alveolar hemorrhage (DAH) mouse model (C57Bl/6). Seven days post-DAH induction with pristane, mice received either MSCs or HXB-319 (2X106 cells, IP). On day 14, peritoneal lavage fluid (PLF) and lung tissue were collected for flow cytometry, histopathological examination, and mRNA. HXB-319 increased gene expression levels of anti-inflammatory, angiogenic, and anti-fibrotic factors (eg, TSG-6, VEGF, and HGF). KEGG pathway analysis confirmed significant activation of relevant anti-inflammatory, angiogenic, and anti-fibrotic proteins, corroborating RT-PCR results. In the DAH model, HXB-319 significantly reduced lung inflammation and alveolar hemorrhage compared to MSC-treated and untreated DAH mice. HXB-319 treatment also significantly decreased neutrophils, plasmacytoid dendritic cells, and RORγT cells, increased FoxP3+ cells in PLF, and reversed alterations in mRNA encoding IL-6, IL-10, and TSG-6 in lung tissue compared to DAH mice. HXB-319 effectively controls inflammation and prevents tissue damage in pristine-induced DAH, highlighting its therapeutic potential for autoimmune inflammatory diseases.
2024-01-30 | The anti-inflammatory effects of mesenchymal stem cells attenuate diffuse pulmonary hemorrhage.
There are few effective treatment options for diffuse pulmonary hemorrhage (DPH). We aimed to elucidate the therapeutic role and underlying mechanisms of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) in DPH. Therapeutic effects of MSCs/MSC-EVs in pristane-induced DPH mice were evaluated via pulmonary function testing and histopathology. Transcriptome sequencing analyzed differentially expressed genes in control, DPH, and MSC groups. The proportion of macrophage polarization was evaluated in vivo and in vitro via fluorescence-activated cell sorting in control, DPH, MSC, MSC-EV inhalation, and MSC-EV intravenous groups. Intraperitoneal injection of pristane induced diffuse alveolar hemorrhage, early fibrosis, and inflammation in C57BL/6 mice. Monocytes were depleted in the peripheral blood in DPH mice and MSCs were recruited to the lungs, resulting in significantly attenuated diffuse alveolar hemorrhage and suppressed immunological response. This was more effective in the hyperacute hemorrhage phase than the early inflammatory phase. An MSC treatment-mediated anti-inflammatory effect was observed in DPH mice. Furthermore, MSC-EVs inhalation or tail-vein injection could effectively reduce DPH injury. MSCs could suppress macrophage M1 polarization in DPH in vivo and in vitro. MSCs displayed significant therapeutic effects in pristane-induced DPH, which may be a promising cell-free therapeutic approach.
2023-01-24 | Updates in idiopathic pulmonary hemosiderosis in 2022: A state of the art review.
This manuscript reports the recent advances in idiopathic pulmonary hemosiderosis (IPH), a rare cause of diffuse alveolar hemorrhage in children and adults. This narrative review of the literature summarizes different aspects of IPH, including proposed pathogenesis, patient demographics, clinical and radiological characteristics, treatment, and prognosis. Additionally, the association between Celiac Disease (CD) and IPH is carefully evaluated. IPH is a frequently misdiagnosed disease. The delay in the diagnosis of IPH is often significant but fortunately, appears to have decreased in recent years. IPH in adults and children have distinct demographic preferences. The autoantibodies are common in IPH but with a definite difference between the adult and pediatric populations. The definitive diagnosis of IPH requires lung biopsy and careful exclusion of all competing diagnoses, even with lung biopsy showing bland pulmonary hemorrhage. The presence of nonspecific inflammatory cells or lymphoid aggregates may suggest a secondary immunologic phenomenon and needs careful evaluation and follow-up. A substantial number of patients suffer from coexisting CD, also known as Lane-Hamilton syndrome (LHS), and all patients with IPH need to be evaluated for LHS by serology. Although strict gluten free diet can manage the majority of patients with LHS, other patients generally require immunosuppressive therapy. The corticosteroids are the backbone of IPH therapy. Recently utilized experimental treatment options include mesenchymal stem cell transplant, liposteroid and bronchial artery embolization. The immunosuppression should be adjusted to achieve optimal disease control. Patients may progress to end-stage lung disease despite all measures, and lung transplantation may be the only viable option.
2022-10-04 | Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Diffuse Alveolar Hemorrhage Associated with Systemic Lupus Erythematosus in Mice by Promoting M2 Macrophage Polarization via the microRNA-146a-5p/NOTCH1 Axis.
Systemic lupus erythematosus (SLE)-associated diffuse alveolar hemorrhage (DAH) is a rare but extremely harmful condition. The current study sought to dissect the mechanisms underlying the effects of human umbilical cord mesenchymal stem cell (HUCMSC)-derived exosomes on M2 macrophage polarization in SLE-associated DAH via the microRNA (miR)-146a-5p/NOTCH1 axis. A DAH mouse model was established using pristane. Exosomes were isolated from HUCMSCs transfected or untransfected with the miR-146a-5p antagonist or agonist and their NCs and then injected into DAH mice. Additionally, miR-146a-5p was overexpressed in macrophages. Expression of miR-146a-5p, NOTCH1, M1 macrophage markers, and M2 macrophage markers was measured in mice and macrophages, and inflammatory factor levels were detected. Mouse lung injuries were evaluated, so was the binding of miR-146a-5p to NOTCH1. Rescue experiments were conducted in mice and macrophages using NOTCH1 shRNA and pcDNA3.1-NOTCH1, respectively. NOTCH1 expression was enhanced in DAH mice. HUCMSC-derived exosomes reduced NOTCH1 expression, bleeding, inflammation, and M1 macrophage polarization but elevated M2 macrophage polarization in lung tissues of DAH mice. Mechanistically, NOTCH1 is negatively targeted by miR-146a-5p. miR-146a-5p overexpression diminished M1 marker and inflammatory factor levels but enhanced M2 marker levels in macrophages, which was nullified by NOTCH1 overexpression. HUCMSC-derived exosomes with miR-146a-5p inhibition increased NOTCH1 expression, worsened bleeding and inflammation, and augmented M1 macrophage polarization while decreasing M2 macrophage polarization in lung tissues of DAH mice, which was abrogated by silencing NOTCH1. HUCMSC-derived exosomes diminished NOTCH1 expression to accelerate M2 macrophage polarization via delivery of miR-146a-5p, thus alleviating SLE-associated DAH in mice.
2012-08-21 | Allogeneic transplantation of umbilical cord-derived mesenchymal stem cells for diffuse alveolar hemorrhage in systemic lupus erythematosus.
Umbilical cord-derived mesenchymal stem cell transplantation (UC-MSCT) has been proved to be effective in the treatment of systemic lupus erythematosus (SLE), based on animal experiments and clinical trials. Diffuse alveolar hemorrhage (DAH) is a rare complication of SLE with a high mortality usually over 50%. This study aimed to assess the efficacy of UC-MSCT in the treatment of SLE-associated DAH. Four SLE patients complicated with DAH, who underwent UC-MSCT, were included. Clinical changes before and after transplantation were assessed by measurements of hemoglobin, platelet level, oxygen saturation, and serological factors. High-resolution CT (HRCT) scans of the chest were performed to evaluate pulmonary manifestation. All the four patients showed dramatic improvements of their clinical manifestations. Hemoglobin was elevated after UC-MSCT and was sustained at a normal level 6 months after UC-MSCT in the four patients. Platelet level was upregulated in two patients who had thrombocytopenia at baseline. Oxygen saturation appeared to be normal at 1 month after UC-MSCT, and this result was confirmed by the HRCT scan of the chest. Serum albumin elevated to 3.5 g/dl 6 months after transplantation. Our findings suggest that UC-MSCT results in amelioration of oxygen saturation as well as hematological and serologic changes, which revealed that UC-MSCT could be applied as a salvage strategy for DAH patients.
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2022-08-26 | Down-regulated miR-146a expression with increased neutrophil extracellular traps and apoptosis formation in autoimmune-mediated diffuse alveolar hemorrhage
Increasing evidences have suggested an important role of microRNAs (miRNAs) in regulating cell death processes including NETosis and apoptosis. Dysregulated expression of miRNAs and increased formation of neutrophil extracellular traps (NETs) and apoptosis participate in autoimmune-mediated diffuse alveolar hemorrhage (DAH), mostly associated with pulmonary capillaritis in systemic lupus erythematosus (SLE) patients. In particular, besides the inhibition of apoptosis, miR-146a can control innate and acquired immune responses, and regulate the toll-like receptor pathway through targeting TRAF6 to reduce the expression of pro-inflammatory cytokines/chemokines like IL-8, a NETosis inducer.Expression of miR-146a, TRAF6 and NETs were examined in peripheral blood neutrophils (PBNs) and lung tissues from SLE-associated DAH patients, and in neutrophils and pristane-induced DAH lung tissues from C57BL/6 mice. To assess NETs formation, we examined NETosis-related DNAs morphology and crucial mediators including protein arginine deiminase 4 and citrullinated Histone 3. Expression of miR-146a and its endogenous RNA SNHG16 were studied in HL-60 promyelocytic cells and MLE-12 alveolar cells during NETosis and apoptosis processes, respectively. MiR-146a-overexpressed and CRISPR-Cas13d-mediated SNHG16-silenced HL-60 cells were investigated for NETosis. MiR-146a-overexpressed MLE-12 cells were analyzed for apoptosis. Pristane-injected mice received intra-pulmonary miR-146a delivery to evaluate therapeutic efficacy in DAH.In DAH patients, there were down-regulated miR-146a levels with increased TRAF6 expression and PMA/LPS-induced NETosis in PBNs, and down-regulated miR-146a levels with increased TRAF6, high-mobility group box 1 (HMGB1), IL-8, NETs and apoptosis expression in lung tissues. HMGB1-stimulated mouse neutrophils had down-regulated miR-146a levels with increased TRAF6, IL-8 and NETs expression. PMA-stimulated HL-60 cells had down-regulated miR-146a levels with enhanced NETosis. MiR-146a-overexpressed or SNHG16-silenced HL-60 cells showed reduced NETosis. Apoptotic MLE-12 cells had down-regulated miR-146a expression and increased HMGB1 release, while miR-146a-overexpressed MLE-12 cells showed reduced apoptosis and HMGB1 production. There were down-regulated miR-146a levels with increased TRAF6, HMGB1, IL-8, NETs and apoptosis expression in mouse DAH lung tissues. Intra-pulmonary miR-146a delivery could suppress DAH by reducing TRAF6, IL-8, NETs and apoptosis expression.Our results demonstrate firstly down-regulated pulmonary miR-146a levels with increased TRAF6 and IL-8 expression and NETs and apoptosis formation in autoimmune-mediated DAH, and implicate a therapeutic potential of intra-pulmonary miR-146a delivery.
2021-06-28 | Targeting Intra-Pulmonary P53-Dependent Long Non-Coding RNA Expression as a Therapeutic Intervention for Systemic Lupus Erythematosus-Associated Diffuse Alveolar Hemorrhage
Diffuse alveolar hemorrhage (DAH) in systemic lupus erythematosus (SLE) is associated with significant mortality, requiring a thorough understanding of its complex mechanisms to develop novel therapeutics for disease control. Activated p53-dependent apoptosis with dysregulated long non-coding RNA (lncRNA) expression is involved in the SLE pathogenesis and correlated with clinical activity. We examined the expression of apoptosis-related p53-dependent lncRNA, including H19, HOTAIR and lincRNA-p21 in SLE-associated DAH patients. Increased lincRNA-p21 levels were detected in circulating mononuclear cells, mainly in CD4+ and CD14+ cells. Higher expression of p53, lincRNA-p21 and cell apoptosis was identified in lung tissues. Lentivirus-based short hairpin RNA (shRNA)-transduced stable transfectants were created for examining the targeting efficacy in lncRNA. Under pristane stimulation, alveolar epithelial cells had increased p53, lincRNA-p21 and downstream Bax levels with elevated apoptotic ratios. After pristane injection, C57/BL6 mice developed DAH with increased pulmonary expression of p53, lincRNA-p21 and cell apoptosis. Intra-pulmonary delivery of shRNA targeting lincRNA-p21 reduced hemorrhage frequencies and improved anemia status through decreasing Bax expression and cell apoptosis. Our findings demonstrate increased p53-dependent lncRNA expression with accelerated cell apoptosis in the lungs of SLE-associated DAH patients, and show the therapeutic potential of targeting intra-pulmonary lncRNA expression in a pristane-induced model of DAH.
2016-03-28 | In Vivo Therapeutic Success of MicroRNA‐155 Antagomir in a Mouse Model of Lupus Alveolar Hemorrhage
Objective Diffuse alveolar hemorrhage (DAH) is a rare but life‐threatening complication of systemic lupus erythematosus (SLE). Pristane‐treated B6 mice develop severe DAH within 2 weeks of treatment. MicroRNA‐155 (miR‐155) is a pleiotropic microRNA that plays a crucial role in the regulation of immune responses. Recent studies have revealed a pathogenic role of miR‐155 in various autoimmune disorders. The purpose of this study was to examine the role of miR‐155 in the development of DAH in pristane‐induced lupus using miR‐155–knockout (miR‐155 −/− ) mice and miR‐155 antagomir to silence miR‐155. Methods DAH was induced by an intraperitoneal injection of 0.5 ml of pristane. MicroRNA‐155 antagomir was administered intravenously to silence miR‐155 expression. Lung tissues were collected for RNA extraction and were embedded in paraffin for sectioning. Gene expression profiling data were analyzed using Ingenuity Pathway Analysis. Real‐time quantitative polymerase chain reaction analysis was used for single‐gene validation. Luciferase reporter assay and argonaute 2 immunoprecipitation were performed for target validation. Results MicroRNA‐155 expression was significantly increased during the development of DAH. Disease progression was reduced in miR‐155 −/− mice as well as by in vivo silencing of miR‐155 using a miR‐155 antagomir. MicroRNA‐155 silencing dampened pristane‐induced ectopic activation of multiple inflammatory pathways and reduced the expression of proinflammatory cytokines. Several negative regulators of NF‐κB signaling were inhibited by pristane and were reactivated in miR‐155 −/− mice. In particular, the antiinflammatory factor peroxisome proliferator–activated receptor α was identified as a direct target of miR‐155. Conclusion MicroRNA‐155 promotes pristane‐induced lung inflammation. It contributes to ectopic activation of NF‐κB signaling pathways by targeting multiple negative regulators. MicroRNA‐155 antagomir may be a promising therapeutic strategy for treating acute lung inflammation in lupus.
2008-10-01 | A NOVEL TREATMENT FOR RECURRENT DIFFUSE ALVEOLAR HEMORRHAGE ASSOCIATED WITH NON-MYELOABLATIVE ALLOGENIC STEM CELL TRANSPLANTATION
INTRODUCTION: Diffuse alveolar hemorrhage (DAH) occurs in about 5% of hematopoietic stem cell transplant (HSCT) recipients with a mortality rate of 30 – 70% (1Afessa B Tefferi A Litzow MR et al.Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients.Am J Respir Crit Care Med. 2002; 166: 641-645Crossref PubMed Scopus (153) Google Scholar). We describe a patient with recurrent episodes of DAH occurring late in the post-HSCT course.
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2026-08-12 | Diffuse Alveolar Hemorrhage Following Trauma: A Diagnostic Dilemma With Rapid Steroid Response.
Diffuse alveolar hemorrhage (DAH) is a rare but potentially life-threatening pulmonary condition that, while classically linked to autoimmune disorders, can occur in the setting of trauma. We report the case of a 20-year-old male who sustained polytrauma following a road traffic accident and initially had a normal chest radiograph. On the fourth day of hospitalization, he developed acute hypoxemia with new bilateral alveolar infiltrates; high-resolution computed tomography revealed diffuse ground-glass opacities with septal thickening. Bronchoalveolar lavage demonstrated progressively hemorrhagic return across aliquots, confirming DAH. Autoimmune markers were largely negative, and in the absence of systemic features, a multifactorial etiology involving trauma-related injury and anticoagulant use was considered. High-dose intravenous corticosteroids produced rapid clinical and radiological recovery. This case underscores the importance of considering DAH in trauma patients presenting with unexplained hypoxemia and bilateral infiltrates, even without hemoptysis, where early bronchoscopy and prompt treatment can be lifesaving.
2026-08-01 | Diffuse alveolar hemorrhage in ANCA-associated vasculitis: Current evidence and multimodal treatment approaches.
Diffuse alveolar hemorrhage (DAH) is a rare but life-threatening complication of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with management largely extrapolated from broader AAV and ARDS literature. We conducted a review of studies published between 2000 and 2025 evaluating treatments and outcomes in AAV-associated DAH, synthesizing evidence across immunosuppressive, plasmapheresis, hemostatic, respiratory and hemodynamic, and infection prevention strategies. Glucocorticoids combined with rituximab or cyclophosphamide induce remission in most patients, although optimal steroid tapering and comparative efficacy in severe, ventilated DAH remain uncertain. Avacopan improves sustained remission and renal recovery in severe AAV and appears to be a feasible steroid-sparing adjunct in early DAH series. Large randomized trials demonstrate no survival benefit of plasma exchange. Local hemostatic therapies may provide rapid bleeding control, but evidence is limited. Respiratory outcomes are driven by hypoxemia severity and need for invasive ventilation or extracorporeal support. Lastly, infection prevention measures are strongly supported.
2026-07-28 | MEK/ERK Mediated Diffuse Alveolar Hemorrhage in Murine Lupus 2261092
Abstract Introduction About 3% of patients with lupus develop severe diffuse alveolar hemorrhage (DAH) with pulmonary vasculitis. C57BL/6 (B6) mice with pristane-induced lupus also develop DAH, but BALB/c mice are resistant. DAH is independent of Toll-like receptor signaling and other inflammatory pathways. This study examined the role of the MEK1/2 pathway Methods B6 and BALB/c mice were treated with pristane with or without inhibitors of MEK1/2 (trametinib/GSK1120212 [GSK]), ERK1/2 (SCH772984 [SCH]), JNK, or p38. Effects on lung hemorrhage and hemostasis were determined Results GSK and SCH abolished DAH, whereas JNK and p38 inhibitors were ineffective. Apoptotic cells were present in lung samples from pristane-treated mice but not in mice receiving pristane and GSK, and endothelial dysfunction was normalized. Expression of the ERK1/2-regulated transcription factor early growth response 1 increased in pristane-treated B6, but not BALB/c, mice and was normalized by GSK. Pristane also increased expression of the anticoagulant genes Tfpi and Thbd in B6 mice. The ratio of Tfpi to tissue factor (F3) to Tfpi increased in B6 (but not BALB/c) mice and was normalized by GSK. Circulating thrombomodulin protein levels increased in B6 mice and returned to normal after GSK treatment. Consistent with augmented endothelial anticoagulant activity, pristane treatment increased tail bleeding in B6 mice. Conclusion Pristane treatment promotes lung endothelial injury and DAH in B6 mice by activating the MEK1/2-ERK1/2 pathway and impairing hemostasis. The hereditary factors determining susceptibility to lung injury and bleeding in pristane-induced lupus are relevant to the pathophysiology of life-threatening DAH in systemic lupus erythematosus and may help to optimize therapy. Funding Source NIH, University of Florida Gatorade fund Topic Categories Therapeutic Approaches to Autoimmunity (THER)
2026-07-26 | A case report of pregnancy complicated by diffuse alveolar hemorrhage: An unexpected link to untreated Graves' disease.
Diffuse Alveolar Hemorrhage (DAH) is a life-threatening condition characterized by widespread bleeding within the alveoli, often resulting from pulmonary capillaritis, bland pulmonary hemorrhage, or diffuse alveolar damage. It presents with hemoptysis, dyspnea, hypoxemia, and anemia, and can lead to respiratory failure. This case report highlights a rare instance of DAH in a pregnant woman with untreated Graves' disease, emphasizing the importance of considering uncommon etiologies in the absence of typical triggers. A 36-year-old pregnant woman at 37 weeks of gestation presented with hemoptysis and dyspnea. Initial evaluations, including pulmonary CT angiography, ruled out pulmonary embolism but revealed bilateral diffuse alveolar involvement. Bronchoscopy confirmed DAH, with serologic tests indicating hyperthyroidism due to Graves' disease. The patient was treated with pulse methylprednisolone and later methimazole, leading to symptom resolution. She delivered a healthy baby at 40 weeks via uncomplicated vaginal delivery. DAH during pregnancy is rare, and its association with untreated Graves' disease is exceptionally uncommon. In this case, untreated Graves' disease may have contributed to left ventricular diastolic dysfunction, exerting shear stress on pulmonary vasculature and potentially resulting in DAH. The absence of coagulopathy, environmental exposures, or autoantibodies supported this conclusion. This case underscores the need to consider thyroid disorders in the differential diagnosis of bland pulmonary hemorrhage, particularly when other causes are excluded. Early identification and management of underlying causes can significantly improve maternal and fetal outcomes. This report highlights the importance of exploring rare etiologies in cases of DAH, especially in pregnant patients, to ensure timely and effective intervention.
2026-07-10 | Idiopathic Pulmonary Hemosiderosis: A Comprehensive Review of Pathophysiology, Diagnostic Paradigms, and Management Strategies in the Context of Diffuse Alveolar Hemorrhage
Idiopathic pulmonary hemosiderosis (IPH) represents a rare, potentially life-threatening pulmonary syndrome characterized by recurrent episodes of diffuse alveolar hemorrhage (DAH) in the absence of an identifiable underlying etiology. As a diagnosis of strict exclusion within the broader spectrum of DAH, IPH poses substantial diagnostic and therapeutic challenges to clinicians across multiple specialties. This comprehensive review synthesizes current evidence regarding the etiopathogenesis, epidemiology, clinical presentation, diagnostic evaluation, and management of IPH, with particular emphasis on its conceptualization as an immune-mediated disorder and its integration within the contemporary classification of children's interstitial lung disease (chILD). The pathogenesis of IPH remains incompletely elucidated; however, accumulating evidence supports a fundamentally immune-dysregulatory mechanism, with autoantibodies detectable in a significant proportion of patients and well-documented associations with autoimmune conditions, most notably celiac disease, which defines the clinically significant Lane–Hamilton syndrome. The clinical presentation is remarkably heterogeneous, ranging from acute respiratory failure and massive hemoptysis to isolated iron-deficiency anemia without overt pulmonary symptoms, particularly in pediatric populations. Diagnosis requires systematic exclusion of vasculitic, infectious, cardiac, coagulopathic, and toxicologic etiologies through a structured approach encompassing serologic evaluation, bronchoalveolar lavage, high-resolution computed tomography, and, when indicated, lung biopsy demonstrating bland alveolar hemorrhage without capillaritis. Management is predicated upon immunosuppressive therapy, with systemic corticosteroids serving as the cornerstone, augmented by steroid-sparing agents in refractory or relapsing disease, and supplemented by strict gluten-free dietary intervention in patients with coexistent celiac disease. Prognosis has improved substantially in the modern immunosuppressive era, although significant morbidity persists, with relapse rates approaching 60% and progressive pulmonary fibrosis representing a major long-term complication. An interprofessional, collaborative approach involving pulmonology, rheumatology, gastroenterology, and supportive care services is essential to optimize diagnostic accuracy, therapeutic adherence, and longitudinal outcomes in this challenging patient population.
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2026-06-30 | Unilateral diffuse alveolar haemorrhage as an atypical presentation of PR3-ANCA-associated vasculitis: A case report.
Diffuse alveolar haemorrhage (DAH) is a life-threatening pulmonary manifestation of small-vessel vasculitis, most commonly associated with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Unilateral DAH has been infrequently reported and may pose diagnostic challenges, as its radiological presentation can mimic pneumonia, pulmonary oedema, or localized haemorrhage. This atypical presentation may delay recognition of the underlying vasculitis and appropriate immunosuppressive therapy. We present a case of a woman in her thirties with previously diagnosed PR3-ANCA-associated vasculitis who presented with acute worsening of dyspnea (mMRC grade IV) and hemoptysis. Radiological assessments revealed extensive right-sided ground-glass opacities with areas of consolidation and minimal left lower lobe involvement. Bronchoscopy with sequential bronchoalveolar lavage (BAL) showed progressively haemorrhagic aliquots consistent with DAH. Laboratory investigations revealed anemia (Hb 7.1 mg/dL) and elevated serum creatinine (5.02 mg/dL). The patient developed type I respiratory failure requiring mechanical ventilation and hemodialysis. She was treated with pulse intravenous methylprednisolone followed by rituximab therapy, along with trimethoprim-sulfamethoxazole prophylaxis. The patient improved clinically, radiologically, and biochemically and was discharged on supplemental oxygen.
2026-05-29 | Alveolar dysregulation of host response in pneumonia and ARDS: implications for immune modulation and infection.
Respiratory failure due to pneumonia and acute respiratory distress syndrome (ARDS) remains a major cause of morbidity and mortality in the intensive care unit. The alveolar compartment plays a central role in both pathogen clearance and tissue injury, yet its biology is poorly captured by systemic measurements. Growing evidence shows that dysregulation of alveolar host responses drives disease progression, shapes susceptibility to secondary infections, and influences recovery. Community-, hospital-, and ventilator-associated pneumonia differ in microbial drivers and host responses, but all share a pattern of localized inflammation. In most cases, pathogens are rapidly controlled following antimicrobial treatment, while alveolar inflammation persists. This persistence likely reflects self-reinforcing cycles between epithelial injury, neutrophil activity, and monocyte-macrophage dysfunction. Mechanical ventilation further disrupts local defenses, promoting microbial overgrowth and ventilator-associated pneumonia.In ARDS, diffuse alveolar damage initiates an early influx of neutrophils and monocyte-derived macrophages. Although peripheral blood has been used to identify systemic inflammatory subphenotypes, molecular signatures in the alveolar compartment often differ and may provide complementary biological information. Patients may diverge into distinct alveolar immune trajectories, ranging from sustained alveolar hyperinflammation to immune exhaustion. These divergent trajectories influence downstream repair, determining whether patients achieve epithelial recovery or develop fibrotic remodeling.Alveolar immune dysregulation also creates a permissive niche for viral and fungal pathogens. Pulmonary reactivation of herpes simplex virus or cytomegalovirus and fungal infections with Aspergillus frequently occur in critically ill patients and may reflect impaired local host defense. These processes are associated with prolonged mechanical ventilation and illustrate how impaired alveolar defenses may sustain injury and propagate complications. Pneumonia and ARDS share common pathways of alveolar immune dysregulation that are not adequately captured by systemic profiling alone. Integrating systemic and alveolar immune assessment, including their concordance and discordance, may improve patient stratification, facilitate identification of treatable traits, and support the development of more personalized, compartment-informed therapeutic strategies, including both immunomodulatory and pathogen-directed interventions. A more refined understanding of compartment-specific host responses will be key to advancing these approaches.
2026-05-01 | A33-41 Libman-Sacks vs. Infective Endocarditis: A Case of Diagnostic Uncertainty in a Patient With Diffuse Alveolar Hemorrhage
Abstract Introduction Libman-Sacks endocarditis is noninfectious endocarditis marked by sterile platelet thrombi on heart valves. It is a rare cardiac manifestation of systemic lupus erythematosus (SLE). Differentiating its vegetations from culture-negative infective endocarditis (IE) is difficult, especially in patients with risk factors for both, as seen in our case. Case Presentation A 51-year-old female with type 2 diabetes mellitus, hypertension, and end-stage renal disease on peritoneal dialysis was recently treated with antibiotics for multifocal pneumonia. Six days post-discharge, she presented with dyspnea, cough, hemoptysis, fever, and hypoxia. Chest CT revealed diffuse ground-glass opacities and pulmonary edema. Transthoracic echocardiography (TTE) showed a large (39 × 10 mm), mobile vegetation on the posterior mitral leaflet with moderate mitral regurgitation. Autoimmune serologies were positive for ANA, anti-dsDNA, lupus anticoagulant, anticardiolipin, and β2-glycoprotein antibodies. The initial bronchoscopy was not favorable for diffuse alveolar hemorrhage (DAH), and blood cultures were negative. A prior kidney biopsy (2021) showed diabetic glomerulosclerosis with resolved immune complex glomerulonephritis. Given the vegetation’s size and mobility, lack of clinical SLE features, elevated WBC, CRP, and procalcitonin, and negative DAH, a multidisciplinary team favored culture-negative IE over Libman-Sacks. Empiric vancomycin and ceftriaxone were initiated. The hospital course was complicated by embolic strokes and DRESS syndrome. Antibiotics were stopped, high-dose prednisone and anticoagulation were started. Repeat TTE showed smaller vegetation and improved mitral regurgitation. She was discharged in stable condition. Ten days later, she returned with hypoxic respiratory failure from DAH (confirmed on bronchoscopy), hemorrhagic toe bullae, and anterior tibial artery occlusion. Lupus flare or catastrophic antiphospholipid syndrome (CAPS) was suspected. She improved with plasmapheresis, rituximab, and corticosteroids, and was discharged on immunosuppressants and warfarin. Discussion and Conclusion Several factors help differentiate Libman-Sacks from IE. Libman-Sacks is more commonly associated with high prevalence of antiphospholipid antibodies but a lower prevalence of SLE-specific autoantibodies. IE typically presents with high WBC, markedly elevated CRP, and procalcitonin, whereas Libman-Sacks may show low WBC and strongly positive antiphospholipid antibodies. Valvular pathology also differs: Libman-Sacks shows small to medium vegetations on either or both sides of the leaflets, while IE typically has large, irregular masses on the valve cusps, often extending to the cords. Our patient’s inflammatory markers and valve findings favored infection initially. This case highlights the diagnostic challenge in patients with risk factors for both. Early multidisciplinary evaluation is essential in guiding management. This abstract is funded by: None
2026-05-01 | A35-09 The Unexpected Hemorrhage: Acute Diffuse Alveolar Hemorrhage Leading to Diagnosis of Eosinophilic Granulomatosis With Polyangiitis Diagnosis
Abstract Introduction Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare vasculitis affecting small- to medium-sized vessels, mainly in adults with asthma, chronic rhinosinusitis (often with nasal polyps), and peripheral eosinophilia. Incidence is ∼2 per million person-years and prevalence 30-35 per million, complicating diagnosis. Patients develop worsening asthma, sinonasal disease, and migratory pulmonary infiltrates; one-third are myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody (ANCA)-positive. Serious complications include neuropathy, cardiac issues, and diffuse alveolar hemorrhage (DAH), which pose significant morbidity. We report a case of EGPA presenting with bronchoscopically confirmed DAH in a young woman, whose persistent asthma and sinonasal polyposis initially masked the vasculitis. Case A 29-year-old woman with severe persistent asthma and nasal polyps presented for elective bronchoscopy for cough and scant hemoptysis. For nine months, she developed worsening dyspnea and recurrent asthma/sinusitis exacerbations despite escalating inhaled therapy and repeated antibiotics and steroids. On admission, vitals were stable, and labs showed leukocytosis (14.32 × 10³/µL) with a normal eosinophil count—likely suppressed by prednisone 60mg started the day prior. Of note, outpatient lab showed peripheral eosinophilia (2,610/µL; 20%). Bronchoscopy showed progressively bloodier bronchoalveolar lavage fluid, consistent with DAH. The differential contained 70% eosinophils. Biopsy revealed chronic inflammation with increased eosinophils and focal granulation tissue. Serology was positive for p-ANCA with MPO specificity; IgE was elevated. Prior outpatient data supported vasculitic, type-2-driven airway disease: CT chest with peribronchovascular ground-glass nodules [Figure 1]; severe obstructive physiology with air trapping, diffuse sinonasal polyposis; and peripheral eosinophilia. The patient was started on pulse-dose intravenous glucocorticoids followed by taper and initiation of mepolizumab, then underwent sinus surgery with improvement. Follow-up with otolaryngology, rheumatology, and pulmonology was arranged. Discussion Our patient presented with hemoptysis alongside severe persistent asthma and chronic rhinosinusitis of unclear cause. EGPA involves two immune processes: a type-2, interleukin-5-driven eosinophilic pathway, and an ANCA-mediated vasculitis. She exemplifies this: refractory asthma with nasal polyps reflects the eosinophil/Th2 axis, while hemoptysis with DAH indicates vasculitic injury. Careful review of her history and testing led her pulmonologist to suspect EGPA and pursue bronchoscopy, which confirmed DAH with eosinophil predominance. Since EGPA often mimics difficult asthma and sinus disease, high clinical suspicion enabled timely glucocorticoids and IL-5-pathway biologic therapy, per guidelines. A coordinated multidisciplinary approach moved care beyond inhaler escalation to vasculitis-directed treatment, underscoring the need for vigilant reassessment when asthma therapies fail and continued work to refine EGPA diagnostic pathways for earlier, targeted management. This abstract is funded by: None
2026-05-01 | B105-11 The Clinical Course Of Pediatric Diffuse Alveolar Hemorrhage Syndrome, Through A Long-term Observation
Abstract Background Previous studies have reported that up to 50% of patients with diffuse alveolar hemorrhage (DAH) die within 2.5 years after onset. However, its clinical subtypes and disease course remain poorly defined. Some reviews have suggested that DAH often follows a ‘relapse-remission’ pattern, while a ‘progressive’ course is less common, though these claims lack detailed description or empirical evidence. This study retrospectively analyzed the long-term outcomes of children with DAH at our center to delineate patterns of clinical progression. Methods Retrospective analysis of 82 pediatric DAH patients (2010-2024) with ≥1 year follow-up at our institution. Results A total of 82 children were enrolled (male:female = 1:2.56). The median age at onset was 3 years (range: 0.3-12.4), and 67 (81.7%) were ≤6 years old. The median interval from onset to diagnosis was 3 months (range: 1 day-7 years).Follow-up ranged from 13 months to 13 years 8 months. Seventy-eight patients (95.1%) experienced relapse, with a median of 4 episodes (range: 1-17). Ten relapsed once, 61 relapsed 2-10 times, and 7 relapsed ≥10 times. Four patients remained relapse-free during follow-up (maximum 9 years 9 months). The median interval from initial treatment to first relapse was 8 months (range: 2-36); 59 patients (75.6%) relapsed within one year, including 13 (22%) in month 7.Based on clinical course, two major types were identified:1.Monocyclic type (25.6%, 21/82): remission after initial treatment with no or ≤2 relapses, showing a single-peak pattern with acute hemorrhagic and stable phases.2.Multicyclic type (74.4%, 61/82): ≥2 relapses after initial treatment, comprising acute hemorrhagic, absorption, chronic persistent, remission, or subsequent relapse phases. Subtypes included:Relapsing-remitting (39%, 32/82): recovery or minimal residual changes between relapses.Relapsing-progressive(31.7%, 26/82): progressive course or residual impairment after each relapse.Relapsing-secondary progressive (3.6%, 3/82): irreversible progression after later relapse, leading to severe respiratory dysfunction or death. Conclusions To our knowledge, this represents the first evidence-based characterization of clinical course patterns in pediatric diffuse alveolar hemorrhage (DAH). Two clinical courses patterns were identified: monocyclic and multicyclic. Approximately one-third of children exhibited a monocyclic course with favorable outcomes, while most demonstrated multicyclic courses, predominantly of the relapsing-remitting or relapsing-progressive types. Our findings indicate that the majority of patients were able to lead normal lives despite experiencing relapses over many years. Clinicians should recognize that recurrent relapses may represent an intrinsic feature of the disease rather than treatment failure. This abstract is funded by: None
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2026-06-08 | The Role of Macrophage M1/M2 Polarization Imbalance in the Pathogenesis of Immune Associated Diffuse Alveolar Hemorrhage: Evidence From the Study of Human Clinical Specimens.
An imbalance in M1/M2 macrophage polarization has been shown to play a critical role in the pathogenesis of diffuse alveolar hemorrhage (DAH) in mouse models. However, its contribution to immune-associated DAH in humans remains unclear. This study aimed to investigate the role of macrophage M1/M2 polarization imbalance in the pathogenesis of immune-associated DAH in children. A total of 24 children with immune-associated DAH (DAH group) and 13 children with acute airway foreign body or mild benign airway stenosis (control group) were enrolled. Bronchoalveolar lavage fluid (BALF) was obtained via bronchoscopy, and supernatant was isolated by centrifugation. Cytokine levels in BALF supernatant were measured using a cytometric bead array. Monocyte-derived macrophages (MDMs) were stimulated in vitro with BALF supernatant. The mRNA expression levels of M1 markers (IL-1β, TNF-α, IL-6, TGM2) and M2 markers (CD163, MRC1) were quantified using real-time PCR. Protein expression of surface markers (CD14, CD80, CD86, CD163, CD206) was analyzed by flow cytometry. (1) Levels of MCP-1, IL-6 and IL-8 in BALF supernatant were significantly higher in the DAH group than those in the control group. (2) MDMs stimulated with BALF supernatant from the DAH group showed significantly elevated mRNA expression of IL-1β and IL-6 and significantly reduced expression of MRC1 compared to those stimulated with control supernatant. (3) Flow cytometry revealed significantly higher CD86 expression and significantly lower CD163 and CD206 expression in MDMs treated with DAH group BALF supernatant. This study provides evidence that macrophage M1/M2 polarization imbalance contributes to the pathogenesis of immune-associated DAH in humans, highlighting a potential target for immunomodulatory therapy.
2026-02-02 | Liraglutide prevents lupus-associated diffuse alveolar hemorrhage via inhibiting lymphocyte infiltration and promoting macrophage M2 polarization.
This study aimed to explore the prophylactic and therapeutic role of liraglutide for lupus-associated diffuse alveolar hemorrhage (DAH). A lupus-associated DAH model was established in 6-8-week-old female C57BL/6 mice via intraperitoneal injection of 0.5 mL pristane. Mice were randomized to receive daily intraperitoneal injections of either saline or liraglutide (2 mg/kg/day), starting either 14 days before or on the day of pristane injection, and continuing until 14 days post-injection. Body weight and blood glucose were monitored. Serum levels of anti-dsDNA, ANA, total IgM and IgG were quantified using ELISA. Lung tissues were collected for histopathological analysis with H&E and Prussian blue staining, respectively, characterization of different types of immune cells infiltration with flow cytometry (t-SNE for subset dimensionality reduction) and immunofluorescence, and quantification of protein levels with Western blot. Liraglutide significantly alleviated pulmonary hemorrhage, as evidenced by reduced lung wet weight, incidence of lung hemorrhage, pulmonary hemosiderin-laden macrophages, and total serum IgG, without affecting body weight or glucose. Mechanistically, liraglutide treatment reduced pulmonary infiltration of multiple T and B lymphocyte subsets (e.g., CD4+, CD8+, B220+), while concurrently increasing alveolar macrophages and promoting M2 macrophage polarization. The phenotypic shift was demonstrated by increased M2 cell numbers, elevated CD206 expression, and downregulation of M1 marker CD86 and upregulation of M2 marker CD163 as confirmed at the protein level. Liraglutide treatment effectively ameliorates lupus-associated DAH, potentially through modulation of T cells, B cells, and macrophages polarization, offering a novel prophylactic and therapeutic strategy for this fatal complication of lupus.
2025-09-30 | Diffuse alveolar hemorrhage in a child with mild hemophilia A who underwent bone marrow transplantation for thalassemia: a case report
Diffuse alveolar hemorrhage (DAH) is a relatively rare complication of bone marrow transplantation (BMT) associated with a high risk of mortality. It generally occurs in the early post-transplant phase during severe thrombocytopenia; however, since most thrombocytopenic cases do not develop DAH, cofactors are at play. Here, we discuss the case of a 4-year-old male child with mild asymptomatic hemophilia A discovered on routine evaluation pre-BMT, who developed DAH after a fully matched sibling BMT for HbE/Beta-thalassemia. The patient presented on day +21 post-BMT with sudden onset of cough followed one day later by hemoptysis. He had received FVIII supplementation with PTT normalization and FVIII levels of 28%. A chest CT scan showed interstitial lung disease with areas of ground glass bilaterally, mainly in the lower lobes. A radiological diagnosis of DAH was made, and the child was treated with additional FVIII concentrate (Advate), blow-by oxygen supplementation, red blood cells transfusion, platelet transfusion, methylprednisolone, tranexamic acid, and antioxidants (vitamin C and E). He responded well and recovered in a few days. Mild hemophilia associated with DAH post-BMT has never been reported before, however, it should be considered as a potentially treatable cause of DAH after BMT. FVIII levels should be part of the routine workup of children developing DAH post-transplantation. In the presence of thrombocytopenia, high FVIII levels of >30-40% might be required to prevent/treat DAH.
2025-09-28 | Management and outcome of immune-mediated diffuse alveolar hemorrhage: a single centre case series
The standard treatment of immune-mediated diffuse alveolar hemorrhage (IM-DAH) encompasses immunosuppression with glucocorticoids (GC) and either cyclophosphamide (CYC) or rituximab (RTX). The role of intravenous immunoglobulin (IVIg) and plasma exchange (PLEX) remains controversial. We conducted a single-centre retrospective observational study on patients admitted with IM-DAH to evaluate treatment approaches and outcomes. Twelve episodes were identified in ten patients. All episodes were treated with GC and nine with CYC. IVIg was administered as first-line and/or bridging therapy in three cases with concomitant infections or high infection risk. PLEX was used in six episodes. IVIg and PLEX were primarily used as add-on therapies or when other immunosuppression was not recommended. After one year, nine patients survived. The combination of GC and CYC was the most common treatment regimen. While the role of PLEX and IVIg is not well established, they may be beneficial as second-line or as add-on therapies in selected cases.
2024-08-27 | Quantitative proteomic analysis and replacement therapy identifies haptoglobin as a therapeutic target in a murine model of SLE-associated diffuse alveolar hemorrhage.
Diffuse alveolar hemorrhage (DAH) is a catastrophic clinical syndrome and one of the manifestations of pulmonary involvement in systemic lupus erythematosus (SLE), which is characterized by hemoptysis, diffuse pulmonary infiltrates, and respiratory failure. However, the treatment options for DAH remain limited, and DAH-related studies are needed to explore more effective therapeutic directions for better disease management and improved prognosis. This study utilized the pristane-induced DAH murine model to mimic the pathological process of DAH in patients with SLE. Proteomic analysis was conducted to detect differentially expressed proteins (DEPs) in the plasma of surviving and non-surviving mice, followed by an analysis of biological functions and pathways. The most significant DEP was then confirmed in the plasma of SLE patients with or without DAH and DAH murine model with or without fatal outcomes. Finally, the therapeutic value of haptoglobin (Hp) replacement was validated in a DAH murine model through lung histopathology, RT-qPCR, and survival analysis. This study identified 178 DEPs, with 118 upregulated and 60 downregulated DEPs in the non-survival group. Within a set of notable Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, complement and coagulation cascades emerged as the most prominent pathway associated with the process of DAH. Later, the most significant DEP, haptoglobin (Hp), was confirmed to exhibit a significant decrease in the plasma of individuals with SLE-DAH and DAH murine model with poor outcomes by the ELISA test. Finally, compared with the control group, the severity of DAH in the Hp treatment group was alleviated significantly, as manifested by the decreased levels of pro-inflammatory cytokines (IL-6 and TNF-α), increased levels of anti-inflammatory cytokines (IL-10 and TGF-β), and decreased mortality. A reduction in plasma Hp levels was observed in SLE-DAH, and the replacement therapy with Hp could alleviate pulmonary hemorrhage and reduce mortality in DAH mice. This study identified Hp as a potential biomarker for its clinical diagnosis and a direction for treatment.
cell therapies
2024-11-19 | Trained mesenchymal stromal cell-based therapy HXB-319 for treating diffuse alveolar hemorrhage in a pristane-induced murine model.
Mesenchymal stromal cells (MSCs) can modulate immune responses and suppress inflammation in autoimmune diseases. Although their safety has been established in clinical trials, the efficacy of MSCs is inconsistent due to variability in potency among different preparations and limited specificity in targeting mechanisms driving autoimmune diseases. We utilized high-dimensional design of experiments methodology to identify factor combinations that modulate gene expression by MSCs to mitigate inflammation. This led to a novel MSC-based cell therapy, HXB-319. Its anti-inflammatory properties were validated in vitro by flow cytometry, RT-PCR, and mass spectrophotometry. To evaluate in vivo efficacy, we treated a diffuse alveolar hemorrhage (DAH) mouse model (C57Bl/6). Seven days post-DAH induction with pristane, mice received either MSCs or HXB-319 (2X106 cells, IP). On day 14, peritoneal lavage fluid (PLF) and lung tissue were collected for flow cytometry, histopathological examination, and mRNA. HXB-319 increased gene expression levels of anti-inflammatory, angiogenic, and anti-fibrotic factors (eg, TSG-6, VEGF, and HGF). KEGG pathway analysis confirmed significant activation of relevant anti-inflammatory, angiogenic, and anti-fibrotic proteins, corroborating RT-PCR results. In the DAH model, HXB-319 significantly reduced lung inflammation and alveolar hemorrhage compared to MSC-treated and untreated DAH mice. HXB-319 treatment also significantly decreased neutrophils, plasmacytoid dendritic cells, and RORγT cells, increased FoxP3+ cells in PLF, and reversed alterations in mRNA encoding IL-6, IL-10, and TSG-6 in lung tissue compared to DAH mice. HXB-319 effectively controls inflammation and prevents tissue damage in pristine-induced DAH, highlighting its therapeutic potential for autoimmune inflammatory diseases.
2024-01-30 | The anti-inflammatory effects of mesenchymal stem cells attenuate diffuse pulmonary hemorrhage.
There are few effective treatment options for diffuse pulmonary hemorrhage (DPH). We aimed to elucidate the therapeutic role and underlying mechanisms of mesenchymal stem cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) in DPH. Therapeutic effects of MSCs/MSC-EVs in pristane-induced DPH mice were evaluated via pulmonary function testing and histopathology. Transcriptome sequencing analyzed differentially expressed genes in control, DPH, and MSC groups. The proportion of macrophage polarization was evaluated in vivo and in vitro via fluorescence-activated cell sorting in control, DPH, MSC, MSC-EV inhalation, and MSC-EV intravenous groups. Intraperitoneal injection of pristane induced diffuse alveolar hemorrhage, early fibrosis, and inflammation in C57BL/6 mice. Monocytes were depleted in the peripheral blood in DPH mice and MSCs were recruited to the lungs, resulting in significantly attenuated diffuse alveolar hemorrhage and suppressed immunological response. This was more effective in the hyperacute hemorrhage phase than the early inflammatory phase. An MSC treatment-mediated anti-inflammatory effect was observed in DPH mice. Furthermore, MSC-EVs inhalation or tail-vein injection could effectively reduce DPH injury. MSCs could suppress macrophage M1 polarization in DPH in vivo and in vitro. MSCs displayed significant therapeutic effects in pristane-induced DPH, which may be a promising cell-free therapeutic approach.
2023-01-24 | Updates in idiopathic pulmonary hemosiderosis in 2022: A state of the art review.
This manuscript reports the recent advances in idiopathic pulmonary hemosiderosis (IPH), a rare cause of diffuse alveolar hemorrhage in children and adults. This narrative review of the literature summarizes different aspects of IPH, including proposed pathogenesis, patient demographics, clinical and radiological characteristics, treatment, and prognosis. Additionally, the association between Celiac Disease (CD) and IPH is carefully evaluated. IPH is a frequently misdiagnosed disease. The delay in the diagnosis of IPH is often significant but fortunately, appears to have decreased in recent years. IPH in adults and children have distinct demographic preferences. The autoantibodies are common in IPH but with a definite difference between the adult and pediatric populations. The definitive diagnosis of IPH requires lung biopsy and careful exclusion of all competing diagnoses, even with lung biopsy showing bland pulmonary hemorrhage. The presence of nonspecific inflammatory cells or lymphoid aggregates may suggest a secondary immunologic phenomenon and needs careful evaluation and follow-up. A substantial number of patients suffer from coexisting CD, also known as Lane-Hamilton syndrome (LHS), and all patients with IPH need to be evaluated for LHS by serology. Although strict gluten free diet can manage the majority of patients with LHS, other patients generally require immunosuppressive therapy. The corticosteroids are the backbone of IPH therapy. Recently utilized experimental treatment options include mesenchymal stem cell transplant, liposteroid and bronchial artery embolization. The immunosuppression should be adjusted to achieve optimal disease control. Patients may progress to end-stage lung disease despite all measures, and lung transplantation may be the only viable option.
2022-10-04 | Exosomes Derived from Human Umbilical Cord Mesenchymal Stem Cells Alleviate Diffuse Alveolar Hemorrhage Associated with Systemic Lupus Erythematosus in Mice by Promoting M2 Macrophage Polarization via the microRNA-146a-5p/NOTCH1 Axis.
Systemic lupus erythematosus (SLE)-associated diffuse alveolar hemorrhage (DAH) is a rare but extremely harmful condition. The current study sought to dissect the mechanisms underlying the effects of human umbilical cord mesenchymal stem cell (HUCMSC)-derived exosomes on M2 macrophage polarization in SLE-associated DAH via the microRNA (miR)-146a-5p/NOTCH1 axis. A DAH mouse model was established using pristane. Exosomes were isolated from HUCMSCs transfected or untransfected with the miR-146a-5p antagonist or agonist and their NCs and then injected into DAH mice. Additionally, miR-146a-5p was overexpressed in macrophages. Expression of miR-146a-5p, NOTCH1, M1 macrophage markers, and M2 macrophage markers was measured in mice and macrophages, and inflammatory factor levels were detected. Mouse lung injuries were evaluated, so was the binding of miR-146a-5p to NOTCH1. Rescue experiments were conducted in mice and macrophages using NOTCH1 shRNA and pcDNA3.1-NOTCH1, respectively. NOTCH1 expression was enhanced in DAH mice. HUCMSC-derived exosomes reduced NOTCH1 expression, bleeding, inflammation, and M1 macrophage polarization but elevated M2 macrophage polarization in lung tissues of DAH mice. Mechanistically, NOTCH1 is negatively targeted by miR-146a-5p. miR-146a-5p overexpression diminished M1 marker and inflammatory factor levels but enhanced M2 marker levels in macrophages, which was nullified by NOTCH1 overexpression. HUCMSC-derived exosomes with miR-146a-5p inhibition increased NOTCH1 expression, worsened bleeding and inflammation, and augmented M1 macrophage polarization while decreasing M2 macrophage polarization in lung tissues of DAH mice, which was abrogated by silencing NOTCH1. HUCMSC-derived exosomes diminished NOTCH1 expression to accelerate M2 macrophage polarization via delivery of miR-146a-5p, thus alleviating SLE-associated DAH in mice.
2012-08-21 | Allogeneic transplantation of umbilical cord-derived mesenchymal stem cells for diffuse alveolar hemorrhage in systemic lupus erythematosus.
Umbilical cord-derived mesenchymal stem cell transplantation (UC-MSCT) has been proved to be effective in the treatment of systemic lupus erythematosus (SLE), based on animal experiments and clinical trials. Diffuse alveolar hemorrhage (DAH) is a rare complication of SLE with a high mortality usually over 50%. This study aimed to assess the efficacy of UC-MSCT in the treatment of SLE-associated DAH. Four SLE patients complicated with DAH, who underwent UC-MSCT, were included. Clinical changes before and after transplantation were assessed by measurements of hemoglobin, platelet level, oxygen saturation, and serological factors. High-resolution CT (HRCT) scans of the chest were performed to evaluate pulmonary manifestation. All the four patients showed dramatic improvements of their clinical manifestations. Hemoglobin was elevated after UC-MSCT and was sustained at a normal level 6 months after UC-MSCT in the four patients. Platelet level was upregulated in two patients who had thrombocytopenia at baseline. Oxygen saturation appeared to be normal at 1 month after UC-MSCT, and this result was confirmed by the HRCT scan of the chest. Serum albumin elevated to 3.5 g/dl 6 months after transplantation. Our findings suggest that UC-MSCT results in amelioration of oxygen saturation as well as hematological and serologic changes, which revealed that UC-MSCT could be applied as a salvage strategy for DAH patients.
other
2022-08-26 | Down-regulated miR-146a expression with increased neutrophil extracellular traps and apoptosis formation in autoimmune-mediated diffuse alveolar hemorrhage
Increasing evidences have suggested an important role of microRNAs (miRNAs) in regulating cell death processes including NETosis and apoptosis. Dysregulated expression of miRNAs and increased formation of neutrophil extracellular traps (NETs) and apoptosis participate in autoimmune-mediated diffuse alveolar hemorrhage (DAH), mostly associated with pulmonary capillaritis in systemic lupus erythematosus (SLE) patients. In particular, besides the inhibition of apoptosis, miR-146a can control innate and acquired immune responses, and regulate the toll-like receptor pathway through targeting TRAF6 to reduce the expression of pro-inflammatory cytokines/chemokines like IL-8, a NETosis inducer.Expression of miR-146a, TRAF6 and NETs were examined in peripheral blood neutrophils (PBNs) and lung tissues from SLE-associated DAH patients, and in neutrophils and pristane-induced DAH lung tissues from C57BL/6 mice. To assess NETs formation, we examined NETosis-related DNAs morphology and crucial mediators including protein arginine deiminase 4 and citrullinated Histone 3. Expression of miR-146a and its endogenous RNA SNHG16 were studied in HL-60 promyelocytic cells and MLE-12 alveolar cells during NETosis and apoptosis processes, respectively. MiR-146a-overexpressed and CRISPR-Cas13d-mediated SNHG16-silenced HL-60 cells were investigated for NETosis. MiR-146a-overexpressed MLE-12 cells were analyzed for apoptosis. Pristane-injected mice received intra-pulmonary miR-146a delivery to evaluate therapeutic efficacy in DAH.In DAH patients, there were down-regulated miR-146a levels with increased TRAF6 expression and PMA/LPS-induced NETosis in PBNs, and down-regulated miR-146a levels with increased TRAF6, high-mobility group box 1 (HMGB1), IL-8, NETs and apoptosis expression in lung tissues. HMGB1-stimulated mouse neutrophils had down-regulated miR-146a levels with increased TRAF6, IL-8 and NETs expression. PMA-stimulated HL-60 cells had down-regulated miR-146a levels with enhanced NETosis. MiR-146a-overexpressed or SNHG16-silenced HL-60 cells showed reduced NETosis. Apoptotic MLE-12 cells had down-regulated miR-146a expression and increased HMGB1 release, while miR-146a-overexpressed MLE-12 cells showed reduced apoptosis and HMGB1 production. There were down-regulated miR-146a levels with increased TRAF6, HMGB1, IL-8, NETs and apoptosis expression in mouse DAH lung tissues. Intra-pulmonary miR-146a delivery could suppress DAH by reducing TRAF6, IL-8, NETs and apoptosis expression.Our results demonstrate firstly down-regulated pulmonary miR-146a levels with increased TRAF6 and IL-8 expression and NETs and apoptosis formation in autoimmune-mediated DAH, and implicate a therapeutic potential of intra-pulmonary miR-146a delivery.
2021-06-28 | Targeting Intra-Pulmonary P53-Dependent Long Non-Coding RNA Expression as a Therapeutic Intervention for Systemic Lupus Erythematosus-Associated Diffuse Alveolar Hemorrhage
Diffuse alveolar hemorrhage (DAH) in systemic lupus erythematosus (SLE) is associated with significant mortality, requiring a thorough understanding of its complex mechanisms to develop novel therapeutics for disease control. Activated p53-dependent apoptosis with dysregulated long non-coding RNA (lncRNA) expression is involved in the SLE pathogenesis and correlated with clinical activity. We examined the expression of apoptosis-related p53-dependent lncRNA, including H19, HOTAIR and lincRNA-p21 in SLE-associated DAH patients. Increased lincRNA-p21 levels were detected in circulating mononuclear cells, mainly in CD4+ and CD14+ cells. Higher expression of p53, lincRNA-p21 and cell apoptosis was identified in lung tissues. Lentivirus-based short hairpin RNA (shRNA)-transduced stable transfectants were created for examining the targeting efficacy in lncRNA. Under pristane stimulation, alveolar epithelial cells had increased p53, lincRNA-p21 and downstream Bax levels with elevated apoptotic ratios. After pristane injection, C57/BL6 mice developed DAH with increased pulmonary expression of p53, lincRNA-p21 and cell apoptosis. Intra-pulmonary delivery of shRNA targeting lincRNA-p21 reduced hemorrhage frequencies and improved anemia status through decreasing Bax expression and cell apoptosis. Our findings demonstrate increased p53-dependent lncRNA expression with accelerated cell apoptosis in the lungs of SLE-associated DAH patients, and show the therapeutic potential of targeting intra-pulmonary lncRNA expression in a pristane-induced model of DAH.
2016-03-28 | In Vivo Therapeutic Success of MicroRNA‐155 Antagomir in a Mouse Model of Lupus Alveolar Hemorrhage
Objective Diffuse alveolar hemorrhage (DAH) is a rare but life‐threatening complication of systemic lupus erythematosus (SLE). Pristane‐treated B6 mice develop severe DAH within 2 weeks of treatment. MicroRNA‐155 (miR‐155) is a pleiotropic microRNA that plays a crucial role in the regulation of immune responses. Recent studies have revealed a pathogenic role of miR‐155 in various autoimmune disorders. The purpose of this study was to examine the role of miR‐155 in the development of DAH in pristane‐induced lupus using miR‐155–knockout (miR‐155 −/− ) mice and miR‐155 antagomir to silence miR‐155. Methods DAH was induced by an intraperitoneal injection of 0.5 ml of pristane. MicroRNA‐155 antagomir was administered intravenously to silence miR‐155 expression. Lung tissues were collected for RNA extraction and were embedded in paraffin for sectioning. Gene expression profiling data were analyzed using Ingenuity Pathway Analysis. Real‐time quantitative polymerase chain reaction analysis was used for single‐gene validation. Luciferase reporter assay and argonaute 2 immunoprecipitation were performed for target validation. Results MicroRNA‐155 expression was significantly increased during the development of DAH. Disease progression was reduced in miR‐155 −/− mice as well as by in vivo silencing of miR‐155 using a miR‐155 antagomir. MicroRNA‐155 silencing dampened pristane‐induced ectopic activation of multiple inflammatory pathways and reduced the expression of proinflammatory cytokines. Several negative regulators of NF‐κB signaling were inhibited by pristane and were reactivated in miR‐155 −/− mice. In particular, the antiinflammatory factor peroxisome proliferator–activated receptor α was identified as a direct target of miR‐155. Conclusion MicroRNA‐155 promotes pristane‐induced lung inflammation. It contributes to ectopic activation of NF‐κB signaling pathways by targeting multiple negative regulators. MicroRNA‐155 antagomir may be a promising therapeutic strategy for treating acute lung inflammation in lupus.
2008-10-01 | A NOVEL TREATMENT FOR RECURRENT DIFFUSE ALVEOLAR HEMORRHAGE ASSOCIATED WITH NON-MYELOABLATIVE ALLOGENIC STEM CELL TRANSPLANTATION
INTRODUCTION: Diffuse alveolar hemorrhage (DAH) occurs in about 5% of hematopoietic stem cell transplant (HSCT) recipients with a mortality rate of 30 – 70% (1Afessa B Tefferi A Litzow MR et al.Diffuse alveolar hemorrhage in hematopoietic stem cell transplant recipients.Am J Respir Crit Care Med. 2002; 166: 641-645Crossref PubMed Scopus (153) Google Scholar). We describe a patient with recurrent episodes of DAH occurring late in the post-HSCT course.
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Drug Discovery Landscape
2 orphan drug designations for Diffuse alveolar hemorrhage.
2 orphan drug designations for Diffuse alveolar hemorrhage.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Recombinant coagulation factor VIIa | proteins | FDA | 2006-04-26 | — | Savara Inc. |
Eptacog alfa (activated) [Newest7] | proteins | EMA | 2005-12-14 | — | [INACTIVE] Savara ApS |
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