RARE DISEASE
Combined pulmonary fibrosis-emphysema syndrome
Combined pulmonary fibrosis-emphysema syndrome
Combined pulmonary fibrosis-emphysema syndrome
Synonyms: CPFE
Synonyms: CPFE
Synonyms: CPFE
Drug discovery
0
drugs
With orphan designations
Overview
Combined Pulmonary Fibrosis-Emphysema Syndrome (CPFE) is a distinct clinical entity characterized by upper-lobe emphysema and lower-lobe fibrosis, predominantly affecting male smokers. Patients exhibit preserved spirometry but severe gas exchange impairment (↓DLCO, exercise hypoxemia) and high rates of pulmonary hypertension (47–90%) and lung cancer (35–46%). Diagnosis relies on HRCT showing centrilobular/paraseptal emphysema with subpleural fibrosis. Mortality exceeds isolated pulmonary fibrosis or emphysema, driven by respiratory failure, cancer, and acute exacerbations [1][4][5][9][19].
Burden
Therapies
Inhaled bronchodilators: Improve CPI (composite physiologic index) when COPD-like features dominate [3][8][16]
Antifibrotics (nintedanib/pirfenidone): Limited evidence; avoid immunosuppressants for IPF due to harm [3][8][12][15]
Oxygen therapy/pulmonary rehabilitation: Address hypoxemia and functional decline [5][8][12]
Lung transplant: Only curative option for eligible patients [6][12][16]
Categories: rare respiratory diseases, rare transplant-related disorders
Research Papers
79 drug discovery papers about Combined pulmonary fibrosis-emphysema syndrome. Recent publications:
79 drug discovery papers about Combined pulmonary fibrosis-emphysema syndrome. Recent publications:
categories:
Small molecules
small molecules
2026-05-01 | B41-08 Characteristics and Management of Patients With Fibrosing Interstitial Lung Disease in Spain: Data From the Separ- ILD Registry
Abstract Introduction Fibrotic interstitial lung diseases (fILD) pose a challenge in clinical practice. Idiopathic pulmonary fibrosis (IPF) is the prototype of progressive fibrotic ILD, and it is estimated that up to one-third of people with fibrotic ILDs other than IPF may develop a progressive course like IPF, called progressive pulmonary fibrosis (PPF). The SEPAR-ILD Registry, from the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), aims to provide real-world data from Spanish patients with fibrosing interstitial lung diseases to better understand the clinical characteristics progression, and management. Methods SEPAR-ILD Registry is an ongoing prospective registry for patients diagnosed with IPF and other fILD since 2022 (Approval December 11, 2023, CEIm minutes 22/23) conducted at 19 expert sites across Spain. Results 481 patients were included. The most frequent diagnoses were IPF 158(32%), Unclassifiable ILD (UILD) (including IPAF) 83 (17,3 %), combined pulmonary fibrosis and emphysema (CPFE) 73(15,2%), connective tissue disease (CTD) ILDs (13.9%), and fibrotic hypersensitivity pneumonitis(fHP) 46(9.6%). The mean (SD) age was 69 (10.6) years; 64.7 % were male, 74.8% former smokers, and 25.2% never smokers. FVC was 83.6 (18.6) % predicted, and diffusion capacity for carbon monoxide (DLCO) was 55.5 (18.3) % predicted. 200 patients (41.7%) were receiving nintedanib and 108 (22.5%) pirfenidone. 132 patients (32.9 %) were on long term oxygen therapy (LTOT)at rest and 138 (34.3 %) during exercise. Comorbidities included high blood pressure 205 (42.7 %), high cholesterol 202(42.1%), diabetes 107 (22,3 %) and ischemic cardiomyopathy 54 (11.3 %). From 336 patients with a median follow up of 12 months disease progression occurred in 151 patients (44.9%) ( In 38 (42%) of patients with IPF, 26 (40%) of CPFE, in 25 (39%) of uILD, 23 (48%) of CTD-ILD and in 12 (44%) of fHP.) presenting worsening of respiratory symptoms 119 (79.3%); worsening of pulmonary function tests 112 (74.7%) and radiological worsening 105 (70.0%). Patients who experienced disease progression exhibited a more severe disease profile, with mean (SD) FVC 77.6 (17.4%) % predicted; DLCO 52.3 (17.8%) % predicted; greater use of LTOT 52.7% of cases; high frequency of hospitalizations (95 [62.9%]), acute exacerbation (32 [22.9%]), and high mortality (37 [40.7%]). Furthermore, they received more frequently nintedanib as antifibrotic therapy (120 [79.5%]). Conclusions Patients with fibrosing ILD in the prospective SEPAR ILD registry had a high rate of disease progression, which is associated with greater severity and a poor outcome. This abstract is funded by: None
2026-05-01 | C29-14 Granzyme K Expressing Cd8 T Cell Expression in Chronic Lung Diseases
Abstract Background Granzyme K (GZMK) expressing CD8 T cells are pro-inflammatory cells enriched in asthma, bronchiolitis obliterans syndrome and autoimmune diseases. These cells activate complement cascade leading to persistent inflammation, however their characteristics have not been comprehensively studied in different chronic lung diseases. We hypothesized that GZMK+ CD8 T cells are differentially abundant across chronic lung disease subtypes and investigated the expression of GZMK+CD8 T cell signatures. Methods We analyzed bulk lung tissue RNA sequencing data from the Lung Tissue Research Consortium, across different disease pathologies including controls (n = 340), chronic obstructive pulmonary disease (COPD, n = 505), combined pulmonary fibrosis and emphysema (CPFE, n = 43), smoking-related interstitial lung disease (smoking-ILD, desquamative interstitial pneumonia [DIP], respiratory bronchiolitis [RB-ILD], n = 16) and other ILDs (n = 340). We used a top 15-gene signature derived from GZMK+ CD8 T cells identified in single cell RNA-seq data and calculated enrichment scores to quantify the GZMK+CD8 T cell signature score for each subject using gene set variation analysis. We performed linear regression models adjusted for age, sex, race, smoking pack years and current smoking status. Results The lung GZMK+CD8 T cell score correlated with blood lymphocyte percentage (Pearson r = 0.2, p < 0.003) and cumulative smoking (pack years, r = 0.23, p = 0.0006). In multivariable models, GZMK+CD8 T cell signature scores were significantly elevated in COPD compared to controls (adjusted mean difference β = 0.1, Tukey-adj. p = 0.003). Among smoking related pathologies, there was no statistical difference between COPD and CPFE, however smoking-related ILD had the highest GZMK+CD8 T cell score with marginal significance (vs. controls β = 0.28, adj. p = 0.06). Among ILD pathology subtypes, usual interstitial pneumonia (UIP, n = 186) had the lowest score while organizing pneumonia (n = 18) had the highest score. Notably, GZMK+CD8 T cell score was positively correlated with DLCO in CPFE(r = 0.3, p = 0.09) but negatively correlated in smoking-ILD (r= -0.5, p = 0.09), suggesting distinct immunological patterns across disease pathology. Conclusions GZMK+CD8 T cell signatures are elevated in COPD and show heterogeneous enrichment patterns across chronic lung disease subtypes. The highest scores in organizing pneumonia and smoking-related ILD, as well as the positive correlation with disease severity (DLCO) in smoking-related ILD suggest GZMK+CD8 T cells may be enriched in airway-centric diseases involving inflammation. This abstract is funded by: K08HL146972
2026-05-01 | C68-08 A Cascade of Cavities: CPFE Complicated by Chronic Cavitary Pulmonary Aspergillosis and Superimposed Mac Infection
Abstract Introduction Chronic pulmonary aspergillosis (CPA) is a rare infection by Aspergillus fumigatus that develops in structurally damaged lungs such as those with COPD or emphysema. Persistent inflammation accelerates parenchymal destruction, worsening fibrosis and predisposing to further opportunistic infections. We present a case of CPFE complicated by chronic cavitary pulmonary aspergillosis and Mycobacterium avium complex infection- a hemorrhagic cascade of cavities. Case Then aged 60, this patient with a history of heavy smoking, DVT/PE s/p IVC filter, opioid use presented in 2013 with hemoptysis. Imaging showed an 8 cm RUL cavity with thin walls superimposed on previously known bilateral upper-lobe bullous emphysema, adjacent bronchiectasis and interstitial fibrotic changes consistent with Combined Pulmonary Fibrosis and Emphysema (CPFE). An extensive evaluation including multiple BALs over 2013-2014 was negative for AFBs but yielded fungal organisms Aspergillus fumigatus and Candida albicans. A diagnosis of chronic pulmonary aspergillosis (CPA) was made, and voriconazole therapy was initiated.The next decade was characterized by intermittent anti-fungal therapy and scattered follow-up complicated by homelessness and ongoing substance use. Management of COPD symptoms included inhaled corticosteroids and courses of oral steroids for exacerbations. In June 2025, the patient presented with brisk hemoptysis prompting an emergent bronchoscopy to localize the bleed and treated with an LUL bronchial artery embolization. Repeat imaging demonstrated progression of bilateral upper-lobe bullous disease, fibrosis and bilateral fungal balls, the largest in the previous RUL cavity and another in the LUL, explaining the source of the bleeding. BAL cultures again grew Aspergillus flavus and now superimposed Mycobacterium avium complex (MAC). The patient was re-intiated on antifungal therapy with isavuconazole; management focused on aspergillosis in the acute period as MAC was deemed a colonizer. Recurrent hemoptysis led to 2 further hospitalizations which were managed conservatively. Multidisciplinary follow-up continues for chronic cavitary pulmonary aspergillosis (CCPA) in the context of CPFE, with the primary goal of preventing further life-threatening hemorrhage from invasive aspergillomas. Discussion Longstanding CPFE creates a substrate for opportunistic colonization. Interruptions in antifungal therapy and corticosteroid use for suspected COPD exacerbations likely promoted fungal growth, leading to invasive aspergillomas and a high risk of recurrent bleeding. Coexistence of CCPA and MAC within the same cavities is rare and challenging, requiring multidisciplinary management. References: Yamakawa H, et al. Patient Background and Prognosis of Chronic Pulmonary Aspergillosis in Fibrosing Interstitial Lung Disease. Respir Investig. 2022;60(5):586-593. Fayos B, et al. Non-Tuberculous Mycobacteria and Aspergillus Lung Co-infection: A Systematic Review. J Fungi (Basel). 2022;8(10):1080. This abstract is funded by: none
2026-04-16 | Treatment of pulmonary fibrosis and combined pulmonary fibrosis and emphysema syndrome with herbs for promoting blood circulation and removing blood stasis: A review of pharmacological studies.
Pulmonary fibrosis (PF) is a progressive interstitial lung disease (ILD), and combined pulmonary fibrosis and emphysema (CPFE) is a complication of this condition. Traditional Chinese medicine (TCM) considers that the deficiency of the lung, spleen, and kidney, complicated by phlegm and blood stasis obstructing the lung, is the main pathological mechanism of CPFE. Promoting blood circulation and removing blood stasis (RBCRBS) is a crucial therapeutic principle in both treating PF and CPFE. Through research on TCM literature and the clinical experience of a renowned TCM doctor, we have found that Pheretima (Dilong), Spatholobi Caulis (Jixueteng), and Rhodiola (Hongjingtian) are important blood-activating and stasis-resolving (BASR) herbs used to treat PF and COPD. They are effective in improving symptoms and the pathological state of patients with PF and CPFE in clinical practice. Through literature research to understand the pathological mechanism of PF and CPFE; By analyzing the traditional application, modern pharmacological research, and network pharmacological research of BASR herbs, to systematically review the effectiveness and unique advantages of these herbs in treating PF and CPFE. Multiple databases, including PubMed, Web of Science, and the China National Knowledge Infrastructure (CNKI), were utilized to screen out relevant literature. The search terms were "pulmonary fibrosis", "CPFE", "promoting blood circulation and removing blood stasis", and relevant Chinese herb names such as "Dilong", "Jixueteng", and "Hongjingtian". The literature spanned mainly from 2000 to the present. Additionally, network pharmacology methods were employed to identify the key active ingredients of these herbs and predict their mechanisms of action in treating PF. The deficiency of the lung, spleen, and kidney, complicated by phlegm and blood stasis obstructing the lung, is the pathogenesis of CPFE. Pheretima, Spatholobi Caulis, and Rhodiola exert antifibrotic effects through the TGF-β1/Smad2/3 pathway, anti-inflammatory/antioxidant, immune homeostasis restoration, and EMT suppression. Subsequent network pharmacology analysis identifies 74 core targets (TP53, AKT1, SRC, STAT3, TNF), and highlights 20 pathways, including EGFR, HIF-1, FoxO, PD-1/PD-L1, and AGE-RAGE. These collectively influence IPF progression by regulating EMT, fibroblast activation, collagen deposition, and immune microenvironment disruption. This review synthesizes research on the material basis and pharmacodynamics of representative BASR herbs, providing novel insights for advancing the therapeutic application of these herbs in PF and its associated complications.
2026-03-27 | Prognostic factors in interstitial lung disease-associated pulmonary hypertension: data from the HYPID cohort and the French Pulmonary Hypertension Registry.
Pulmonary hypertension (PH) frequently complicates interstitial lung diseases (ILD), adversely affecting outcome. Identifying prognostic factors of patients with ILD-PH could facilitate early identification of patients who may benefit from PH therapy. We included patients with ILD-PH from the prospective HYPID cohort and the French National Pulmonary Hypertension Registry (2007-2022). Univariable and multivariable analyses were performed to identify predictors of 1-year mortality. A total of 581 patients (mean age 69.4±9.3 years, 450 males) were analysed. ILD diagnoses were combined pulmonary fibrosis and emphysema syndrome (30.8%), idiopathic pulmonary fibrosis (29.6%), unclassifiable ILD (13.1%), and fibrotic hypersensitivity pneumonitis (10.3%). Mean pulmonary artery pressure was 40.7±9.1 mmHg, and mean pulmonary vascular resistance was 7.6 ±3.5 Wood units. Off-label PH therapy was initiated after initial evaluation in 215 patients (37%). The median transplant-free survival time was 17 months (95% CI 15.2 - not reached). Multivariable analysis identified male sex (p<0.001), functional class III (p=0.003) or IV (p=0.003), 6 MWD≤228 m (p<0.001), PVR>5 Wood units (p=0.008), and absence of PH therapy (p<0.001) as independent predictors of death or lung transplantation at 1 year. Non-invasive (6 MWD, WHO FC) and invasive (PVR) variables are associated with prognosis in patients with ILD-PH, including in patients with CPFE. PH medication might improve outcomes in this patient population.
antibodies
2026-06-02 | Tolerability and effectiveness of definitive chemoradiotherapy in locally advanced lung cancer patients with combined pulmonary fibrosis and emphysema.
This study evaluated the efficacy and safety of definitive chemoradiotherapy (CRT) for lung cancer in patients with combined pulmonary fibrosis and emphysema (CPFE), focusing on radiation pneumonitis (RP). This retrospective cohort study included patients with locally advanced lung cancer treated with definitive CRT at Kishiwada City Hospital from 2014 to 2024. CPFE was defined as coexisting upper-lobe emphysema and lower-lobe fibrosis. Outcomes included RP incidence, progression-free survival (PFS), and overall survival (OS). Among 182 patients, 40 (22%) had CPFE. The incidence of grade ≥1 RP was comparable between the CPFE and non-CPFE groups (75%vs 81%, p = 0.41) with no significant difference in severity. Among patients with non-small cell lung cancer, the CPFE group exhibited shorter PFS and OS than the non-CPFE group (median PFS: 10 vs. 19 months, p = 0.01; median OS: 13 vs. 70 months, p < 0.01; respectively). However, among those who received durvalumab, PFS was comparable between the CPFE and non-CPFE groups (hazard ratio, 1.41; 95% confidence interval 0.69-2.90). Among patients with small cell lung cancer (n = 42), the CPFE and non-CPFE groups exhibited comparable PFS (median 11 vs. 12 months, p = 0.43), although the CPFE group exhibited a trend for shorter OS (median 23 vs. 34 months, p = 0.05). Definitive CRT did not increase RP risk in patients with CPFE. Despite poorer prognosis, CRT, particularly when followed by durvalumab, might serve as a feasible and beneficial therapeutic approach for CPFE-associated lung cancer.
2022-07-21 | The upregulation and SNP of Transforming growth factor-β1 in COPD patients with or without pulmonary fibrosis
Abstract Background: Pulmonary fibrosis is a common pathogenic change of COPD and associated with worse outcome, however, there is a lack of research on mechanisms of COPD with pulmonary fibrosis. In our study, we studied the influence of TGF-β1 and its single nucleotide polymorphism (SNP) on COPD complicated with pulmonary fibrosis. Methods: In this research, six GEO datasets were included to screen dysregulated genes in COPD patients. The dysregulated genes were detected by PCR-DNA sequencing based on 98 COPD patients and 90 healthy volunteers. Results: Five genes were upregulated in COPD patients including CDCP1, CYP1B1, PELO, RNF24 and TGF-β1. However, of the five genes, only TGF-β and CYP1B1 expression were significantly increased in COPD compared with normal group validated by R2 database. And only TGF-β1 highly expressed in 1-4 stage of COPD versus 0 stage. The expression of TGF-β in COPD patients with fibrosis was significantly higher than normal and COPD patients. Moreover, allele C of TGF-β1 +869 locus was associated with the susceptibility of COPD and airflow restriction. The genotype frequency of CC in patients with severe airflow restriction (23.1%) was significantly higher than that in patients with mild and moderate airflow restriction (6.5%). Conclusion: TGF-β1 was upregulated in the COPD patients with fibrosis, especially in patients with pulmonary fibrosis. The SNP at +869 allele C in TGF-β1 may be a genetic locus and therapeutic target for COPD with fibrosis.
2020-12-10 | Integrative Analysis Reveals Common and Unique Roles of Tetraspanins in Fibrosis and Emphysema
While both chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are multifactorial disorders characterized by distinct clinical and pathological features, their commonalities and differences have not been fully elucidated. We sought to investigate the preventive roles of tetraspanins Cd151 and Cd9 -that are involved in diverse cellular processes in lung pathophysiology- in pulmonary fibrosis and emphysema, respectively, and to obtain a deeper understanding of their underlying molecular mechanisms toward facilitating improved therapeutic outcomes. Using an integrative approach, we examined the transcriptomic changes in the lungs of Cd151- and Cd9-deficient mice using functional-enrichment-analysis, pathway-perturbation-analysis and protein-protein-interaction (PPI) network analysis. Circadian-rhythm, extracellular-matrix (ECM), cell-adhesion and inflammatory responses and associated factors were prominently influenced by Cd151-deletion. Conversely, cellular-junctions, focal-adhesion, vascular-remodeling, and TNF-signaling were deeply impacted by Cd9-deletion. We also highlighted a “common core” of factors and signaling cascades that underlie the functions of both Cd151 and Cd9 in lung pathology. Circadian dysregulation following Cd151-deletion seemingly facilitated progressive fibrotic lung phenotype. Conversely, TGF-β signaling attenuation and TNF-signaling activation emerged as potentially novel functionaries of Cd9-deletion-induced emphysema. Our findings offer promising avenues for developing novel therapeutic treatments for pulmonary fibrosis and emphysema.
2015-04-06 | Inflammatory Response Mechanisms Exacerbating Hypoxemia in Coexistent Pulmonary Fibrosis and Sleep Apnea
Mediators of inflammation, oxidative stress, and chemoattractants drive the hypoxemic mechanisms that accompany pulmonary fibrosis. Patients with idiopathic pulmonary fibrosis commonly have obstructive sleep apnea, which potentiates the hypoxic stimuli for oxidative stress, culminating in systemic inflammation and generalized vascular endothelial damage. Comorbidities like pulmonary hypertension, obesity, gastroesophageal reflux disease, and hypoxic pulmonary vasoconstriction contribute to chronic hypoxemia leading to the release of proinflammatory cytokines that may propagate clinical deterioration and alter the pulmonary fibrotic pathway. Tissue inhibitor of metalloproteinase (TIMP-1), interleukin- (IL-) 1 α , cytokine-induced neutrophil chemoattractant (CINC-1, CINC-2 α / β ), lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG-1), macrophage inflammatory protein- (MIP-) 1 α , MIP-3 α , and nuclear factor- (NF-) κ B appear to mediate disease progression. Adipocytes may induce hypoxia inducible factor (HIF) 1 α production; GERD is associated with increased levels of lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and tumor necrosis factor alpha (TNF- α ); pulmonary artery myocytes often exhibit increased cytosolic free Ca2+. Protein kinase C (PKC) mediated upregulation of TNF- α and IL-1 β also occurs in the pulmonary arteries. Increased understanding of the inflammatory mechanisms driving hypoxemia in pulmonary fibrosis and obstructive sleep apnea may potentiate the identification of appropriate therapeutic targets for developing effective therapies.
2013-05-22 | Increased incidence of autoimmune markers in patients with combined pulmonary fibrosis and emphysema
Combined pulmonary fibrosis and emphysema (CPFE) is an umbrella term encompassing upper lobe emphysema and lower lobe pulmonary fibrosis with pathogenesis elusive. The aim of our study was to investigate the incidence of autoimmune markers in patients with CPFE.In this multicenter study we retrospectively evaluated records from patients with CPFE (n=40) and IPF (n=60) without emphysema. Baseline demographic characteristics, high-resolution computed tomography (HRCT), spirometry, histopathological, treatment, serum immunologic and survival data were investigated. B cell presence was estimated with CD20 immunostaining in representative lung biopsy samples from CPFE patients and control subjects.A statistically significant increased number of CPFE patients with elevated serum ANA with or without positive p-ANCA titers compared to patients with IPF without emphysema was observed. Patients with CPFE and positive autoimmune markers exhibited improved survival compared to patients with a negative autoimmune profile. A massive infiltration of clusters of CD20+ B cells forming lymphoid follicles within the fibrotic lung in CPFE patients with positive serum immunologic profile compared to patients with negative profile, was noted and positively correlated with improved survival.A significant proportion of patients with CPFE may present with underlying auto-immune disorders that may reside insidiously and be associated with favorable prognosis. Early identification of these patients using a panel of auto-antibodies may lead to more targeted and effective therapeutic applications.
proteins
2024-05-07 | Protective role of overexpressed MUC5AC against fibrosis in MHV-68-induced combined pulmonary fibrosis and emphysema mouse model.
Mucins have long been regarded to play a role as a barrier to prevent mucosal infections; however, some studies report that overexpression of mucins induces obstruction and inflammation of airways. We investigated whether the secretion of overexpressed mucin, mucin5ac (MUC5AC), could improve protection against pathogens. To examine the possible roles of mucin hypersecretion in augmenting host defense against disease-promoting muco-obstructive lung disease, a mouse model that overexpressed MUC5AC was generated. We had previously proved that murine gammaherpesvirus-68 (MHV-68) infection could induce emphysema in mice, which later developed into combined pulmonary fibrosis and emphysema (CPFE). We further explored whether increased MUC5AC secretion could provide benefits against MHV-68 induced fibrosis. We initially developed a pcDNA3.1-MUC5AC mouse model. Next, the experimental mice were randomly divided into five groups: normal control, pcDNA3.1 control, pcDNA3.1-MUC5AC, CPFE, and pcDNA3.1- MUC5AC + CPFE. Morphometric analysis of each group was performed by hematoxylin and eosin staining and Masson trichrome staining. MUC5AC levels in lung tissues were analyzed by immunohistochemical staining, real-time polymerase chain reaction, and Western blot analysis. The airway inflammation was determined by differential cell counts of bronchoalveolar lavage fluid (BALF) and measurement of cytokines and chemokines in BALF by enzyme-linked immunosorbent assay. MUC5AC hypersecretion alone was not sufficient to drive goblet cell metaplasia to induce obvious mucus plugging and airway inflammation. However, MUC5AC overexpression served as a protective barrier against MHV-68 virus infection in vivo. Infectivity of MHV-68 was decreased in the pcDNA3.1-MUC5AC + CPFE group compared with that in CPFE group. Meanwhile, a reduction of MHV-68 virus attenuated the expressions of chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-X-C motif) ligand 5 (CXCL5), interleukin-13 (IL-13), and transforming growth factor-β1 (TGF-β1), and weakened airway inflammation and fibrosis in the pcDNA3.1-MUC5AC + CPFE group. Overexpression of MUC5AC appears to exhibit a protective role against MHV-68 infection in mice with emphysema that subsequently developed into CPFE and to further decrease airway inflammation and fibrosis induced by MHV-68 by decreasing the expressions of CCL2, CXCL5, IL-13, and TGF-β1.
2020-01-10 | Air Space Distension Precedes Spontaneous Fibrotic Remodeling and Impaired Cholesterol Metabolism in the Absence of Surfactant Protein C
Surfactant protein (SP)-C deficiency is found in samples from patients with idiopathic pulmonary fibrosis, especially in familial forms of this disease. We hypothesized that SP-C may contribute to fibrotic remodeling in aging mice and alveolar lipid homeostasis. For this purpose, we analyzed lung function, alveolar dynamics, lung structure, collagen content, and expression of genes related to lipid and cholesterol metabolism of aging SP-C knockout mice. In addition, in vitro experiments with an alveolar macrophage cell line exposed to lipid vesicles with or without cholesterol and/or SP-C were performed. Alveolar dynamics showed progressive alveolar derecruitment with age and impaired oxygen saturation. Lung structure revealed that decreasing volume density of alveolar spaces was accompanied by increasing of the ductal counterparts. Simultaneously, septal wall thickness steadily increased, and fibrotic wounds appeared in lungs from the age of 50 weeks. This remarkable phenotype is unique to the 129Sv strain, which has an increased absorption of cholesterol, linking the accumulation of cholesterol and the absence of SP-C to a fibrotic remodeling process. The findings of this study suggest that overall loss of SP-C results in an age-dependent, complex, heterogeneous phenotype characterized by a combination of overdistended air spaces and fibrotic wounds that resembles combined emphysema and pulmonary fibrosis in patients with idiopathic pulmonary fibrosis. Addition of SP-C to cholesterol-laden lipid vesicles enhanced the expression of cholesterol metabolism and transport genes in an alveolar macrophage cell line, identifying a potential new lipid-protein axis involved in lung remodeling.
2017-04-20 | Klotho, an antiaging molecule, attenuates oxidant-induced alveolar epithelial cell mtDNA damage and apoptosis
Alveolar epithelial cell (AEC) apoptosis and inadequate repair resulting from "exaggerated" lung aging and mitochondrial dysfunction are critical determinants promoting lung fibrosis. α-Klotho, which is an antiaging molecule that is expressed predominantly in the kidney and secreted in the blood, can protect lung epithelial cells against hyperoxia-induced apoptosis. We reasoned that Klotho protects AEC exposed to oxidative stress in part by maintaining mitochondrial DNA (mtDNA) integrity and mitigating apoptosis. We find that Klotho levels are decreased in both serum and alveolar type II (AT2) cells from asbestos-exposed mice. We show that oxidative stress reduces AEC Klotho mRNA and protein expression, whereas Klotho overexpression is protective while Klotho silencing augments AEC mtDNA damage. Compared with wild-type, Klotho heterozygous hypomorphic allele (kl/+) mice have increased asbestos-induced lung fibrosis due in part to increased AT2 cell mtDNA damage. Notably, we demonstrate that serum Klotho levels are reduced in wild-type but not mitochondrial catalase overexpressing (MCAT) mice 3 wk following exposure to asbestos and that EUK-134, a MnSOD/catalase mimetic, mitigates oxidant-induced reductions in AEC Klotho expression. Using pharmacologic and genetic silencing studies, we show that Klotho attenuates oxidant-induced AEC mtDNA damage and apoptosis via mechanisms dependent on AKT activation arising from upstream fibroblast growth factor receptor 1 activation. Our findings suggest that Klotho preserves AEC mtDNA integrity in the setting of oxidative stress necessary for preventing apoptosis and asbestos-induced lung fibrosis. We reason that strategies aimed at augmenting AEC Klotho levels may be an innovative approach for mitigating age-related lung diseases.
cell therapies
2026-02-01 | Clinical efficacy of lung transplantation for combined pulmonary fibrosis and emphysema syndrome
Background The clinical efficacy of lung transplantation for the treatment of CPFE remains unclear. Methods Clinical data of patients with CPFE who underwent lung transplantation at the Affiliated Wuxi People's Hospital of Nanjing Medical University between January 2018 and December 2021 were retrospectively reviewed. They were divided into the SLT and BLT groups. Results Fifty-seven patients with CPFE, including 33 in the SLT group and 24 in the BLT group, were included. Patients in the BLT group were younger and had a longer surgery duration and extracorporeal membrane oxygenation support time, more blood loss and transfusion requirements, and lower pulmonary artery pressure postoperatively. The carbon monoxide diffusion capacity (DLCO) was significantly better after BLT than after SLT (P = 0.0026). The risk of short- and medium-term mortality after BLT was 21.4 % of that after SLT, though the survival rate was not significantly different between the groups. Conclusion After good and effective perioperative management, lung transplantation is feasible for patients with CPFE, which effectively improves the lung function, oxygenation index and pulmonary artery pressure, and prolongs survival. Short - and medium-term survival rates were similar between SLT group and BLT group, but BLT resulted in a better improvement of DLCO and a lower risk of death. Patients aged 65 years or older have worse survival rates after lung transplantation.
2025-07-04 | Mid-term outcomes of a bio-artificial pleura composed of autologous dermal fibroblasts used to close intraoperative pulmonary air leaks caused by intraoperative pleural injury: A case report.
The visceral pleura is a thin, serous membrane that closely covers the surface of the lung. The pleura is injured or ruptured, causing air to accumulate in the thoracic cavity and the lung to collapse. Increased pleural pressure due to lung air leaks (LALs) from the lung can have serious effects. LALs are frequently observed due to pleural injury caused by lung resection. Postoperative LALs prolongs hospital stay and has a significant impact on patients' postoperative quality of life. Based on the above background, we developed and reported the effectiveness of dermal fibroblast sheet (DFS) as a bio-artificial pleura for closing LALs caused by intraoperative pleural injury in humans for the first time in a clinical study. There are no mid-term reports of bio-artificial pleura created using tissue engineering. In this study, we report the safety of bio-artificial pleural transplantation using cultured autologous DFS for pleural injury in two cases. Two of the five patients who met the criteria and underwent LAL closure using a bio-artificial pleura between May 2016 and March 2018 were followed up mid-term. Although the criteria included a 6-month monitoring period after LAL closure, these two patients continued to visit our hospital beyond the monitoring period for treatment of other comorbid conditions. Case 1. A male in his 40s who was receiving long-term steroid therapy for Takayasu's disease and underwent thoracoscopic lung wedge resection for a benign lung tumor in the left anteromedial basal segment. During surgery, the minor LALs from the resection margins with an automatic stapler were closed with a bio-artificial pleura, specifically, a total of three DFSs. During the patient's 51-month follow-up, no LAL recurrence, tumor development, infiltration, and fibrogenesis were observed. Case 2. A female patient in her 70s had bullae associated with combined pulmonary fibrosis and emphysema (CPFE). Thoracoscopic bullectomy of the left lower lobe was performed, and the major LALs were closed intraoperatively with a bio-artificial pleura consisting of a total of eight DFSs. She was readmitted for contralateral pneumonia 2 months after surgery. During a follow-up period of 82 months, no LAL recurrence and tumor development was observed in the operated left lung. However, chest CT revealed slowly progressing CPFE lesions. This report of two cases demonstrated the mid-term safety of bio-artificial pleural transplantation using cultured autologous DFS for pleural injury.
2017-08-05 | Pulmonary CCR2+CD4+T cells are immune regulatory and attenuate lung fibrosis development
Animal models have suggested that CCR2-dependent signalling contributes to the pathogenesis of pulmonary fibrosis, but global blockade of CCL2 failed to improve the clinical course of patients with lung fibrosis. However, as levels of CCR2+CD4+ T cells in paediatric lung fibrosis had previously been found to be increased, correlating with clinical symptoms, we hypothesised that distinct CCR2+ cell populations might either increase or decrease disease pathogenesis depending on their subtype.To investigate the role of CCR2+CD4+ T cells in experimental lung fibrosis and in patients with idiopathic pulmonary fibrosis and other fibrosis.Pulmonary CCR2+CD4+ T cells were analysed using flow cytometry and mRNA profiling, followed by in silico pathway analysis, in vitro assays and adoptive transfer experiments.Frequencies of CCR2+CD4+ T cells were increased in experimental fibrosis-specifically the CD62L-CD44+ effector memory T cell phenotype, displaying a distinct chemokine receptor profile. mRNA profiling of isolated CCR2+CD4+ T cells from fibrotic lungs suggested immune regulatory functions, a finding that was confirmed in vitro using suppressor assays. Importantly, adoptive transfer of CCR2+CD4+ T cells attenuated fibrosis development. The results were partly corroborated in patients with lung fibrosis, by showing higher percentages of Foxp3+ CD25+ cells within bronchoalveolar lavage fluid CCR2+CD4+ T cells as compared with CCR2-CD4+ T cells.Pulmonary CCR2+CD4+ T cells are immunosuppressive, and could attenuate lung inflammation and fibrosis. Therapeutic strategies completely abrogating CCR2-dependent signalling will therefore also eliminate cell populations with protective roles in fibrotic lung disease. This emphasises the need for a detailed understanding of the functions of immune cell subsets in fibrotic lung disease.
other
2024-07-30 | Explicate molecular landscape of combined pulmonary fibrosis and emphysema through explainable artificial intelligence: a comprehensive analysis of ILD and COPD interactions using RNA from whole lung homogenates.
Combined pulmonary fibrosis and emphysema (CPFE) presents a unique challenge in respiratory disorders, merging features of interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). Using the random forest algorithm, our study thoroughly examines the molecular details of CPFE. Analyzing gene expression datasets from GSE47460 (ILD: 254, COPD: 220, control: 108), we identify key genes namely ADRB2, CDH3, IRS2, MATN3, CD38, PDIA4, VEGFC, and among twenty others, crucial in airway regulation, lung function, and apoptosis, shaping the complex pathogenesis of CPFE. Additionally, miRNAs (hsa-mir-101-3p, hsa-mir-1343-3p, hsa-mir-27a-3p, and miR-16-5p) showcase regulatory impacts on CPFE-related molecular pathways. Our machine learning model unveils these intricate interactions, offering a comprehensive insight into CPFE's molecular mechanisms. This research not only pinpoints potential therapeutic targets and biomarkers but also opens avenues for innovative approaches in managing CPFE, linking ILD and COPD within this complex respiratory condition.
small molecules
2026-05-01 | B41-08 Characteristics and Management of Patients With Fibrosing Interstitial Lung Disease in Spain: Data From the Separ- ILD Registry
Abstract Introduction Fibrotic interstitial lung diseases (fILD) pose a challenge in clinical practice. Idiopathic pulmonary fibrosis (IPF) is the prototype of progressive fibrotic ILD, and it is estimated that up to one-third of people with fibrotic ILDs other than IPF may develop a progressive course like IPF, called progressive pulmonary fibrosis (PPF). The SEPAR-ILD Registry, from the Spanish Society of Pulmonology and Thoracic Surgery (SEPAR), aims to provide real-world data from Spanish patients with fibrosing interstitial lung diseases to better understand the clinical characteristics progression, and management. Methods SEPAR-ILD Registry is an ongoing prospective registry for patients diagnosed with IPF and other fILD since 2022 (Approval December 11, 2023, CEIm minutes 22/23) conducted at 19 expert sites across Spain. Results 481 patients were included. The most frequent diagnoses were IPF 158(32%), Unclassifiable ILD (UILD) (including IPAF) 83 (17,3 %), combined pulmonary fibrosis and emphysema (CPFE) 73(15,2%), connective tissue disease (CTD) ILDs (13.9%), and fibrotic hypersensitivity pneumonitis(fHP) 46(9.6%). The mean (SD) age was 69 (10.6) years; 64.7 % were male, 74.8% former smokers, and 25.2% never smokers. FVC was 83.6 (18.6) % predicted, and diffusion capacity for carbon monoxide (DLCO) was 55.5 (18.3) % predicted. 200 patients (41.7%) were receiving nintedanib and 108 (22.5%) pirfenidone. 132 patients (32.9 %) were on long term oxygen therapy (LTOT)at rest and 138 (34.3 %) during exercise. Comorbidities included high blood pressure 205 (42.7 %), high cholesterol 202(42.1%), diabetes 107 (22,3 %) and ischemic cardiomyopathy 54 (11.3 %). From 336 patients with a median follow up of 12 months disease progression occurred in 151 patients (44.9%) ( In 38 (42%) of patients with IPF, 26 (40%) of CPFE, in 25 (39%) of uILD, 23 (48%) of CTD-ILD and in 12 (44%) of fHP.) presenting worsening of respiratory symptoms 119 (79.3%); worsening of pulmonary function tests 112 (74.7%) and radiological worsening 105 (70.0%). Patients who experienced disease progression exhibited a more severe disease profile, with mean (SD) FVC 77.6 (17.4%) % predicted; DLCO 52.3 (17.8%) % predicted; greater use of LTOT 52.7% of cases; high frequency of hospitalizations (95 [62.9%]), acute exacerbation (32 [22.9%]), and high mortality (37 [40.7%]). Furthermore, they received more frequently nintedanib as antifibrotic therapy (120 [79.5%]). Conclusions Patients with fibrosing ILD in the prospective SEPAR ILD registry had a high rate of disease progression, which is associated with greater severity and a poor outcome. This abstract is funded by: None
2026-05-01 | C29-14 Granzyme K Expressing Cd8 T Cell Expression in Chronic Lung Diseases
Abstract Background Granzyme K (GZMK) expressing CD8 T cells are pro-inflammatory cells enriched in asthma, bronchiolitis obliterans syndrome and autoimmune diseases. These cells activate complement cascade leading to persistent inflammation, however their characteristics have not been comprehensively studied in different chronic lung diseases. We hypothesized that GZMK+ CD8 T cells are differentially abundant across chronic lung disease subtypes and investigated the expression of GZMK+CD8 T cell signatures. Methods We analyzed bulk lung tissue RNA sequencing data from the Lung Tissue Research Consortium, across different disease pathologies including controls (n = 340), chronic obstructive pulmonary disease (COPD, n = 505), combined pulmonary fibrosis and emphysema (CPFE, n = 43), smoking-related interstitial lung disease (smoking-ILD, desquamative interstitial pneumonia [DIP], respiratory bronchiolitis [RB-ILD], n = 16) and other ILDs (n = 340). We used a top 15-gene signature derived from GZMK+ CD8 T cells identified in single cell RNA-seq data and calculated enrichment scores to quantify the GZMK+CD8 T cell signature score for each subject using gene set variation analysis. We performed linear regression models adjusted for age, sex, race, smoking pack years and current smoking status. Results The lung GZMK+CD8 T cell score correlated with blood lymphocyte percentage (Pearson r = 0.2, p < 0.003) and cumulative smoking (pack years, r = 0.23, p = 0.0006). In multivariable models, GZMK+CD8 T cell signature scores were significantly elevated in COPD compared to controls (adjusted mean difference β = 0.1, Tukey-adj. p = 0.003). Among smoking related pathologies, there was no statistical difference between COPD and CPFE, however smoking-related ILD had the highest GZMK+CD8 T cell score with marginal significance (vs. controls β = 0.28, adj. p = 0.06). Among ILD pathology subtypes, usual interstitial pneumonia (UIP, n = 186) had the lowest score while organizing pneumonia (n = 18) had the highest score. Notably, GZMK+CD8 T cell score was positively correlated with DLCO in CPFE(r = 0.3, p = 0.09) but negatively correlated in smoking-ILD (r= -0.5, p = 0.09), suggesting distinct immunological patterns across disease pathology. Conclusions GZMK+CD8 T cell signatures are elevated in COPD and show heterogeneous enrichment patterns across chronic lung disease subtypes. The highest scores in organizing pneumonia and smoking-related ILD, as well as the positive correlation with disease severity (DLCO) in smoking-related ILD suggest GZMK+CD8 T cells may be enriched in airway-centric diseases involving inflammation. This abstract is funded by: K08HL146972
2026-05-01 | C68-08 A Cascade of Cavities: CPFE Complicated by Chronic Cavitary Pulmonary Aspergillosis and Superimposed Mac Infection
Abstract Introduction Chronic pulmonary aspergillosis (CPA) is a rare infection by Aspergillus fumigatus that develops in structurally damaged lungs such as those with COPD or emphysema. Persistent inflammation accelerates parenchymal destruction, worsening fibrosis and predisposing to further opportunistic infections. We present a case of CPFE complicated by chronic cavitary pulmonary aspergillosis and Mycobacterium avium complex infection- a hemorrhagic cascade of cavities. Case Then aged 60, this patient with a history of heavy smoking, DVT/PE s/p IVC filter, opioid use presented in 2013 with hemoptysis. Imaging showed an 8 cm RUL cavity with thin walls superimposed on previously known bilateral upper-lobe bullous emphysema, adjacent bronchiectasis and interstitial fibrotic changes consistent with Combined Pulmonary Fibrosis and Emphysema (CPFE). An extensive evaluation including multiple BALs over 2013-2014 was negative for AFBs but yielded fungal organisms Aspergillus fumigatus and Candida albicans. A diagnosis of chronic pulmonary aspergillosis (CPA) was made, and voriconazole therapy was initiated.The next decade was characterized by intermittent anti-fungal therapy and scattered follow-up complicated by homelessness and ongoing substance use. Management of COPD symptoms included inhaled corticosteroids and courses of oral steroids for exacerbations. In June 2025, the patient presented with brisk hemoptysis prompting an emergent bronchoscopy to localize the bleed and treated with an LUL bronchial artery embolization. Repeat imaging demonstrated progression of bilateral upper-lobe bullous disease, fibrosis and bilateral fungal balls, the largest in the previous RUL cavity and another in the LUL, explaining the source of the bleeding. BAL cultures again grew Aspergillus flavus and now superimposed Mycobacterium avium complex (MAC). The patient was re-intiated on antifungal therapy with isavuconazole; management focused on aspergillosis in the acute period as MAC was deemed a colonizer. Recurrent hemoptysis led to 2 further hospitalizations which were managed conservatively. Multidisciplinary follow-up continues for chronic cavitary pulmonary aspergillosis (CCPA) in the context of CPFE, with the primary goal of preventing further life-threatening hemorrhage from invasive aspergillomas. Discussion Longstanding CPFE creates a substrate for opportunistic colonization. Interruptions in antifungal therapy and corticosteroid use for suspected COPD exacerbations likely promoted fungal growth, leading to invasive aspergillomas and a high risk of recurrent bleeding. Coexistence of CCPA and MAC within the same cavities is rare and challenging, requiring multidisciplinary management. References: Yamakawa H, et al. Patient Background and Prognosis of Chronic Pulmonary Aspergillosis in Fibrosing Interstitial Lung Disease. Respir Investig. 2022;60(5):586-593. Fayos B, et al. Non-Tuberculous Mycobacteria and Aspergillus Lung Co-infection: A Systematic Review. J Fungi (Basel). 2022;8(10):1080. This abstract is funded by: none
2026-04-16 | Treatment of pulmonary fibrosis and combined pulmonary fibrosis and emphysema syndrome with herbs for promoting blood circulation and removing blood stasis: A review of pharmacological studies.
Pulmonary fibrosis (PF) is a progressive interstitial lung disease (ILD), and combined pulmonary fibrosis and emphysema (CPFE) is a complication of this condition. Traditional Chinese medicine (TCM) considers that the deficiency of the lung, spleen, and kidney, complicated by phlegm and blood stasis obstructing the lung, is the main pathological mechanism of CPFE. Promoting blood circulation and removing blood stasis (RBCRBS) is a crucial therapeutic principle in both treating PF and CPFE. Through research on TCM literature and the clinical experience of a renowned TCM doctor, we have found that Pheretima (Dilong), Spatholobi Caulis (Jixueteng), and Rhodiola (Hongjingtian) are important blood-activating and stasis-resolving (BASR) herbs used to treat PF and COPD. They are effective in improving symptoms and the pathological state of patients with PF and CPFE in clinical practice. Through literature research to understand the pathological mechanism of PF and CPFE; By analyzing the traditional application, modern pharmacological research, and network pharmacological research of BASR herbs, to systematically review the effectiveness and unique advantages of these herbs in treating PF and CPFE. Multiple databases, including PubMed, Web of Science, and the China National Knowledge Infrastructure (CNKI), were utilized to screen out relevant literature. The search terms were "pulmonary fibrosis", "CPFE", "promoting blood circulation and removing blood stasis", and relevant Chinese herb names such as "Dilong", "Jixueteng", and "Hongjingtian". The literature spanned mainly from 2000 to the present. Additionally, network pharmacology methods were employed to identify the key active ingredients of these herbs and predict their mechanisms of action in treating PF. The deficiency of the lung, spleen, and kidney, complicated by phlegm and blood stasis obstructing the lung, is the pathogenesis of CPFE. Pheretima, Spatholobi Caulis, and Rhodiola exert antifibrotic effects through the TGF-β1/Smad2/3 pathway, anti-inflammatory/antioxidant, immune homeostasis restoration, and EMT suppression. Subsequent network pharmacology analysis identifies 74 core targets (TP53, AKT1, SRC, STAT3, TNF), and highlights 20 pathways, including EGFR, HIF-1, FoxO, PD-1/PD-L1, and AGE-RAGE. These collectively influence IPF progression by regulating EMT, fibroblast activation, collagen deposition, and immune microenvironment disruption. This review synthesizes research on the material basis and pharmacodynamics of representative BASR herbs, providing novel insights for advancing the therapeutic application of these herbs in PF and its associated complications.
2026-03-27 | Prognostic factors in interstitial lung disease-associated pulmonary hypertension: data from the HYPID cohort and the French Pulmonary Hypertension Registry.
Pulmonary hypertension (PH) frequently complicates interstitial lung diseases (ILD), adversely affecting outcome. Identifying prognostic factors of patients with ILD-PH could facilitate early identification of patients who may benefit from PH therapy. We included patients with ILD-PH from the prospective HYPID cohort and the French National Pulmonary Hypertension Registry (2007-2022). Univariable and multivariable analyses were performed to identify predictors of 1-year mortality. A total of 581 patients (mean age 69.4±9.3 years, 450 males) were analysed. ILD diagnoses were combined pulmonary fibrosis and emphysema syndrome (30.8%), idiopathic pulmonary fibrosis (29.6%), unclassifiable ILD (13.1%), and fibrotic hypersensitivity pneumonitis (10.3%). Mean pulmonary artery pressure was 40.7±9.1 mmHg, and mean pulmonary vascular resistance was 7.6 ±3.5 Wood units. Off-label PH therapy was initiated after initial evaluation in 215 patients (37%). The median transplant-free survival time was 17 months (95% CI 15.2 - not reached). Multivariable analysis identified male sex (p<0.001), functional class III (p=0.003) or IV (p=0.003), 6 MWD≤228 m (p<0.001), PVR>5 Wood units (p=0.008), and absence of PH therapy (p<0.001) as independent predictors of death or lung transplantation at 1 year. Non-invasive (6 MWD, WHO FC) and invasive (PVR) variables are associated with prognosis in patients with ILD-PH, including in patients with CPFE. PH medication might improve outcomes in this patient population.
antibodies
2026-06-02 | Tolerability and effectiveness of definitive chemoradiotherapy in locally advanced lung cancer patients with combined pulmonary fibrosis and emphysema.
This study evaluated the efficacy and safety of definitive chemoradiotherapy (CRT) for lung cancer in patients with combined pulmonary fibrosis and emphysema (CPFE), focusing on radiation pneumonitis (RP). This retrospective cohort study included patients with locally advanced lung cancer treated with definitive CRT at Kishiwada City Hospital from 2014 to 2024. CPFE was defined as coexisting upper-lobe emphysema and lower-lobe fibrosis. Outcomes included RP incidence, progression-free survival (PFS), and overall survival (OS). Among 182 patients, 40 (22%) had CPFE. The incidence of grade ≥1 RP was comparable between the CPFE and non-CPFE groups (75%vs 81%, p = 0.41) with no significant difference in severity. Among patients with non-small cell lung cancer, the CPFE group exhibited shorter PFS and OS than the non-CPFE group (median PFS: 10 vs. 19 months, p = 0.01; median OS: 13 vs. 70 months, p < 0.01; respectively). However, among those who received durvalumab, PFS was comparable between the CPFE and non-CPFE groups (hazard ratio, 1.41; 95% confidence interval 0.69-2.90). Among patients with small cell lung cancer (n = 42), the CPFE and non-CPFE groups exhibited comparable PFS (median 11 vs. 12 months, p = 0.43), although the CPFE group exhibited a trend for shorter OS (median 23 vs. 34 months, p = 0.05). Definitive CRT did not increase RP risk in patients with CPFE. Despite poorer prognosis, CRT, particularly when followed by durvalumab, might serve as a feasible and beneficial therapeutic approach for CPFE-associated lung cancer.
2022-07-21 | The upregulation and SNP of Transforming growth factor-β1 in COPD patients with or without pulmonary fibrosis
Abstract Background: Pulmonary fibrosis is a common pathogenic change of COPD and associated with worse outcome, however, there is a lack of research on mechanisms of COPD with pulmonary fibrosis. In our study, we studied the influence of TGF-β1 and its single nucleotide polymorphism (SNP) on COPD complicated with pulmonary fibrosis. Methods: In this research, six GEO datasets were included to screen dysregulated genes in COPD patients. The dysregulated genes were detected by PCR-DNA sequencing based on 98 COPD patients and 90 healthy volunteers. Results: Five genes were upregulated in COPD patients including CDCP1, CYP1B1, PELO, RNF24 and TGF-β1. However, of the five genes, only TGF-β and CYP1B1 expression were significantly increased in COPD compared with normal group validated by R2 database. And only TGF-β1 highly expressed in 1-4 stage of COPD versus 0 stage. The expression of TGF-β in COPD patients with fibrosis was significantly higher than normal and COPD patients. Moreover, allele C of TGF-β1 +869 locus was associated with the susceptibility of COPD and airflow restriction. The genotype frequency of CC in patients with severe airflow restriction (23.1%) was significantly higher than that in patients with mild and moderate airflow restriction (6.5%). Conclusion: TGF-β1 was upregulated in the COPD patients with fibrosis, especially in patients with pulmonary fibrosis. The SNP at +869 allele C in TGF-β1 may be a genetic locus and therapeutic target for COPD with fibrosis.
2020-12-10 | Integrative Analysis Reveals Common and Unique Roles of Tetraspanins in Fibrosis and Emphysema
While both chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are multifactorial disorders characterized by distinct clinical and pathological features, their commonalities and differences have not been fully elucidated. We sought to investigate the preventive roles of tetraspanins Cd151 and Cd9 -that are involved in diverse cellular processes in lung pathophysiology- in pulmonary fibrosis and emphysema, respectively, and to obtain a deeper understanding of their underlying molecular mechanisms toward facilitating improved therapeutic outcomes. Using an integrative approach, we examined the transcriptomic changes in the lungs of Cd151- and Cd9-deficient mice using functional-enrichment-analysis, pathway-perturbation-analysis and protein-protein-interaction (PPI) network analysis. Circadian-rhythm, extracellular-matrix (ECM), cell-adhesion and inflammatory responses and associated factors were prominently influenced by Cd151-deletion. Conversely, cellular-junctions, focal-adhesion, vascular-remodeling, and TNF-signaling were deeply impacted by Cd9-deletion. We also highlighted a “common core” of factors and signaling cascades that underlie the functions of both Cd151 and Cd9 in lung pathology. Circadian dysregulation following Cd151-deletion seemingly facilitated progressive fibrotic lung phenotype. Conversely, TGF-β signaling attenuation and TNF-signaling activation emerged as potentially novel functionaries of Cd9-deletion-induced emphysema. Our findings offer promising avenues for developing novel therapeutic treatments for pulmonary fibrosis and emphysema.
2015-04-06 | Inflammatory Response Mechanisms Exacerbating Hypoxemia in Coexistent Pulmonary Fibrosis and Sleep Apnea
Mediators of inflammation, oxidative stress, and chemoattractants drive the hypoxemic mechanisms that accompany pulmonary fibrosis. Patients with idiopathic pulmonary fibrosis commonly have obstructive sleep apnea, which potentiates the hypoxic stimuli for oxidative stress, culminating in systemic inflammation and generalized vascular endothelial damage. Comorbidities like pulmonary hypertension, obesity, gastroesophageal reflux disease, and hypoxic pulmonary vasoconstriction contribute to chronic hypoxemia leading to the release of proinflammatory cytokines that may propagate clinical deterioration and alter the pulmonary fibrotic pathway. Tissue inhibitor of metalloproteinase (TIMP-1), interleukin- (IL-) 1 α , cytokine-induced neutrophil chemoattractant (CINC-1, CINC-2 α / β ), lipopolysaccharide induced CXC chemokine (LIX), monokine induced by gamma interferon (MIG-1), macrophage inflammatory protein- (MIP-) 1 α , MIP-3 α , and nuclear factor- (NF-) κ B appear to mediate disease progression. Adipocytes may induce hypoxia inducible factor (HIF) 1 α production; GERD is associated with increased levels of lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and tumor necrosis factor alpha (TNF- α ); pulmonary artery myocytes often exhibit increased cytosolic free Ca2+. Protein kinase C (PKC) mediated upregulation of TNF- α and IL-1 β also occurs in the pulmonary arteries. Increased understanding of the inflammatory mechanisms driving hypoxemia in pulmonary fibrosis and obstructive sleep apnea may potentiate the identification of appropriate therapeutic targets for developing effective therapies.
2013-05-22 | Increased incidence of autoimmune markers in patients with combined pulmonary fibrosis and emphysema
Combined pulmonary fibrosis and emphysema (CPFE) is an umbrella term encompassing upper lobe emphysema and lower lobe pulmonary fibrosis with pathogenesis elusive. The aim of our study was to investigate the incidence of autoimmune markers in patients with CPFE.In this multicenter study we retrospectively evaluated records from patients with CPFE (n=40) and IPF (n=60) without emphysema. Baseline demographic characteristics, high-resolution computed tomography (HRCT), spirometry, histopathological, treatment, serum immunologic and survival data were investigated. B cell presence was estimated with CD20 immunostaining in representative lung biopsy samples from CPFE patients and control subjects.A statistically significant increased number of CPFE patients with elevated serum ANA with or without positive p-ANCA titers compared to patients with IPF without emphysema was observed. Patients with CPFE and positive autoimmune markers exhibited improved survival compared to patients with a negative autoimmune profile. A massive infiltration of clusters of CD20+ B cells forming lymphoid follicles within the fibrotic lung in CPFE patients with positive serum immunologic profile compared to patients with negative profile, was noted and positively correlated with improved survival.A significant proportion of patients with CPFE may present with underlying auto-immune disorders that may reside insidiously and be associated with favorable prognosis. Early identification of these patients using a panel of auto-antibodies may lead to more targeted and effective therapeutic applications.
proteins
2024-05-07 | Protective role of overexpressed MUC5AC against fibrosis in MHV-68-induced combined pulmonary fibrosis and emphysema mouse model.
Mucins have long been regarded to play a role as a barrier to prevent mucosal infections; however, some studies report that overexpression of mucins induces obstruction and inflammation of airways. We investigated whether the secretion of overexpressed mucin, mucin5ac (MUC5AC), could improve protection against pathogens. To examine the possible roles of mucin hypersecretion in augmenting host defense against disease-promoting muco-obstructive lung disease, a mouse model that overexpressed MUC5AC was generated. We had previously proved that murine gammaherpesvirus-68 (MHV-68) infection could induce emphysema in mice, which later developed into combined pulmonary fibrosis and emphysema (CPFE). We further explored whether increased MUC5AC secretion could provide benefits against MHV-68 induced fibrosis. We initially developed a pcDNA3.1-MUC5AC mouse model. Next, the experimental mice were randomly divided into five groups: normal control, pcDNA3.1 control, pcDNA3.1-MUC5AC, CPFE, and pcDNA3.1- MUC5AC + CPFE. Morphometric analysis of each group was performed by hematoxylin and eosin staining and Masson trichrome staining. MUC5AC levels in lung tissues were analyzed by immunohistochemical staining, real-time polymerase chain reaction, and Western blot analysis. The airway inflammation was determined by differential cell counts of bronchoalveolar lavage fluid (BALF) and measurement of cytokines and chemokines in BALF by enzyme-linked immunosorbent assay. MUC5AC hypersecretion alone was not sufficient to drive goblet cell metaplasia to induce obvious mucus plugging and airway inflammation. However, MUC5AC overexpression served as a protective barrier against MHV-68 virus infection in vivo. Infectivity of MHV-68 was decreased in the pcDNA3.1-MUC5AC + CPFE group compared with that in CPFE group. Meanwhile, a reduction of MHV-68 virus attenuated the expressions of chemokine (C-C motif) ligand 2 (CCL2), chemokine (C-X-C motif) ligand 5 (CXCL5), interleukin-13 (IL-13), and transforming growth factor-β1 (TGF-β1), and weakened airway inflammation and fibrosis in the pcDNA3.1-MUC5AC + CPFE group. Overexpression of MUC5AC appears to exhibit a protective role against MHV-68 infection in mice with emphysema that subsequently developed into CPFE and to further decrease airway inflammation and fibrosis induced by MHV-68 by decreasing the expressions of CCL2, CXCL5, IL-13, and TGF-β1.
2020-01-10 | Air Space Distension Precedes Spontaneous Fibrotic Remodeling and Impaired Cholesterol Metabolism in the Absence of Surfactant Protein C
Surfactant protein (SP)-C deficiency is found in samples from patients with idiopathic pulmonary fibrosis, especially in familial forms of this disease. We hypothesized that SP-C may contribute to fibrotic remodeling in aging mice and alveolar lipid homeostasis. For this purpose, we analyzed lung function, alveolar dynamics, lung structure, collagen content, and expression of genes related to lipid and cholesterol metabolism of aging SP-C knockout mice. In addition, in vitro experiments with an alveolar macrophage cell line exposed to lipid vesicles with or without cholesterol and/or SP-C were performed. Alveolar dynamics showed progressive alveolar derecruitment with age and impaired oxygen saturation. Lung structure revealed that decreasing volume density of alveolar spaces was accompanied by increasing of the ductal counterparts. Simultaneously, septal wall thickness steadily increased, and fibrotic wounds appeared in lungs from the age of 50 weeks. This remarkable phenotype is unique to the 129Sv strain, which has an increased absorption of cholesterol, linking the accumulation of cholesterol and the absence of SP-C to a fibrotic remodeling process. The findings of this study suggest that overall loss of SP-C results in an age-dependent, complex, heterogeneous phenotype characterized by a combination of overdistended air spaces and fibrotic wounds that resembles combined emphysema and pulmonary fibrosis in patients with idiopathic pulmonary fibrosis. Addition of SP-C to cholesterol-laden lipid vesicles enhanced the expression of cholesterol metabolism and transport genes in an alveolar macrophage cell line, identifying a potential new lipid-protein axis involved in lung remodeling.
2017-04-20 | Klotho, an antiaging molecule, attenuates oxidant-induced alveolar epithelial cell mtDNA damage and apoptosis
Alveolar epithelial cell (AEC) apoptosis and inadequate repair resulting from "exaggerated" lung aging and mitochondrial dysfunction are critical determinants promoting lung fibrosis. α-Klotho, which is an antiaging molecule that is expressed predominantly in the kidney and secreted in the blood, can protect lung epithelial cells against hyperoxia-induced apoptosis. We reasoned that Klotho protects AEC exposed to oxidative stress in part by maintaining mitochondrial DNA (mtDNA) integrity and mitigating apoptosis. We find that Klotho levels are decreased in both serum and alveolar type II (AT2) cells from asbestos-exposed mice. We show that oxidative stress reduces AEC Klotho mRNA and protein expression, whereas Klotho overexpression is protective while Klotho silencing augments AEC mtDNA damage. Compared with wild-type, Klotho heterozygous hypomorphic allele (kl/+) mice have increased asbestos-induced lung fibrosis due in part to increased AT2 cell mtDNA damage. Notably, we demonstrate that serum Klotho levels are reduced in wild-type but not mitochondrial catalase overexpressing (MCAT) mice 3 wk following exposure to asbestos and that EUK-134, a MnSOD/catalase mimetic, mitigates oxidant-induced reductions in AEC Klotho expression. Using pharmacologic and genetic silencing studies, we show that Klotho attenuates oxidant-induced AEC mtDNA damage and apoptosis via mechanisms dependent on AKT activation arising from upstream fibroblast growth factor receptor 1 activation. Our findings suggest that Klotho preserves AEC mtDNA integrity in the setting of oxidative stress necessary for preventing apoptosis and asbestos-induced lung fibrosis. We reason that strategies aimed at augmenting AEC Klotho levels may be an innovative approach for mitigating age-related lung diseases.
cell therapies
2026-02-01 | Clinical efficacy of lung transplantation for combined pulmonary fibrosis and emphysema syndrome
Background The clinical efficacy of lung transplantation for the treatment of CPFE remains unclear. Methods Clinical data of patients with CPFE who underwent lung transplantation at the Affiliated Wuxi People's Hospital of Nanjing Medical University between January 2018 and December 2021 were retrospectively reviewed. They were divided into the SLT and BLT groups. Results Fifty-seven patients with CPFE, including 33 in the SLT group and 24 in the BLT group, were included. Patients in the BLT group were younger and had a longer surgery duration and extracorporeal membrane oxygenation support time, more blood loss and transfusion requirements, and lower pulmonary artery pressure postoperatively. The carbon monoxide diffusion capacity (DLCO) was significantly better after BLT than after SLT (P = 0.0026). The risk of short- and medium-term mortality after BLT was 21.4 % of that after SLT, though the survival rate was not significantly different between the groups. Conclusion After good and effective perioperative management, lung transplantation is feasible for patients with CPFE, which effectively improves the lung function, oxygenation index and pulmonary artery pressure, and prolongs survival. Short - and medium-term survival rates were similar between SLT group and BLT group, but BLT resulted in a better improvement of DLCO and a lower risk of death. Patients aged 65 years or older have worse survival rates after lung transplantation.
2025-07-04 | Mid-term outcomes of a bio-artificial pleura composed of autologous dermal fibroblasts used to close intraoperative pulmonary air leaks caused by intraoperative pleural injury: A case report.
The visceral pleura is a thin, serous membrane that closely covers the surface of the lung. The pleura is injured or ruptured, causing air to accumulate in the thoracic cavity and the lung to collapse. Increased pleural pressure due to lung air leaks (LALs) from the lung can have serious effects. LALs are frequently observed due to pleural injury caused by lung resection. Postoperative LALs prolongs hospital stay and has a significant impact on patients' postoperative quality of life. Based on the above background, we developed and reported the effectiveness of dermal fibroblast sheet (DFS) as a bio-artificial pleura for closing LALs caused by intraoperative pleural injury in humans for the first time in a clinical study. There are no mid-term reports of bio-artificial pleura created using tissue engineering. In this study, we report the safety of bio-artificial pleural transplantation using cultured autologous DFS for pleural injury in two cases. Two of the five patients who met the criteria and underwent LAL closure using a bio-artificial pleura between May 2016 and March 2018 were followed up mid-term. Although the criteria included a 6-month monitoring period after LAL closure, these two patients continued to visit our hospital beyond the monitoring period for treatment of other comorbid conditions. Case 1. A male in his 40s who was receiving long-term steroid therapy for Takayasu's disease and underwent thoracoscopic lung wedge resection for a benign lung tumor in the left anteromedial basal segment. During surgery, the minor LALs from the resection margins with an automatic stapler were closed with a bio-artificial pleura, specifically, a total of three DFSs. During the patient's 51-month follow-up, no LAL recurrence, tumor development, infiltration, and fibrogenesis were observed. Case 2. A female patient in her 70s had bullae associated with combined pulmonary fibrosis and emphysema (CPFE). Thoracoscopic bullectomy of the left lower lobe was performed, and the major LALs were closed intraoperatively with a bio-artificial pleura consisting of a total of eight DFSs. She was readmitted for contralateral pneumonia 2 months after surgery. During a follow-up period of 82 months, no LAL recurrence and tumor development was observed in the operated left lung. However, chest CT revealed slowly progressing CPFE lesions. This report of two cases demonstrated the mid-term safety of bio-artificial pleural transplantation using cultured autologous DFS for pleural injury.
2017-08-05 | Pulmonary CCR2+CD4+T cells are immune regulatory and attenuate lung fibrosis development
Animal models have suggested that CCR2-dependent signalling contributes to the pathogenesis of pulmonary fibrosis, but global blockade of CCL2 failed to improve the clinical course of patients with lung fibrosis. However, as levels of CCR2+CD4+ T cells in paediatric lung fibrosis had previously been found to be increased, correlating with clinical symptoms, we hypothesised that distinct CCR2+ cell populations might either increase or decrease disease pathogenesis depending on their subtype.To investigate the role of CCR2+CD4+ T cells in experimental lung fibrosis and in patients with idiopathic pulmonary fibrosis and other fibrosis.Pulmonary CCR2+CD4+ T cells were analysed using flow cytometry and mRNA profiling, followed by in silico pathway analysis, in vitro assays and adoptive transfer experiments.Frequencies of CCR2+CD4+ T cells were increased in experimental fibrosis-specifically the CD62L-CD44+ effector memory T cell phenotype, displaying a distinct chemokine receptor profile. mRNA profiling of isolated CCR2+CD4+ T cells from fibrotic lungs suggested immune regulatory functions, a finding that was confirmed in vitro using suppressor assays. Importantly, adoptive transfer of CCR2+CD4+ T cells attenuated fibrosis development. The results were partly corroborated in patients with lung fibrosis, by showing higher percentages of Foxp3+ CD25+ cells within bronchoalveolar lavage fluid CCR2+CD4+ T cells as compared with CCR2-CD4+ T cells.Pulmonary CCR2+CD4+ T cells are immunosuppressive, and could attenuate lung inflammation and fibrosis. Therapeutic strategies completely abrogating CCR2-dependent signalling will therefore also eliminate cell populations with protective roles in fibrotic lung disease. This emphasises the need for a detailed understanding of the functions of immune cell subsets in fibrotic lung disease.
other
2024-07-30 | Explicate molecular landscape of combined pulmonary fibrosis and emphysema through explainable artificial intelligence: a comprehensive analysis of ILD and COPD interactions using RNA from whole lung homogenates.
Combined pulmonary fibrosis and emphysema (CPFE) presents a unique challenge in respiratory disorders, merging features of interstitial lung disease (ILD) and chronic obstructive pulmonary disease (COPD). Using the random forest algorithm, our study thoroughly examines the molecular details of CPFE. Analyzing gene expression datasets from GSE47460 (ILD: 254, COPD: 220, control: 108), we identify key genes namely ADRB2, CDH3, IRS2, MATN3, CD38, PDIA4, VEGFC, and among twenty others, crucial in airway regulation, lung function, and apoptosis, shaping the complex pathogenesis of CPFE. Additionally, miRNAs (hsa-mir-101-3p, hsa-mir-1343-3p, hsa-mir-27a-3p, and miR-16-5p) showcase regulatory impacts on CPFE-related molecular pathways. Our machine learning model unveils these intricate interactions, offering a comprehensive insight into CPFE's molecular mechanisms. This research not only pinpoints potential therapeutic targets and biomarkers but also opens avenues for innovative approaches in managing CPFE, linking ILD and COPD within this complex respiratory condition.
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