RARE DISEASE
High altitude pulmonary edema
High altitude pulmonary edema
High altitude pulmonary edema
Synonyms: HAPE
Synonyms: HAPE
Synonyms: HAPE
Drug discovery
2
drugs
With orphan designations
Overview
High-altitude pulmonary edema (HAPE) is a life-threatening, non-cardiogenic pulmonary edema caused by rapid ascent to altitudes >2,500 meters. Pathophysiology involves exaggerated hypoxic pulmonary vasoconstriction, leading to elevated pulmonary artery pressure, capillary stress failure, and protein-rich fluid leakage into alveoli. Symptoms include dyspnea at rest, productive cough, cyanosis, and rales. Untreated, mortality exceeds 50% due to hypoxemia and respiratory failure [1][2][16].
Therapies
Immediate descent (500–1,000m) and supplemental oxygen to maintain SpO₂ ≥90% [2][16].
Pharmacotherapy: Nifedipine (30mg SR BID) or PDE5 inhibitors (e.g., sildenafil 50mg TID) for vasodilation; dexamethasone (8mg BID) in severe cases [3][8][9].
Portable hyperbaric chambers (Gamow Bag®) as temporizing measures in remote settings [1][2].
Categories: rare respiratory diseases
Research Papers
528 drug discovery papers about High altitude pulmonary edema, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
528 drug discovery papers about High altitude pulmonary edema, with 2 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-07-08 | High-Altitude Oxygenation: A Comprehensive Review of Physiological Mechanisms, Clinical Applications, and Emerging Therapeutic Strategies in Hypobaric Environments
High-altitude oxygenation represents a critical physiological and therapeutic intervention designed to mitigate the profound challenges posed by hypobaric hypoxia in elevated terrestrial environments. This comprehensive review examines the fundamental pathophysiological mechanisms underlying high-altitude illness, explores the diagnostic and therapeutic approaches available for prevention and management, and evaluates emerging strategies for optimizing oxygen delivery in extreme environments. The progressive reduction in barometric pressure with increasing elevation diminishes the partial pressure of inspired oxygen, precipitating a cascade of physiological responses that may culminate in acute mountain sickness, high-altitude pulmonary edema, or high-altitude cerebral edema. The International Society for Mountain Medicine categorizes high-altitude environments into three distinct tiers—high (1,500-3,500 m), very high (3,500-5,500 m), and extreme (≥5,500 m)—each corresponding to progressively diminished oxygen availability and escalating physiological challenge. Recent advances in molecular genetics have elucidated specific mitochondrial DNA haplogroups and nuclear gene variants, including EPAS1, EGLN1, and NOS3, that modulate individual susceptibility to altitude illness, revealing evolutionary adaptations in high-altitude populations. Diagnostic capabilities have been enhanced through point-of-care ultrasound, optic nerve sheath diameter measurement, and wearable oximetry technologies, facilitating early detection in remote settings. Therapeutic approaches encompass pharmacological interventions—predominantly acetazolamide, dexamethasone, and emerging phytochemical agents—alongside nonpharmacological strategies including supplemental oxygen, portable hyperbaric chambers, and auto-positive end-expiratory pressure techniques. Interprofessional collaboration, augmented by telemedicine platforms and continuous physiologic monitoring, remains essential for optimizing outcomes in high-altitude environments. This review synthesizes current evidence to provide a framework for understanding the pathophysiology, diagnosis, prevention, and treatment of high-altitude illness, while identifying promising directions for future research and clinical practice.
2026-06-30 | Cognitive-behavioral therapy in high-altitude respiratory care: Critical considerations for physiological interpretation
High-altitude respiratory diseases, characterized by hypoxia-induced complications such as pulmonary edema and chronic bronchitis, present critical challenges to both physical and mental health in vulnerable populations. The recent study by Meng et al demonstrates that integrating cognitive-behavioral therapy (CBT) with standard care significantly improves anxiety levels and sleep quality in affected patients. These key findings hold direct implications for advancing respiratory management in hypoxic environments. Meng et al ’s observation of reduced serum hypoxia biomarkers (hypoxia-inducible factor-1α and erythropoietin) further suggests potential enhancements in physiological adaptation. However, the interpretation of these biomarker changes as evidence of improved hypoxia tolerance requires cautious examination. The study’s reliance on indirect indicators fails to establish whether CBT’s benefits stem primarily from psychological modulation or genuine cellular adaptation. Furthermore, the 5-day intervention window coincides with the half-life of erythropoietin, raising questions about the durability of these effects in the context of hypoxic acclimatization, which typically requires weeks to months. To resolve these ambiguities, future studies should prioritize longitudinal designs tracking both respiratory function and molecular biomarkers over clinically relevant timeframes. Integrating CBT with objective pulmonary assessments would clarify its role in optimizing oxygen utilization pathways. Such advances could refine targeted interventions for high-altitude respiratory rehabilitation, ultimately strengthening evidence-based care for this unique patient population.
2026-06-12 | Multi-omics analysis of genetic drivers linking aortic stenosis and left ventricular diastolic dysfunction in heart failure.
Aortic stenosis (AS) and left ventricular diastolic dysfunction (LVDD) often coexist in heart failure (HF), but the mechanisms linking them remain unclear. While AS increases afterload and promotes myocardial stiffening, emerging AI-based evidence suggests LVDD can precede the development of AS or progress simultaneously, indicating shared upstream mechanobiological and inflammatory drivers. This study explores the genetic contributors connecting AS and LVDD to identify early molecular markers and convergent pathways in HF. We analyzed Whole Genome Sequence (WGS) and RNA-seq data of the HF patients, generated using their Peripheral Blood Mononuclear Cells (PBMCs) samples. Overall bioinformatics analysis was divided into two modules, 1) gene variant and annotation analysis, and 2) gene expression and enrichment analysis. We utilized our peer review published and open source WGS and RNA-seq pipelines to process Next-Generation Sequence (NGS) data. Furthermore, we performed bioinformatics and statistical analysis to identify genetic variations, expressions, regulation, enrichments, and disease annotations. We identified genetic markers uniquely associated with AS, LVDD, and shared between them. Furthermore, we report genes with significant expression, and functional variations, and discuss their relationship with other cardiovascular diseases (e.g. Vascular and Cardiac Stiffness, Aortic Dissection, Left Atrial Enlargement, Left Ventricular Hypertrophy, Outflow Tract Obstructive Defects, Non-Compaction Coronary Artery Disease, Arrhythmia, Congestive Heart Failure, and Hypertrophic, Dilated, and Ischemic Cardiomyopathy) and non-cardiovascular diseases (non-CVDs) (e.g. Type 1 Diabetes, Diabetic Nephropathy, Skeletal Anomalies, Rheumatoid Arthritis, Atypical Femoral Fractures, Chronic Kidney Disease, Dehydrated Hereditary Stomatocytosis, Schizophrenia, Varicose Veins, High-Altitude Pulmonary Edema, Periodontitis, and Respiratory Disorder) including multiple cancer types (e.g. Breast, Lung, Colorectal, Pancreatic, Hypopharyngeal, Acute Lymphoblastic, and Oral Squamous Cell Carcinomas) and rare genetic disorders (e.g. Hypophosphatasia, Multiple Sclerosis, Campomelic Dysplasia, Lymphatic Malformation). We validated our results through state of science literature, gene-disease annotation databases, and electronic health records. AS and LVDD share both clinical and genomic associations, with overlapping genetic drivers that are enriched in pathways related to inflammation, extracellular matrix remodeling, and vascular stress responses. This work supports the potential of blood-based multi-omics profiling to uncover early, systemic molecular signals of cardiac dysfunction and lays the groundwork for future tissue-specific studies to guide precision diagnosis, risk stratification, and targeted therapeutics in HF.
2026-06-01 | High-altitude adaptation and associated mortality risk in relocated Holstein cattle
This study evaluated the adaptability of Holstein cattle to high-altitude environments following their relocation from low-altitude regions (<500 m) to the Qinghai-Tibet Plateau (>3,500 m) and identified risk factors associated with physiological maladaptation. A cohort of 1,000 healthy Holstein heifers was relocated and monitored over a 5-mo period, with observations focusing on mortality rates, clinical symptoms, hematological parameters, and pulmonary arterial pressure. Postmortem examinations and 16S rRNA sequencing of gut microbiota were conducted. The observed mortality rate was 30.5%. The predominant clinical manifestations included anorexia, edema, pulmonary hypertension, and hematological abnormalities. Postmortem analyses confirmed that right-sided heart failure secondary to hypoxic pulmonary hypertension was the principal cause of mortality. Holstein heifers that survived exhibited a higher relative abundance of bacteria associated with energy metabolism, such as Tenericutes, TM7, Clostridium, Treponema, and Paludibacter, in comparison to those that did not survive. Immediate relocation to elevations exceeding 3,500 m presents significant risks. To mitigate these risks, it is recommended to restrict altitude transitions to 1,500 m or less. An alternative approach involves implementing a gradual acclimatization strategy, which includes adaptive rearing at elevations of 2,500 m or lower for a minimum period of 5 mo, alongside specific dietary modifications and probiotic supplementation. These findings provide both practical and theoretical foundations for the effective health management of Holstein heifers in high-altitude environments.
2026-05-30 | Glucocorticoid Programming of Erythrocyte Hypoxic Memory Enables Rapid High-Altitude Acclimatization
ABSTRACT Background Rapid ascent to high altitude causes acute mountain sickness (AMS) and life-threatening pulmonary/cerebral edema, yet no prophylaxis enables immediate acclimatization. Intermittent hypoxia training (IHT) establishes a “hypoxic memory” that accelerates adaptation, to high altitude, but its cellular and molecular basis remains undefined, precluding effective pharmacological strategies. Methods A human cohort of 18 sea-level inhibitants was equally divided into two groups, one group received IHT prior to ascent to 3,500 meters, the other group did not. Multi-omics profiling of erythrocytes and plasma, along with isotopic glucose tracing, was employed to examine the metabolic effects of IHT upon high altitude acclimatization. Preclinical studies with genetically engineered mice were used to further define the molecular and metabolic basis of IHT-induced hypoxic memory allowing rapid acclimatization to high altitude. Results Metabolomics revealed glucocorticoids as previously unrecognized endogenous erythroid hypoxic memory orchestrators induced by IHT that negatively correlated with AMS severity. Lipidomics and isotopic glucose tracing demonstrated that glucocorticoid signaling via the glucocorticoid receptor (GR) coordinately enhanced glucose metabolism and activated sphingosine kinase-1 (SPHK1)-driven sphingosine-1-phosphate (S1P) synthesis, pre-conditioning erythrocyte oxygen unloading and antioxidant capacity. Glucocorticoid supplementation enhanced erythrocyte SPHK1 activation and oxygen delivery, counteracting multi-tissue hypoxia and pulmonary and renal neutrophil infiltration. Conversely, erythrocyte-specific Sphk1 ablation abolished glucocorticoid-induced S1P production causing severe tissue hypoxia and exaggerated pulmonary neutrophil infiltration. Conclusions We establish a new function of glucocorticoids in erythrocyte metabolic plasticity to enhance oxygen delivery as a hypoxic memory mechanism for rapid adaptation to high altitude. This previously unrecognized GR-mediated reprograming of glucose and sphingolipid metabolism offers a transformative precision pharmacologic strategy for high altitude preconditioning, high altitude emergencies and hypoxia-driven diseases.
proteins
2026-06-16 | PARK7 alleviates high-altitude pulmonary edema by suppressing BACH1 to attenuate lipid peroxidation-driven pro-inflammatory skewing of macrophages.
With the steady increase in global travel, mountaineering, and logistics at extreme elevations, high-altitude pulmonary edema (HAPE) remains a life-threatening emergency with mortality rates reaching up to 50% if untreated. Current clinical management relies heavily on rapid descent or supplemental oxygen, which are often logistically unfeasible in remote areas, while existing pharmacological interventions face challenges regarding efficacy and side effects. There is an urgent need to identify the fundamental molecular switches that translate hypobaric hypoxia into the catastrophic "cytokine storm" and barrier failure characteristic of HAPE. This study investigates the role of the antioxidant protein parkinsonism associated deglycase (PARK7) as a potential therapeutic target. A mouse model simulating 6000 m altitude (72 h) and CoCl₂-induced hypoxia in MLE-12 and RAW264.7 cells were used. PARK7 expression in lung tissue and hypoxic cells was analyzed via RNA-seq, qPCR, and western blot analyses. Lung-specific PARK7 and Bach1 overexpression or knockdown was achieved using AAV9-mediated intratracheal instillation. Pulmonary edema, vascular permeability, histopathology, and ultrastructure were assessed. Lipid peroxidation and M1 macrophage polarization (F4/80⁺iNOS⁺) were evaluated using C11-BODIPY staining, 4-HNE immunohistochemistry, and flow cytometry. PARK7 expression was markedly reduced in HAPE lungs and hypoxic cells. Restoration of PARK7 alleviated pulmonary edema, barrier dysfunction, mitochondrial damage, and inflammatory cell infiltration, primarily macrophages. Mechanistically, PARK7 suppressed lipid peroxidation, reducing MDA and 4-HNE accumulation, thereby blocking pro-inflammatory M1 macrophage polarization. Hypoxia stabilized the antioxidant repressor BTB and CNC Homology 1 (BACH1), whereas PARK7 inhibited BACH1 to exert its protective effect. Re-expression of BACH1 negated PARK7's benefits, restoring lipid peroxidation and M1 macrophage infiltration. This study suggests PARK7 as a key protective factor during HAPE progression. PARK7 inhibits lipid peroxidation through downregulation of BACH1, thereby preventing pro-inflammatory M1 polarization of macrophages and ultimately preserving alveolar-capillary barrier integrity. Targeting the PARK7-BACH1 axis may offer a novel therapeutic strategy for the prevention and treatment of HAPE.
2026-05-12 | Ferroptosis, orchestrated by GPX4 downregulation, serves as a critical mediator of neutrophil extracellular trap-driven pathology in hypoxic pulmonary edema.
This study explores the contribution of ferroptosis, a tightly regulated form of cell death, to the development of high-altitude pulmonary edema (HAPE) under hypoxic conditions. We focused on the central ferroptosis regulator glutathione peroxidase 4 (GPX4) and its interaction with neutrophil extracellular trap (NET) formation. Utilizing a murine model of high-altitude hypoxia and in vitro hypoxia/reoxygenation models, we employed a multi-omics approach to map the molecular landscape of HAPE. Transcriptomic and metabolomic analyses of lung tissues confirmed a significant downregulation of GPX4 and a marked activation of ferroptosis-related pathways. Single-cell RNA sequencing identified pulmonary endothelial cells as a key site for this dysregulation, showing decreased GPX4 alongside upregulation of pro-ferroptotic factors. Functional validation demonstrated that GPX4 deficiency in human pulmonary microvascular endothelial cells exacerbated reactive oxygen species accumulation, ferroptosis, and subsequent NET formation. Conversely, GPX4 overexpression effectively mitigated these cytotoxic effects. Furthermore, we elucidated that GPX4 modulates NET formation through key signaling pathways, including Nrf2 nuclear translocation, ERK1/2 and NF-κB phosphorylation, and the HMGB1-TLR4/MyD88 axis. In vivo, therapeutic augmentation of GPX4 levels attenuated pulmonary edema, improved lung function, and suppressed markers of both ferroptosis and NETosis. Our findings establish a novel pathogenic cascade in HAPE where hypoxia-induced GPX4 suppression promotes ferroptotic cell death, which in turn drives NET-associated inflammation, identifying GPX4 as a critical therapeutic target for preventing this condition.
2026-04-09 | Hypobaric hypoxia can lead to an increase in lung dendritic cells and promote T-cell immunosuppression, thereby preventing the excessive progression of high-altitude pulmonary edema.
More and more studies have shown that the immune system regulates the body's response to hypoxic stress. Immune dysregulation may increase vascular permeability, leading to edema and tissue damage, thereby causing high-altitude pulmonary edema (HAPE). Here, we found an increase in lung dendritic cells (DCs) in rat and mouse models of HAPE, but its specific role in HAPE remains unclear. In this study, the function of rat lung DCs and its impact on T cells were analyzed through single-cell sequencing, flow cytometry and in vitro co-culture. Then, we confirmed its effects on DCs and T cells by intraperitoneal injection of TNF-α or by using TNF-α -deficient mice. Finally, we evaluated the role of CD4+ T cells in the progression of HAPE by eliminating CD4 in mice with neutralizing antibodies. We demonstrated that hypobaric hypoxia (HH) induced the recruitment of pulmonary DCs in rats and promoted the immunosuppression of T cells (especially CD4+ T cells). By injecting TNF-α into rats, we found that the number of DC and CD4+CD25+ T cells in the lung of HH rats slightly decreased. Interestingly, in vivo injection of TNF-α actually led to the production of less TNF-α by CD4+ T cells in the lung of HH rats. In the HAPE mouse model, the proportion and the number of DC in the lung of TNF-α -deficient mice were significantly increased, and the level of IL-6 production was significantly decreased. Furthermore, the proportion of CD4+CD25+ T cells in the lung of TNF-α -deficient mice increased significantly. By eliminating CD4 in mice with neutralizing antibodies, we found that CD4+ T cells play a protective role in HAPE. Our results indicate that hypoxia induces the recruitment of DCs in the lung and mediates the differentiation of T cells into immunosuppressive phenotypes in HAPE rat and mouse models, thereby delaying the progression of HAPE. These findings highlight the potential approach of using immune regulation as a treatment for HAPE.
2024-01-15 | B2M is a Biomarker Associated With Immune Infiltration In High Altitude Pulmonary Edema.
High altitude pulmonary edema (HAPE) is a serious mountain sickness with certain mortality. Its early diagnosis is very important. However, the mechanism of its onset and progression is still controversial. This study aimed to analyze the HAPE occurrence and development mechanism and search for prospective biomarkers in peripheral blood. The difference genes (DEGs) of the Control group and the HAPE group were enriched by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and then GSEA analysis was performed. After identifying the immune-related hub genes, QPCR was used to verify and analyze the hub gene function and diagnostic value with single-gene GSEA and ROC curves, and the drugs that acted on the hub gene was found in the CTD database. Immune infiltration and its association with the hub genes were analyzed using CIBERSORT. Finally, WGCNA was employed to investigate immune invasion cells' significantly related gene modules, following enrichment analysis of their GO and KEGG. The dataset enrichment analysis, immune invasion analysis and WGCNA analysis showed that the occurrence and early progression of HAPE were unrelated to inflammation. The hub genes associated with immunity obtained with MCODE algorithm of Cytoscape were JAK2 and B2M.. RT-qPCR and ROC curves confirmed that the hub gene B2M was a specific biomarker of HAPE and had diagnostic value, and single-gene GSEA analysis confirmed that it participated in MHC I molecule-mediated antigen presentation ability decreased, resulting in reduced immunity. Occurrence and early progression of high altitude pulmonary edema may not be related to inflammation. B2M may be a new clinical potential biomarker for HAPE for early diagnosis and therapeutic evaluation as well as therapeutic targets, and its decrease may be related to reduced immunity due to reduced ability of MCH I to participate in antigen submission.
2021-02-24 | D4F prophylaxis enables redox and energy homeostasis while preventing inflammation during hypoxia exposure.
Apo-A1 is correlated with conditions like hyperlipidemia, cardiovascular diseases, high altitude pulmonary edema and etc. where hypoxia constitutes an important facet.Hypoxia causes oxidative stress, vaso-destructive and inflammatory outcomes.Apo-A1 is reported to have vasoprotective, anti-oxidative, anti-apoptotic, and anti-inflammatory effects. However, effects of Apo-A1 augmentation during hypoxia exposure are unknown.In this study, we investigated the effects of exogenously supplementing Apo-A1-mimetic peptide on SD rats during hypoxia exposure. For easing the processes of delivery, absorption and bio-availability, Apo-A1 mimetic peptide D4F was used. The rats were given 10 mg/kg BW dose (i.p.) of D4F for 7 days and then exposed to hypoxia. D4F was observed to attenuate both oxidative stress and inflammation during hypoxic exposure. D4F improved energy homeostasis during hypoxic exposure. D4F did not affect HIF-1a levels during hypoxia but increased MnSOD levels while decreasing CRP and Apo-B levels. D4F showed promise as a prophylactic against hypoxia exposure.
oligonucleotides
2025-01-23 | Biomimetic exosome harnessing exosomal lipidomics and functional proteins for PEDF-pDNA delivery in high altitude pulmonary edema intervention.
In the realm of gene therapy, given the exceptional performance of native exosomes, researchers have redirected their innovative focus towards exosome-mimetic nanovesicles (EMNs); however, the current design of most EMNs relies heavily on native cells or their components, inevitably introducing inter-batch variability issues and posing significant challenges for quality control. To overcome the excessive reliance on native cellular components, this study adopts a unique approach by precisely mimicking the lipid composition of exosomes and innovatively incorporating histone components to recapitulate the gene transfer characteristics of exosomes. We selected sphingomyelin (SM), phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE), and cholesterol as the lipid components, and employed the double emulsion method to prepare biomimetic exosomes carrying histone A and PEDF-DNA plasmids (His-pDNA@EMNs). These vesicles exhibited an ideal particle size (102 ± 2 nm) and Zeta potential (-20 ± 2 mV) with cup-shaped structure, similar to native exosomes. Compared with the commercial gene transfection reagent Lipo6000, His-pDNA@EMNs significantly improved the transfection efficiency of the PEDF gene in HUVEC cells by 18.74 % while significantly reducing cytotoxicity, demonstrating their superior biocompatibility and efficiency. Mechanism exploration revealed that the lipid composition of these EMNs delicately promoted each step of gene delivery: PC facilitated efficient cellular uptake, the synergistic effect of PE and PS significantly enhanced lysosomal escape ability, and the specific combination of PS and SM assisted vesicles in penetrating into the nucleus. Notably, EMNs escaped from lysosomes in their intact form through a local membrane fusion mechanism. Further cellular and animal experiments fully verified that His-pDNA@EMNs could effectively enhance PEDF protein expression both in vitro and in vivo, effectively inhibiting hypoxia-induced vascular remodeling and endothelial injury, providing a novel and effective intervention of high-altitude pulmonary edema (HAPE). In summary, this study not only demonstrates the feasibility of preparing efficient gene delivery vectors by mimicking the functions of native exosomes with synthetic phospholipids and histones, but also opens up a new path for the development of gene therapy vectors. His-pDNA@EMNs also provide a new strategy for the prevention of HAPE.
2024-07-15 | Long noncoding RNA ANRIL alleviates hypoxia-induced pulmonary microvascular endothelial cell damage.
High-altitude pulmonary oedema (HAPE) is a form of noncardiogenic pulmonary oedema. Studies have found that long noncoding RNA (lncRNA) plays an important role in HAPE. ANRIL is significant in pulmonary illnesses, which implies that alterations in ANRIL expression levels may be involved in the beginning and development of HAPE. However, the specific mechanism is indistinct. The present study is meant to explore the effect and mechanism of ANRIL on hypoxic-induced injury of pulmonary microvascular endothelial cells (PMEVCs). In the hypoxic model of PMVECs, overexpression of ANRIL or knockdown of miR-181c-5p was performed to assess cell proliferation, apoptosis, and migration. Furthermore, the levels of apoptosis-related proteins, inflammatory factors, and vascular active factors were also measured. The results showed that, after 24 h of hypoxia, PMVECs proliferation and migration were suppressed in comparison to the control group, along with an increase in apoptosis, a decrease in the expression of ANRIL, and an increase in the expression of miR-181c-5p (all p < .05). The damage caused by hypoxia in PMVECs can be lessened by overexpressing ANRIL, which also inhibits the production of TNF-α, iNOS, and VEGF as well as BAX and cleaved caspase-3 (all p < .05). Further experimental results showed that overexpression of ANRIL and knockdown of miR-181c-5p had the same protection against hypoxic injury in PMVECs (all p < .05). Our study suggests that ANRIL may prevent hypoxia injury to PMVECs in HAPE through the negative regulation of miR-181c-5p.
2021-11-08 | Novel HIF-1-target gene isthmin1 contributes to hypoxia-induced hyperpermeability of pulmonary microvascular endothelial cells monolayers.
Hypoxia-induced pulmonary microvascular endothelial cell (PMVEC) monolayers hyperpermeability is vital for vascular leakage, which participates in vascular diseases, such as acute lung injury (ALI) and high-altitude pulmonary edema (HAPE). We previously observed that PMVEC permeability was markedly elevated in hypoxia when cocultured with primary type II alveolar epithelial cells (AECII) in which isthmin1 (ISM1) was highly upregulated. However, whether the upregulation of ISM1 plays a role in hypoxia-induced PMVEC hyperpermeability is unclear. In this study, we assessed the role of AECII-derived ISM1 in hypoxia-induced PMVEC hyperpermeability with an AECII/PMVEC coculture system and uncovered the underlying mechanism whereby hypoxia stimulates ISM1 gene expression. We found that ISM1 gene expression was upregulated in cultured AECII cells exposed to hypoxia (3% O2) and that AECII-derived ISM1 participated in hypoxia-induced hyperpermeability of PMVEC monolayers, as small interference RNA (siRNA)-mediated knockdown of ISM1 in AECII markedly attenuated the increase in PMVEC permeability in coculture system under hypoxia. In addition, we confirmed that ISM1 was regulated by hypoxia-inducible factor-1α (HIF1α) according to the evidence that silencing of HIF1α inhibited the hypoxia-mediated upregulation of ISM1. Mechanismly, overexpression of HIF1α transcriptionally activated ISM1 gene expression by directly binding to the conserved regulatory elements upstream of the ism1 locus. We identified a novel HIF-1-target gene ISM1, which involves in hyperpermeability of pulmonary microvascular endothelial cell monolayers under hypoxia. Our in vitro cell experiments implied that the upregulated ISM1 derived from alveolar epithelium might be a vital modulator in hypoxia-induced endothelial hyperpermeability and thereby implicates with hypoxic pulmonary-related diseases.
2021-02-22 | Network Biology led identification of critical miRNA modules for High Altitude hypoxia and their potential as dietary supplements
Abstract Early ascent to high altitude can cause severe damage to body functions and may lead to many fatal high-altitude disorders. To cope up with such conditions, the human body undergoes physiological and biochemical changes in order to adapt to extreme environmental conditions at high altitudes. Several microRNAs (miRNAs), Transcription Factors (TFs), and genes have been studied separately for their role in early adaptive molecular responses. We hypothesize that network analysis of miRNA-TF-gene co-regulatory networks of circulatory miRNAs (CmiRNAs) which are differentially expressed at high altitudes could reveal a complex regulatory functional module that might be controlling molecular adaptive responses at high altitude. A comprehensive and non-redundant list of differentially expressed human CmiRNAs during high altitude ascent was collated and 470 Feed-Forward Loops (FFLs) tripartite motifs were identified in the miRNA-TF-gene co-regulatory networks. Network analysis and K-means clustering identified 11 biologically overrepresented FFLs regulated by 8 miRNAs hsa-miR-335-5p, hsa-miR-26a-1-3p, hsa-miR-210-3p, hsa-miR-193b-3p, hsa-miR-17-5p, hsa-miR-16-5p, hsa-miR-5582-5p and hsa-miR-130a-3p. Pathway enrichment identified metabolism and inflammation as important hallmark responses responsible for high altitude adaptation. These miRNAs were evaluated for their supplementation from dietary sources. Phylogenetic analysis with 4 other mammalian and non-mammalian species showed that Bos taurus (cattle) milk could be a possible source of these dietary miRNAs. Exogenous miRNAs bta-mir-16-1, bta-mir-130a, bta-miR-335, and bta-miR-210 have >95% of sequence similarity and could become potential dietary miRNAs candidates. The sequence, structural properties, and high AGO2 binding efficiency of all these exogenous miRNAs show good serum stability and cellular uptake possibility in the mammalian host. Bta-miR-210 with highest Minimal Folding free Energy Index (MFEI) and highest Atomic Contact Energy (ACE) with AGO2 has the best potential to be a dietary supplement.
2020-11-20 | Susceptibility to high-altitude pulmonary edema is associated with circulating miRNA levels under hypobaric hypoxia conditions.
Hypobaric hypoxia poses stress to sojourners traveling to high-altitude. A cascade of physiological changes occurs to cope with or adapt to hypobaric hypoxia. However, an insufficient physiological response to the hypoxic condition resulting from imbalanced vascular homeostasis pathways results in high-altitude pulmonary edema (HAPE). The present study aims to identify the implication of miRNAs associating with HAPE and adaptation. We analyzed the expression of 1,113 miRNAs in HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), and highland natives (HLs). Based on miRNA profiling and in silico analyses, miR-124-3p emerged relevantly. We observed a significant overexpression of miR-124-3p in HAPE-p. In silico analyses revealed a direct interaction of miR-124-3p with vascular homeostasis and hypoxia-associated genes NOS3 (endothelial nitric oxide synthase), Apelin, and ETS1 (V-Ets avian erythroblastosis virus E2 oncogene homolog 1). Moreover, the transcript and biolevel expression of these genes were significantly decreased in HAPE-p when compared with HAPE-f or HLs. Our in vitro analysis in human umbilical vein endothelial cells demonstrated a significant knockdown of these genes both at transcript and protein levels following miR-124-3p overexpression. Conclusively, our results showed that miR-124-3p might play a plausible role in HAPE pathophysiology by inhibiting the expression of NOS3, Apelin, and ETS1.
cell therapies
2026-05-04 | Prophylactic Nebulized hUC-MSC-EVs Attenuate Hypobaric Hypoxia-Induced Lung Injury via Alveolar-Capillary Barrier Stabilization and TEK/Tie2 Preservation.
Background/Objectives: High-altitude pulmonary edema (HAPE) remains a serious condition with limited preventive options. This study evaluated the prophylactic protective effects of nebulized human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) in a rat model of hypobaric hypoxia-induced lung injury and explored potential mechanistic clues, with a focus on oxidative stress and TEK/Tie2 signaling. Methods: Rats were exposed to hypobaric hypoxia (47 kPa; 9.7% O2) for 72 h and received prophylactic nebulized hUC-MSC-EVs (300 μg/rat). Lung injury was evaluated by histopathology, wet-to-dry ratio, and bronchoalveolar lavage fluid (BALF) protein concentration. Invasive pulmonary function indices were measured using a forced oscillation system. BALF cytokines (TNF-α, IL-6, and IL-10), reactive oxygen species (ROS), and TEK/Tie2 expression in lung tissue were assessed. In addition, transcriptome sequencing (RNA-seq) was performed to characterize global transcriptional changes. N-acetylcysteine (NAC), a classical antioxidant, was included as an auxiliary mechanistic intervention to assess the association of ROS with TEK/Tie2 changes. Results: Compared with hypoxia controls, prophylactic nebulized hUC-MSC-EVs reduced histopathological injury, pulmonary edema, and barrier leakage, and improved pulmonary function indices. hUC-MSC-EV intervention also attenuated inflammatory responses in BALF, with decreased TNF-α and IL-6 and increased IL-10. Hypobaric hypoxia increased ROS accumulation and decreased TEK/Tie2 expression, whereas nebulized hUC-MSC-EVs reduced ROS and partially preserved TEK/Tie2 expression. NAC pretreatment similarly reduced ROS and was accompanied by Tie2 preservation. Conclusions: Prophylactic nebulized hUC-MSC-EVs mitigated hypobaric hypoxia-induced lung injury, accompanied by reduced oxidative stress, improved vascular barrier integrity, and preservation of TEK/Tie2 expression. These findings support nebulized hUC-MSC-EVs as a potential lung-targeted prophylactic strategy for hypobaric hypoxia-induced lung injury and suggest that ROS imbalance may be associated with Tie2 preservation.
2026-03-18 | Scalable Production of Multi-Source Hybrid Biomimetic Exosomes Co-Loaded with Therapeutic Plasmids for Treatment of High-Altitude Pulmonary Edema.
Exosomes show therapeutic promise but face limitations in simultaneous targeting and potency. While hybrid exosome strategies combining multiple cell components can address this, current methods rely on native exosome extraction and drug loading, suffering from low yield and encapsulation efficiency. We developed a biological origin-based hybrid biomimetic exosome (BOB-HBE) platform that synthetically assembles exosomes using parent cell-derived components through a water/oil/water emulsion method, overcoming production bottlenecks. For high-altitude pulmonary edema (HAPE) treatment, we engineered hybrid exosomes combining: (1) vascular endothelial cell membranes for lung targeting, (2) mesenchymal stem cell factors for regeneration, and (3) eNOS-encoding plasmid DNA to restore nitric oxide signaling. The BOB-HBE platform achieved >150-fold higher production yield than natural exosome isolation while enhancing pulmonary endothelial specificity. In HAPE models, these hybrid exosomes demonstrated triple therapeutic effects: restoring NO bioavailability, inhibiting pathogenic HIF-1α/TGF/Smad1/5 signaling, and preventing endothelial-mesenchymal transition and vascular remodeling. Consequently, they significantly attenuated HAPE progression by addressing both molecular pathways and tissue-level pathology. This study establishes a scalable platform for constructing multifunctional exosome mimetics that maintain native exosome advantages while solving key production challenges. The cell-origin-informed design strategy offers a versatile approach for targeted therapy in pulmonary and vascular disorders, with potential clinical translation advantages.
2025-02-05 | Small extracellular vesicles derived from miRNA-486 overexpressed dental pulp stem cells mitigate high altitude pulmonary edema through PTEN/PI3K/AKT/eNOS pathway.
High altitude pulmonary edema (HAPE) is a life-threatening, non-cardiogenic pulmonary edema characterized by rapid onset and high mortality. Extracellular vesicles of mesenchymal stem cells are used in the treatment of a variety of lung diseases, but their use in HAPE remains underreported. This study explores the therapeutic potential of miRNA-486 modified extracellular vesicles from dental pulp stem cells (sEVmiR-486) against HAPE, aiming to decipher the associated molecular mechanisms. The rat HAPE model was established by exposing subjects to a simulated high-altitude, low-oxygen environment within a specialized chamber. The HAPE-afflicted rats received sEVNull and sEVmiR-486 intravenously, and the therapeutic effect was assessed through histopathological analysis, pulmonary artery pressure, lung water content, as well as markers of oxidative stress and inflammation. To supplement in vivo findings, pulmonary microvascular endothelial cells (PMVEC) were stressed with cobalt chloride to emulate hypoxic damage, and then treated with sEVNull and sEVmiR-486 to unravel the mechanism of action. The sEVNull mitigated pathological changes in the lungs, reduced pulmonary artery pressure and lung water content, and alleviated oxidative stress and inflammatory responses in cases of HAPE. Moreover, sEVNull enhanced vascular reactivity and restored pulmonary permeability and tight junction integrity, these effects were intensified by miRNA-486 overexpression. Notably, sEVmiR-486 attenuated oxidative damage in hypoxic PMVEC cells by modulating the PTEN/PI3K/Akt/eNOS signaling pathway. miRNA-486 fortified DPSC-sEVs intervention as a novel and potent treatment strategy for HAPE.
2025-01-28 | hUC-MSCs Prevent Acute High-Altitude Injury through Apoe/Pdgf-b/p-Erk1/2 Axis in Mice.
The hypobaric hypoxic atmosphere can cause adverse reactions or sickness. The purpose of this study was to explore the preventive effect and mechanism of human umbilical cord mesenchymal stem cells (hUC-MSCs) on acute pathological injury in mice exposed to high-altitude. We pretreated C57BL/6 mice with hUC-MSCs via the tail vein injection, and then the mice were subjected to hypobaric hypoxic conditions for five days. The effects of hUC-MSCs on the pathological injury of lung, heart, brain were assessed by biochemical analysis, histopathological testing, quantitative real-time polymerase chain reaction (qPCR), and western blot (WB). Further, transcriptome sequencing was used to screen for the potential therapeutic targets of hUC-MSCs in acute pathological injury, the identified signaling axis was characterized using Apoe-/- mice, qPCR and WB. hUC-MSCs administration notably prevented and relieved gastrointestinal symptoms and inflammation of lung and heart, increased blood oxygen saturation and serum superoxide dismutase (SOD) level, decreased serum malondialdehyde (MDA) level, rescued lung tissue injury and myocardial mitochondrial disorder, elevated nissl bodies number in brain tissue and reduced the degree of pulmonary and cerebral edema. Furthermore, hUC-MSCs pretreatment reversed the down-regulated Apoe and up-regulated Pdgf-b and p-Erk1/2 in the lung of hypobaric hypoxic mice. Thus, hUC-MSCs protected against acute pathological injury caused by hypobaric hypoxic condition via the Apoe/Pdgf-b/p-Erk1/2 axis, and the identified pathway was confirmed by the negative results of Apoe-/- mice. hUC-MSCs possess the preventive effect on acute pathological injury caused by hypobaric hypoxia environment at high-altitude.
2024-07-18 | Superoxide dismutase 1-modified dental pulp stem cells alleviate high-altitude pulmonary edema by inhibiting oxidative stress through the Nrf2/HO-1 pathway.
High-altitude pulmonary edema (HAPE) is a deadly form of altitude sickness, and there is no effective treatment for HAPE. Dental pulp stem cells (DPSCs) are a type of mesenchymal stem cell isolated from dental pulp tissues and possess various functions, such as anti-inflammatory and anti-oxidative stress. DPSCs have been used to treat a variety of diseases, but there are no studies on treating HAPE. In this study, Sprague-Dawley rats were exposed to acute low-pressure hypoxia to establish the HAPE model, and SOD1-modified DPSCs (DPSCsHiSOD1) were administered through the tail vein. Pulmonary arterial pressure, lung water content (LWC), total lung protein content of bronchoalveolar lavage fluid (BALF) and lung homogenates, oxidative stress, and inflammatory indicators were detected to evaluate the effects of DPSCsHiSOD1 on HAPE. Rat type II alveolar epithelial cells (RLE-6TN) were used to investigate the effects and mechanism of DPSCsHiSOD1 on hypoxia injury. We found that DPSCs could treat HAPE, and the effect was better than that of dexamethasone treatment. SOD1 modification could enhance the function of DPSCs in improving the structure of lung tissue, decreasing pulmonary arterial pressure and LWC, and reducing the total lung protein content of BALF and lung homogenates, through anti-oxidative stress and anti-inflammatory effects. Furthermore, we found that DPSCsHiSOD1 could protect RLE-6TN from hypoxic injury by reducing the accumulation of reactive oxygen species (ROS) and activating the Nrf2/HO-1 pathway. Our findings confirm that SOD1 modification could enhance the anti-oxidative stress ability of DPSCs through the Nrf2/HO-1 signalling pathway. DPSCs, especially DPSCsHiSOD1, could be a potential treatment for HAPE. Schematic diagram of the antioxidant stress mechanism of DPSCs in the treatment of high-altitude pulmonary edema. DPSCs can alleviate oxidative stress by releasing superoxide dismutase 1, thereby reducing ROS production and activating the Nrf2/HO-1 signalling pathway to ameliorate lung cell injury in HAPE.
other
2025-08-03 | Elevated cytokine levels in patients with High-altitude pulmonary edema.
Immunomodulation is integral to the body's adaptation to varying altitudes. Nevertheless, the effects of immune regulation on the onset of high-altitude pulmonary edema (HAPE) are not well understood. This research aimed to explore the influence of immune regulation on HAPE pathogenesis through the assessment of cytokine levels. We analyzed the cytokine profiles of 28 HAPE patients at high altitudes and compared them to 25 healthy individuals who had successfully acclimatized. The levels of seven cytokines released by T helper cells (Th)1/2/17, alongside monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-8, and IL-1β in serum, were quantified using cytometric bead array (CBA) technology. Our findings revealed significantly higher concentrations of IL-2, IL-10, and tumor necrosis factor (TNF) in the peripheral blood of HAPE patients when contrasted with those of healthy individuals (P < 0.001). A comprehensive analysis of these cytokines indicated a robust diagnostic capability for predicting HAPE, achieving an area under the curve (AUC) of 0.98. Conversely, no significant differences were observed in the levels of IL-6, IL-8, interferon-γ (IFN-γ), IL-4, IL-17 A, MCP-1, and IL-1β between the two cohorts. Elevated IL-2, IL-10, and TNF in HAPE patients underscore immune dysregulation as a disease driver. Clinically, these cytokines may guide risk prediction (IL-2-hypoxemia link) and targeted therapies (anti-TNF for vascular leakage). Future work should define hypoxia-specific cytokine networks, validate interventions in altitude cohorts, and integrate multi-omics to map immune-vascular crosstalk.
2023-09-20 | NLRC3 deficiency promotes hypoxia-induced pulmonary hypertension development via IKK/NF-κB p65/HIF-1α pathway.
Hypoxia-induced pulmonary hypertension is a subgroup of type 3 pulmonary hypertension (PH) with the recommended treatment limited to oxygen therapy and lacks potential therapeutic targets. To investigate the role of NLRC3 in hypoxia-induced PH and its potential mechanism, we first collected lung tissues of high-altitude pulmonary hypertension (HAPH) patients. Immunohistochemistry and immunofluorescence showed that NLRC3 was downregulated and was mainly co-localized with the smooth muscle cells of the pulmonary vessels in HAPH patients. Besides, we found that NLRC3 was also expressed in endothelial cells in HAPH patients for the first time. Then, wild type (WT) and NLRC3 knockout (NLRC3-/-) mice were used to construct hypoxia models and primary pulmonary arterial smooth muscle cells (PASMCs) of rats and endothelial cells were cultured for verification. Right heart catheterization and echocardiography suggested that NLRC3 knockout promoted right ventricular systolic pressure (RVSP) up-regulation, right ventricular hypertrophy and fibrosis in hypoxia-induced mice. This study first demonstrated that NLRC3 deficiency promoted hypoxia-stimulated PASMCs proliferation, Human umbilical vein endothelial cells (HUVECs) apoptosis, migration and inflammation through IKK/NF-κB p65/HIF-1α pathway in vitro and in vivo, further promoted vascular remodeling and PH progression, which provided a new target for the treatment of hypoxia-induced PH.
2004-12-01 | Pathogenesis of High Altitude Pulmonary Edema: Does Alveolar Epithelial Lining Fluid Vascular Endothelial Growth Factor Exacerbate Capillary Leak?
Kaner, Robert J., and Ronald G. Crystal. Pathogenesis of high altitude pulmonary edema: Does alveolar epithelial lining fluid vascular endothelial growth factor exacerbate capillary leak? High Alt. Med. Biol. 5:399–409, 2004.—Vascular endothelial growth factor (VEGF) is a potent mediator of capillary leak if it gains access to its receptors on the capillary endothelium. We have observed that there are high levels of VEGF compartmentalized in the alveolar epithelial lining fluid of normal humans at levels 500-fold greater than plasma. The potential for high altitude to result in compromise of alveolar epithelial tight junctions and experimental animal studies in which pulmonary edema is induced when VEGF is overexpressed in the alveolar epithelium, suggest a mechanism. We hypothesize that when the epithelial barrier is compromised at high altitude the normally high level of VEGF in the alveolar epithelial fluid has access to the pulmonary endothelium, where it acutely alters permeability, markedly exacerbating the high permeability pulmonary edema that characterizes high altitude pulmonary edema. If correct, this paradigm opens the possibility of testing available anti-VEGF therapies to treat this potentially fatal disorder.
small molecules
2026-07-08 | High-Altitude Oxygenation: A Comprehensive Review of Physiological Mechanisms, Clinical Applications, and Emerging Therapeutic Strategies in Hypobaric Environments
High-altitude oxygenation represents a critical physiological and therapeutic intervention designed to mitigate the profound challenges posed by hypobaric hypoxia in elevated terrestrial environments. This comprehensive review examines the fundamental pathophysiological mechanisms underlying high-altitude illness, explores the diagnostic and therapeutic approaches available for prevention and management, and evaluates emerging strategies for optimizing oxygen delivery in extreme environments. The progressive reduction in barometric pressure with increasing elevation diminishes the partial pressure of inspired oxygen, precipitating a cascade of physiological responses that may culminate in acute mountain sickness, high-altitude pulmonary edema, or high-altitude cerebral edema. The International Society for Mountain Medicine categorizes high-altitude environments into three distinct tiers—high (1,500-3,500 m), very high (3,500-5,500 m), and extreme (≥5,500 m)—each corresponding to progressively diminished oxygen availability and escalating physiological challenge. Recent advances in molecular genetics have elucidated specific mitochondrial DNA haplogroups and nuclear gene variants, including EPAS1, EGLN1, and NOS3, that modulate individual susceptibility to altitude illness, revealing evolutionary adaptations in high-altitude populations. Diagnostic capabilities have been enhanced through point-of-care ultrasound, optic nerve sheath diameter measurement, and wearable oximetry technologies, facilitating early detection in remote settings. Therapeutic approaches encompass pharmacological interventions—predominantly acetazolamide, dexamethasone, and emerging phytochemical agents—alongside nonpharmacological strategies including supplemental oxygen, portable hyperbaric chambers, and auto-positive end-expiratory pressure techniques. Interprofessional collaboration, augmented by telemedicine platforms and continuous physiologic monitoring, remains essential for optimizing outcomes in high-altitude environments. This review synthesizes current evidence to provide a framework for understanding the pathophysiology, diagnosis, prevention, and treatment of high-altitude illness, while identifying promising directions for future research and clinical practice.
2026-06-30 | Cognitive-behavioral therapy in high-altitude respiratory care: Critical considerations for physiological interpretation
High-altitude respiratory diseases, characterized by hypoxia-induced complications such as pulmonary edema and chronic bronchitis, present critical challenges to both physical and mental health in vulnerable populations. The recent study by Meng et al demonstrates that integrating cognitive-behavioral therapy (CBT) with standard care significantly improves anxiety levels and sleep quality in affected patients. These key findings hold direct implications for advancing respiratory management in hypoxic environments. Meng et al ’s observation of reduced serum hypoxia biomarkers (hypoxia-inducible factor-1α and erythropoietin) further suggests potential enhancements in physiological adaptation. However, the interpretation of these biomarker changes as evidence of improved hypoxia tolerance requires cautious examination. The study’s reliance on indirect indicators fails to establish whether CBT’s benefits stem primarily from psychological modulation or genuine cellular adaptation. Furthermore, the 5-day intervention window coincides with the half-life of erythropoietin, raising questions about the durability of these effects in the context of hypoxic acclimatization, which typically requires weeks to months. To resolve these ambiguities, future studies should prioritize longitudinal designs tracking both respiratory function and molecular biomarkers over clinically relevant timeframes. Integrating CBT with objective pulmonary assessments would clarify its role in optimizing oxygen utilization pathways. Such advances could refine targeted interventions for high-altitude respiratory rehabilitation, ultimately strengthening evidence-based care for this unique patient population.
2026-06-12 | Multi-omics analysis of genetic drivers linking aortic stenosis and left ventricular diastolic dysfunction in heart failure.
Aortic stenosis (AS) and left ventricular diastolic dysfunction (LVDD) often coexist in heart failure (HF), but the mechanisms linking them remain unclear. While AS increases afterload and promotes myocardial stiffening, emerging AI-based evidence suggests LVDD can precede the development of AS or progress simultaneously, indicating shared upstream mechanobiological and inflammatory drivers. This study explores the genetic contributors connecting AS and LVDD to identify early molecular markers and convergent pathways in HF. We analyzed Whole Genome Sequence (WGS) and RNA-seq data of the HF patients, generated using their Peripheral Blood Mononuclear Cells (PBMCs) samples. Overall bioinformatics analysis was divided into two modules, 1) gene variant and annotation analysis, and 2) gene expression and enrichment analysis. We utilized our peer review published and open source WGS and RNA-seq pipelines to process Next-Generation Sequence (NGS) data. Furthermore, we performed bioinformatics and statistical analysis to identify genetic variations, expressions, regulation, enrichments, and disease annotations. We identified genetic markers uniquely associated with AS, LVDD, and shared between them. Furthermore, we report genes with significant expression, and functional variations, and discuss their relationship with other cardiovascular diseases (e.g. Vascular and Cardiac Stiffness, Aortic Dissection, Left Atrial Enlargement, Left Ventricular Hypertrophy, Outflow Tract Obstructive Defects, Non-Compaction Coronary Artery Disease, Arrhythmia, Congestive Heart Failure, and Hypertrophic, Dilated, and Ischemic Cardiomyopathy) and non-cardiovascular diseases (non-CVDs) (e.g. Type 1 Diabetes, Diabetic Nephropathy, Skeletal Anomalies, Rheumatoid Arthritis, Atypical Femoral Fractures, Chronic Kidney Disease, Dehydrated Hereditary Stomatocytosis, Schizophrenia, Varicose Veins, High-Altitude Pulmonary Edema, Periodontitis, and Respiratory Disorder) including multiple cancer types (e.g. Breast, Lung, Colorectal, Pancreatic, Hypopharyngeal, Acute Lymphoblastic, and Oral Squamous Cell Carcinomas) and rare genetic disorders (e.g. Hypophosphatasia, Multiple Sclerosis, Campomelic Dysplasia, Lymphatic Malformation). We validated our results through state of science literature, gene-disease annotation databases, and electronic health records. AS and LVDD share both clinical and genomic associations, with overlapping genetic drivers that are enriched in pathways related to inflammation, extracellular matrix remodeling, and vascular stress responses. This work supports the potential of blood-based multi-omics profiling to uncover early, systemic molecular signals of cardiac dysfunction and lays the groundwork for future tissue-specific studies to guide precision diagnosis, risk stratification, and targeted therapeutics in HF.
2026-06-01 | High-altitude adaptation and associated mortality risk in relocated Holstein cattle
This study evaluated the adaptability of Holstein cattle to high-altitude environments following their relocation from low-altitude regions (<500 m) to the Qinghai-Tibet Plateau (>3,500 m) and identified risk factors associated with physiological maladaptation. A cohort of 1,000 healthy Holstein heifers was relocated and monitored over a 5-mo period, with observations focusing on mortality rates, clinical symptoms, hematological parameters, and pulmonary arterial pressure. Postmortem examinations and 16S rRNA sequencing of gut microbiota were conducted. The observed mortality rate was 30.5%. The predominant clinical manifestations included anorexia, edema, pulmonary hypertension, and hematological abnormalities. Postmortem analyses confirmed that right-sided heart failure secondary to hypoxic pulmonary hypertension was the principal cause of mortality. Holstein heifers that survived exhibited a higher relative abundance of bacteria associated with energy metabolism, such as Tenericutes, TM7, Clostridium, Treponema, and Paludibacter, in comparison to those that did not survive. Immediate relocation to elevations exceeding 3,500 m presents significant risks. To mitigate these risks, it is recommended to restrict altitude transitions to 1,500 m or less. An alternative approach involves implementing a gradual acclimatization strategy, which includes adaptive rearing at elevations of 2,500 m or lower for a minimum period of 5 mo, alongside specific dietary modifications and probiotic supplementation. These findings provide both practical and theoretical foundations for the effective health management of Holstein heifers in high-altitude environments.
2026-05-30 | Glucocorticoid Programming of Erythrocyte Hypoxic Memory Enables Rapid High-Altitude Acclimatization
ABSTRACT Background Rapid ascent to high altitude causes acute mountain sickness (AMS) and life-threatening pulmonary/cerebral edema, yet no prophylaxis enables immediate acclimatization. Intermittent hypoxia training (IHT) establishes a “hypoxic memory” that accelerates adaptation, to high altitude, but its cellular and molecular basis remains undefined, precluding effective pharmacological strategies. Methods A human cohort of 18 sea-level inhibitants was equally divided into two groups, one group received IHT prior to ascent to 3,500 meters, the other group did not. Multi-omics profiling of erythrocytes and plasma, along with isotopic glucose tracing, was employed to examine the metabolic effects of IHT upon high altitude acclimatization. Preclinical studies with genetically engineered mice were used to further define the molecular and metabolic basis of IHT-induced hypoxic memory allowing rapid acclimatization to high altitude. Results Metabolomics revealed glucocorticoids as previously unrecognized endogenous erythroid hypoxic memory orchestrators induced by IHT that negatively correlated with AMS severity. Lipidomics and isotopic glucose tracing demonstrated that glucocorticoid signaling via the glucocorticoid receptor (GR) coordinately enhanced glucose metabolism and activated sphingosine kinase-1 (SPHK1)-driven sphingosine-1-phosphate (S1P) synthesis, pre-conditioning erythrocyte oxygen unloading and antioxidant capacity. Glucocorticoid supplementation enhanced erythrocyte SPHK1 activation and oxygen delivery, counteracting multi-tissue hypoxia and pulmonary and renal neutrophil infiltration. Conversely, erythrocyte-specific Sphk1 ablation abolished glucocorticoid-induced S1P production causing severe tissue hypoxia and exaggerated pulmonary neutrophil infiltration. Conclusions We establish a new function of glucocorticoids in erythrocyte metabolic plasticity to enhance oxygen delivery as a hypoxic memory mechanism for rapid adaptation to high altitude. This previously unrecognized GR-mediated reprograming of glucose and sphingolipid metabolism offers a transformative precision pharmacologic strategy for high altitude preconditioning, high altitude emergencies and hypoxia-driven diseases.
proteins
2026-06-16 | PARK7 alleviates high-altitude pulmonary edema by suppressing BACH1 to attenuate lipid peroxidation-driven pro-inflammatory skewing of macrophages.
With the steady increase in global travel, mountaineering, and logistics at extreme elevations, high-altitude pulmonary edema (HAPE) remains a life-threatening emergency with mortality rates reaching up to 50% if untreated. Current clinical management relies heavily on rapid descent or supplemental oxygen, which are often logistically unfeasible in remote areas, while existing pharmacological interventions face challenges regarding efficacy and side effects. There is an urgent need to identify the fundamental molecular switches that translate hypobaric hypoxia into the catastrophic "cytokine storm" and barrier failure characteristic of HAPE. This study investigates the role of the antioxidant protein parkinsonism associated deglycase (PARK7) as a potential therapeutic target. A mouse model simulating 6000 m altitude (72 h) and CoCl₂-induced hypoxia in MLE-12 and RAW264.7 cells were used. PARK7 expression in lung tissue and hypoxic cells was analyzed via RNA-seq, qPCR, and western blot analyses. Lung-specific PARK7 and Bach1 overexpression or knockdown was achieved using AAV9-mediated intratracheal instillation. Pulmonary edema, vascular permeability, histopathology, and ultrastructure were assessed. Lipid peroxidation and M1 macrophage polarization (F4/80⁺iNOS⁺) were evaluated using C11-BODIPY staining, 4-HNE immunohistochemistry, and flow cytometry. PARK7 expression was markedly reduced in HAPE lungs and hypoxic cells. Restoration of PARK7 alleviated pulmonary edema, barrier dysfunction, mitochondrial damage, and inflammatory cell infiltration, primarily macrophages. Mechanistically, PARK7 suppressed lipid peroxidation, reducing MDA and 4-HNE accumulation, thereby blocking pro-inflammatory M1 macrophage polarization. Hypoxia stabilized the antioxidant repressor BTB and CNC Homology 1 (BACH1), whereas PARK7 inhibited BACH1 to exert its protective effect. Re-expression of BACH1 negated PARK7's benefits, restoring lipid peroxidation and M1 macrophage infiltration. This study suggests PARK7 as a key protective factor during HAPE progression. PARK7 inhibits lipid peroxidation through downregulation of BACH1, thereby preventing pro-inflammatory M1 polarization of macrophages and ultimately preserving alveolar-capillary barrier integrity. Targeting the PARK7-BACH1 axis may offer a novel therapeutic strategy for the prevention and treatment of HAPE.
2026-05-12 | Ferroptosis, orchestrated by GPX4 downregulation, serves as a critical mediator of neutrophil extracellular trap-driven pathology in hypoxic pulmonary edema.
This study explores the contribution of ferroptosis, a tightly regulated form of cell death, to the development of high-altitude pulmonary edema (HAPE) under hypoxic conditions. We focused on the central ferroptosis regulator glutathione peroxidase 4 (GPX4) and its interaction with neutrophil extracellular trap (NET) formation. Utilizing a murine model of high-altitude hypoxia and in vitro hypoxia/reoxygenation models, we employed a multi-omics approach to map the molecular landscape of HAPE. Transcriptomic and metabolomic analyses of lung tissues confirmed a significant downregulation of GPX4 and a marked activation of ferroptosis-related pathways. Single-cell RNA sequencing identified pulmonary endothelial cells as a key site for this dysregulation, showing decreased GPX4 alongside upregulation of pro-ferroptotic factors. Functional validation demonstrated that GPX4 deficiency in human pulmonary microvascular endothelial cells exacerbated reactive oxygen species accumulation, ferroptosis, and subsequent NET formation. Conversely, GPX4 overexpression effectively mitigated these cytotoxic effects. Furthermore, we elucidated that GPX4 modulates NET formation through key signaling pathways, including Nrf2 nuclear translocation, ERK1/2 and NF-κB phosphorylation, and the HMGB1-TLR4/MyD88 axis. In vivo, therapeutic augmentation of GPX4 levels attenuated pulmonary edema, improved lung function, and suppressed markers of both ferroptosis and NETosis. Our findings establish a novel pathogenic cascade in HAPE where hypoxia-induced GPX4 suppression promotes ferroptotic cell death, which in turn drives NET-associated inflammation, identifying GPX4 as a critical therapeutic target for preventing this condition.
2026-04-09 | Hypobaric hypoxia can lead to an increase in lung dendritic cells and promote T-cell immunosuppression, thereby preventing the excessive progression of high-altitude pulmonary edema.
More and more studies have shown that the immune system regulates the body's response to hypoxic stress. Immune dysregulation may increase vascular permeability, leading to edema and tissue damage, thereby causing high-altitude pulmonary edema (HAPE). Here, we found an increase in lung dendritic cells (DCs) in rat and mouse models of HAPE, but its specific role in HAPE remains unclear. In this study, the function of rat lung DCs and its impact on T cells were analyzed through single-cell sequencing, flow cytometry and in vitro co-culture. Then, we confirmed its effects on DCs and T cells by intraperitoneal injection of TNF-α or by using TNF-α -deficient mice. Finally, we evaluated the role of CD4+ T cells in the progression of HAPE by eliminating CD4 in mice with neutralizing antibodies. We demonstrated that hypobaric hypoxia (HH) induced the recruitment of pulmonary DCs in rats and promoted the immunosuppression of T cells (especially CD4+ T cells). By injecting TNF-α into rats, we found that the number of DC and CD4+CD25+ T cells in the lung of HH rats slightly decreased. Interestingly, in vivo injection of TNF-α actually led to the production of less TNF-α by CD4+ T cells in the lung of HH rats. In the HAPE mouse model, the proportion and the number of DC in the lung of TNF-α -deficient mice were significantly increased, and the level of IL-6 production was significantly decreased. Furthermore, the proportion of CD4+CD25+ T cells in the lung of TNF-α -deficient mice increased significantly. By eliminating CD4 in mice with neutralizing antibodies, we found that CD4+ T cells play a protective role in HAPE. Our results indicate that hypoxia induces the recruitment of DCs in the lung and mediates the differentiation of T cells into immunosuppressive phenotypes in HAPE rat and mouse models, thereby delaying the progression of HAPE. These findings highlight the potential approach of using immune regulation as a treatment for HAPE.
2024-01-15 | B2M is a Biomarker Associated With Immune Infiltration In High Altitude Pulmonary Edema.
High altitude pulmonary edema (HAPE) is a serious mountain sickness with certain mortality. Its early diagnosis is very important. However, the mechanism of its onset and progression is still controversial. This study aimed to analyze the HAPE occurrence and development mechanism and search for prospective biomarkers in peripheral blood. The difference genes (DEGs) of the Control group and the HAPE group were enriched by gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and then GSEA analysis was performed. After identifying the immune-related hub genes, QPCR was used to verify and analyze the hub gene function and diagnostic value with single-gene GSEA and ROC curves, and the drugs that acted on the hub gene was found in the CTD database. Immune infiltration and its association with the hub genes were analyzed using CIBERSORT. Finally, WGCNA was employed to investigate immune invasion cells' significantly related gene modules, following enrichment analysis of their GO and KEGG. The dataset enrichment analysis, immune invasion analysis and WGCNA analysis showed that the occurrence and early progression of HAPE were unrelated to inflammation. The hub genes associated with immunity obtained with MCODE algorithm of Cytoscape were JAK2 and B2M.. RT-qPCR and ROC curves confirmed that the hub gene B2M was a specific biomarker of HAPE and had diagnostic value, and single-gene GSEA analysis confirmed that it participated in MHC I molecule-mediated antigen presentation ability decreased, resulting in reduced immunity. Occurrence and early progression of high altitude pulmonary edema may not be related to inflammation. B2M may be a new clinical potential biomarker for HAPE for early diagnosis and therapeutic evaluation as well as therapeutic targets, and its decrease may be related to reduced immunity due to reduced ability of MCH I to participate in antigen submission.
2021-02-24 | D4F prophylaxis enables redox and energy homeostasis while preventing inflammation during hypoxia exposure.
Apo-A1 is correlated with conditions like hyperlipidemia, cardiovascular diseases, high altitude pulmonary edema and etc. where hypoxia constitutes an important facet.Hypoxia causes oxidative stress, vaso-destructive and inflammatory outcomes.Apo-A1 is reported to have vasoprotective, anti-oxidative, anti-apoptotic, and anti-inflammatory effects. However, effects of Apo-A1 augmentation during hypoxia exposure are unknown.In this study, we investigated the effects of exogenously supplementing Apo-A1-mimetic peptide on SD rats during hypoxia exposure. For easing the processes of delivery, absorption and bio-availability, Apo-A1 mimetic peptide D4F was used. The rats were given 10 mg/kg BW dose (i.p.) of D4F for 7 days and then exposed to hypoxia. D4F was observed to attenuate both oxidative stress and inflammation during hypoxic exposure. D4F improved energy homeostasis during hypoxic exposure. D4F did not affect HIF-1a levels during hypoxia but increased MnSOD levels while decreasing CRP and Apo-B levels. D4F showed promise as a prophylactic against hypoxia exposure.
oligonucleotides
2025-01-23 | Biomimetic exosome harnessing exosomal lipidomics and functional proteins for PEDF-pDNA delivery in high altitude pulmonary edema intervention.
In the realm of gene therapy, given the exceptional performance of native exosomes, researchers have redirected their innovative focus towards exosome-mimetic nanovesicles (EMNs); however, the current design of most EMNs relies heavily on native cells or their components, inevitably introducing inter-batch variability issues and posing significant challenges for quality control. To overcome the excessive reliance on native cellular components, this study adopts a unique approach by precisely mimicking the lipid composition of exosomes and innovatively incorporating histone components to recapitulate the gene transfer characteristics of exosomes. We selected sphingomyelin (SM), phosphatidylcholine (PC), phosphatidylserine (PS), phosphatidylethanolamine (PE), and cholesterol as the lipid components, and employed the double emulsion method to prepare biomimetic exosomes carrying histone A and PEDF-DNA plasmids (His-pDNA@EMNs). These vesicles exhibited an ideal particle size (102 ± 2 nm) and Zeta potential (-20 ± 2 mV) with cup-shaped structure, similar to native exosomes. Compared with the commercial gene transfection reagent Lipo6000, His-pDNA@EMNs significantly improved the transfection efficiency of the PEDF gene in HUVEC cells by 18.74 % while significantly reducing cytotoxicity, demonstrating their superior biocompatibility and efficiency. Mechanism exploration revealed that the lipid composition of these EMNs delicately promoted each step of gene delivery: PC facilitated efficient cellular uptake, the synergistic effect of PE and PS significantly enhanced lysosomal escape ability, and the specific combination of PS and SM assisted vesicles in penetrating into the nucleus. Notably, EMNs escaped from lysosomes in their intact form through a local membrane fusion mechanism. Further cellular and animal experiments fully verified that His-pDNA@EMNs could effectively enhance PEDF protein expression both in vitro and in vivo, effectively inhibiting hypoxia-induced vascular remodeling and endothelial injury, providing a novel and effective intervention of high-altitude pulmonary edema (HAPE). In summary, this study not only demonstrates the feasibility of preparing efficient gene delivery vectors by mimicking the functions of native exosomes with synthetic phospholipids and histones, but also opens up a new path for the development of gene therapy vectors. His-pDNA@EMNs also provide a new strategy for the prevention of HAPE.
2024-07-15 | Long noncoding RNA ANRIL alleviates hypoxia-induced pulmonary microvascular endothelial cell damage.
High-altitude pulmonary oedema (HAPE) is a form of noncardiogenic pulmonary oedema. Studies have found that long noncoding RNA (lncRNA) plays an important role in HAPE. ANRIL is significant in pulmonary illnesses, which implies that alterations in ANRIL expression levels may be involved in the beginning and development of HAPE. However, the specific mechanism is indistinct. The present study is meant to explore the effect and mechanism of ANRIL on hypoxic-induced injury of pulmonary microvascular endothelial cells (PMEVCs). In the hypoxic model of PMVECs, overexpression of ANRIL or knockdown of miR-181c-5p was performed to assess cell proliferation, apoptosis, and migration. Furthermore, the levels of apoptosis-related proteins, inflammatory factors, and vascular active factors were also measured. The results showed that, after 24 h of hypoxia, PMVECs proliferation and migration were suppressed in comparison to the control group, along with an increase in apoptosis, a decrease in the expression of ANRIL, and an increase in the expression of miR-181c-5p (all p < .05). The damage caused by hypoxia in PMVECs can be lessened by overexpressing ANRIL, which also inhibits the production of TNF-α, iNOS, and VEGF as well as BAX and cleaved caspase-3 (all p < .05). Further experimental results showed that overexpression of ANRIL and knockdown of miR-181c-5p had the same protection against hypoxic injury in PMVECs (all p < .05). Our study suggests that ANRIL may prevent hypoxia injury to PMVECs in HAPE through the negative regulation of miR-181c-5p.
2021-11-08 | Novel HIF-1-target gene isthmin1 contributes to hypoxia-induced hyperpermeability of pulmonary microvascular endothelial cells monolayers.
Hypoxia-induced pulmonary microvascular endothelial cell (PMVEC) monolayers hyperpermeability is vital for vascular leakage, which participates in vascular diseases, such as acute lung injury (ALI) and high-altitude pulmonary edema (HAPE). We previously observed that PMVEC permeability was markedly elevated in hypoxia when cocultured with primary type II alveolar epithelial cells (AECII) in which isthmin1 (ISM1) was highly upregulated. However, whether the upregulation of ISM1 plays a role in hypoxia-induced PMVEC hyperpermeability is unclear. In this study, we assessed the role of AECII-derived ISM1 in hypoxia-induced PMVEC hyperpermeability with an AECII/PMVEC coculture system and uncovered the underlying mechanism whereby hypoxia stimulates ISM1 gene expression. We found that ISM1 gene expression was upregulated in cultured AECII cells exposed to hypoxia (3% O2) and that AECII-derived ISM1 participated in hypoxia-induced hyperpermeability of PMVEC monolayers, as small interference RNA (siRNA)-mediated knockdown of ISM1 in AECII markedly attenuated the increase in PMVEC permeability in coculture system under hypoxia. In addition, we confirmed that ISM1 was regulated by hypoxia-inducible factor-1α (HIF1α) according to the evidence that silencing of HIF1α inhibited the hypoxia-mediated upregulation of ISM1. Mechanismly, overexpression of HIF1α transcriptionally activated ISM1 gene expression by directly binding to the conserved regulatory elements upstream of the ism1 locus. We identified a novel HIF-1-target gene ISM1, which involves in hyperpermeability of pulmonary microvascular endothelial cell monolayers under hypoxia. Our in vitro cell experiments implied that the upregulated ISM1 derived from alveolar epithelium might be a vital modulator in hypoxia-induced endothelial hyperpermeability and thereby implicates with hypoxic pulmonary-related diseases.
2021-02-22 | Network Biology led identification of critical miRNA modules for High Altitude hypoxia and their potential as dietary supplements
Abstract Early ascent to high altitude can cause severe damage to body functions and may lead to many fatal high-altitude disorders. To cope up with such conditions, the human body undergoes physiological and biochemical changes in order to adapt to extreme environmental conditions at high altitudes. Several microRNAs (miRNAs), Transcription Factors (TFs), and genes have been studied separately for their role in early adaptive molecular responses. We hypothesize that network analysis of miRNA-TF-gene co-regulatory networks of circulatory miRNAs (CmiRNAs) which are differentially expressed at high altitudes could reveal a complex regulatory functional module that might be controlling molecular adaptive responses at high altitude. A comprehensive and non-redundant list of differentially expressed human CmiRNAs during high altitude ascent was collated and 470 Feed-Forward Loops (FFLs) tripartite motifs were identified in the miRNA-TF-gene co-regulatory networks. Network analysis and K-means clustering identified 11 biologically overrepresented FFLs regulated by 8 miRNAs hsa-miR-335-5p, hsa-miR-26a-1-3p, hsa-miR-210-3p, hsa-miR-193b-3p, hsa-miR-17-5p, hsa-miR-16-5p, hsa-miR-5582-5p and hsa-miR-130a-3p. Pathway enrichment identified metabolism and inflammation as important hallmark responses responsible for high altitude adaptation. These miRNAs were evaluated for their supplementation from dietary sources. Phylogenetic analysis with 4 other mammalian and non-mammalian species showed that Bos taurus (cattle) milk could be a possible source of these dietary miRNAs. Exogenous miRNAs bta-mir-16-1, bta-mir-130a, bta-miR-335, and bta-miR-210 have >95% of sequence similarity and could become potential dietary miRNAs candidates. The sequence, structural properties, and high AGO2 binding efficiency of all these exogenous miRNAs show good serum stability and cellular uptake possibility in the mammalian host. Bta-miR-210 with highest Minimal Folding free Energy Index (MFEI) and highest Atomic Contact Energy (ACE) with AGO2 has the best potential to be a dietary supplement.
2020-11-20 | Susceptibility to high-altitude pulmonary edema is associated with circulating miRNA levels under hypobaric hypoxia conditions.
Hypobaric hypoxia poses stress to sojourners traveling to high-altitude. A cascade of physiological changes occurs to cope with or adapt to hypobaric hypoxia. However, an insufficient physiological response to the hypoxic condition resulting from imbalanced vascular homeostasis pathways results in high-altitude pulmonary edema (HAPE). The present study aims to identify the implication of miRNAs associating with HAPE and adaptation. We analyzed the expression of 1,113 miRNAs in HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), and highland natives (HLs). Based on miRNA profiling and in silico analyses, miR-124-3p emerged relevantly. We observed a significant overexpression of miR-124-3p in HAPE-p. In silico analyses revealed a direct interaction of miR-124-3p with vascular homeostasis and hypoxia-associated genes NOS3 (endothelial nitric oxide synthase), Apelin, and ETS1 (V-Ets avian erythroblastosis virus E2 oncogene homolog 1). Moreover, the transcript and biolevel expression of these genes were significantly decreased in HAPE-p when compared with HAPE-f or HLs. Our in vitro analysis in human umbilical vein endothelial cells demonstrated a significant knockdown of these genes both at transcript and protein levels following miR-124-3p overexpression. Conclusively, our results showed that miR-124-3p might play a plausible role in HAPE pathophysiology by inhibiting the expression of NOS3, Apelin, and ETS1.
cell therapies
2026-05-04 | Prophylactic Nebulized hUC-MSC-EVs Attenuate Hypobaric Hypoxia-Induced Lung Injury via Alveolar-Capillary Barrier Stabilization and TEK/Tie2 Preservation.
Background/Objectives: High-altitude pulmonary edema (HAPE) remains a serious condition with limited preventive options. This study evaluated the prophylactic protective effects of nebulized human umbilical cord mesenchymal stem cell-derived extracellular vesicles (hUC-MSC-EVs) in a rat model of hypobaric hypoxia-induced lung injury and explored potential mechanistic clues, with a focus on oxidative stress and TEK/Tie2 signaling. Methods: Rats were exposed to hypobaric hypoxia (47 kPa; 9.7% O2) for 72 h and received prophylactic nebulized hUC-MSC-EVs (300 μg/rat). Lung injury was evaluated by histopathology, wet-to-dry ratio, and bronchoalveolar lavage fluid (BALF) protein concentration. Invasive pulmonary function indices were measured using a forced oscillation system. BALF cytokines (TNF-α, IL-6, and IL-10), reactive oxygen species (ROS), and TEK/Tie2 expression in lung tissue were assessed. In addition, transcriptome sequencing (RNA-seq) was performed to characterize global transcriptional changes. N-acetylcysteine (NAC), a classical antioxidant, was included as an auxiliary mechanistic intervention to assess the association of ROS with TEK/Tie2 changes. Results: Compared with hypoxia controls, prophylactic nebulized hUC-MSC-EVs reduced histopathological injury, pulmonary edema, and barrier leakage, and improved pulmonary function indices. hUC-MSC-EV intervention also attenuated inflammatory responses in BALF, with decreased TNF-α and IL-6 and increased IL-10. Hypobaric hypoxia increased ROS accumulation and decreased TEK/Tie2 expression, whereas nebulized hUC-MSC-EVs reduced ROS and partially preserved TEK/Tie2 expression. NAC pretreatment similarly reduced ROS and was accompanied by Tie2 preservation. Conclusions: Prophylactic nebulized hUC-MSC-EVs mitigated hypobaric hypoxia-induced lung injury, accompanied by reduced oxidative stress, improved vascular barrier integrity, and preservation of TEK/Tie2 expression. These findings support nebulized hUC-MSC-EVs as a potential lung-targeted prophylactic strategy for hypobaric hypoxia-induced lung injury and suggest that ROS imbalance may be associated with Tie2 preservation.
2026-03-18 | Scalable Production of Multi-Source Hybrid Biomimetic Exosomes Co-Loaded with Therapeutic Plasmids for Treatment of High-Altitude Pulmonary Edema.
Exosomes show therapeutic promise but face limitations in simultaneous targeting and potency. While hybrid exosome strategies combining multiple cell components can address this, current methods rely on native exosome extraction and drug loading, suffering from low yield and encapsulation efficiency. We developed a biological origin-based hybrid biomimetic exosome (BOB-HBE) platform that synthetically assembles exosomes using parent cell-derived components through a water/oil/water emulsion method, overcoming production bottlenecks. For high-altitude pulmonary edema (HAPE) treatment, we engineered hybrid exosomes combining: (1) vascular endothelial cell membranes for lung targeting, (2) mesenchymal stem cell factors for regeneration, and (3) eNOS-encoding plasmid DNA to restore nitric oxide signaling. The BOB-HBE platform achieved >150-fold higher production yield than natural exosome isolation while enhancing pulmonary endothelial specificity. In HAPE models, these hybrid exosomes demonstrated triple therapeutic effects: restoring NO bioavailability, inhibiting pathogenic HIF-1α/TGF/Smad1/5 signaling, and preventing endothelial-mesenchymal transition and vascular remodeling. Consequently, they significantly attenuated HAPE progression by addressing both molecular pathways and tissue-level pathology. This study establishes a scalable platform for constructing multifunctional exosome mimetics that maintain native exosome advantages while solving key production challenges. The cell-origin-informed design strategy offers a versatile approach for targeted therapy in pulmonary and vascular disorders, with potential clinical translation advantages.
2025-02-05 | Small extracellular vesicles derived from miRNA-486 overexpressed dental pulp stem cells mitigate high altitude pulmonary edema through PTEN/PI3K/AKT/eNOS pathway.
High altitude pulmonary edema (HAPE) is a life-threatening, non-cardiogenic pulmonary edema characterized by rapid onset and high mortality. Extracellular vesicles of mesenchymal stem cells are used in the treatment of a variety of lung diseases, but their use in HAPE remains underreported. This study explores the therapeutic potential of miRNA-486 modified extracellular vesicles from dental pulp stem cells (sEVmiR-486) against HAPE, aiming to decipher the associated molecular mechanisms. The rat HAPE model was established by exposing subjects to a simulated high-altitude, low-oxygen environment within a specialized chamber. The HAPE-afflicted rats received sEVNull and sEVmiR-486 intravenously, and the therapeutic effect was assessed through histopathological analysis, pulmonary artery pressure, lung water content, as well as markers of oxidative stress and inflammation. To supplement in vivo findings, pulmonary microvascular endothelial cells (PMVEC) were stressed with cobalt chloride to emulate hypoxic damage, and then treated with sEVNull and sEVmiR-486 to unravel the mechanism of action. The sEVNull mitigated pathological changes in the lungs, reduced pulmonary artery pressure and lung water content, and alleviated oxidative stress and inflammatory responses in cases of HAPE. Moreover, sEVNull enhanced vascular reactivity and restored pulmonary permeability and tight junction integrity, these effects were intensified by miRNA-486 overexpression. Notably, sEVmiR-486 attenuated oxidative damage in hypoxic PMVEC cells by modulating the PTEN/PI3K/Akt/eNOS signaling pathway. miRNA-486 fortified DPSC-sEVs intervention as a novel and potent treatment strategy for HAPE.
2025-01-28 | hUC-MSCs Prevent Acute High-Altitude Injury through Apoe/Pdgf-b/p-Erk1/2 Axis in Mice.
The hypobaric hypoxic atmosphere can cause adverse reactions or sickness. The purpose of this study was to explore the preventive effect and mechanism of human umbilical cord mesenchymal stem cells (hUC-MSCs) on acute pathological injury in mice exposed to high-altitude. We pretreated C57BL/6 mice with hUC-MSCs via the tail vein injection, and then the mice were subjected to hypobaric hypoxic conditions for five days. The effects of hUC-MSCs on the pathological injury of lung, heart, brain were assessed by biochemical analysis, histopathological testing, quantitative real-time polymerase chain reaction (qPCR), and western blot (WB). Further, transcriptome sequencing was used to screen for the potential therapeutic targets of hUC-MSCs in acute pathological injury, the identified signaling axis was characterized using Apoe-/- mice, qPCR and WB. hUC-MSCs administration notably prevented and relieved gastrointestinal symptoms and inflammation of lung and heart, increased blood oxygen saturation and serum superoxide dismutase (SOD) level, decreased serum malondialdehyde (MDA) level, rescued lung tissue injury and myocardial mitochondrial disorder, elevated nissl bodies number in brain tissue and reduced the degree of pulmonary and cerebral edema. Furthermore, hUC-MSCs pretreatment reversed the down-regulated Apoe and up-regulated Pdgf-b and p-Erk1/2 in the lung of hypobaric hypoxic mice. Thus, hUC-MSCs protected against acute pathological injury caused by hypobaric hypoxic condition via the Apoe/Pdgf-b/p-Erk1/2 axis, and the identified pathway was confirmed by the negative results of Apoe-/- mice. hUC-MSCs possess the preventive effect on acute pathological injury caused by hypobaric hypoxia environment at high-altitude.
2024-07-18 | Superoxide dismutase 1-modified dental pulp stem cells alleviate high-altitude pulmonary edema by inhibiting oxidative stress through the Nrf2/HO-1 pathway.
High-altitude pulmonary edema (HAPE) is a deadly form of altitude sickness, and there is no effective treatment for HAPE. Dental pulp stem cells (DPSCs) are a type of mesenchymal stem cell isolated from dental pulp tissues and possess various functions, such as anti-inflammatory and anti-oxidative stress. DPSCs have been used to treat a variety of diseases, but there are no studies on treating HAPE. In this study, Sprague-Dawley rats were exposed to acute low-pressure hypoxia to establish the HAPE model, and SOD1-modified DPSCs (DPSCsHiSOD1) were administered through the tail vein. Pulmonary arterial pressure, lung water content (LWC), total lung protein content of bronchoalveolar lavage fluid (BALF) and lung homogenates, oxidative stress, and inflammatory indicators were detected to evaluate the effects of DPSCsHiSOD1 on HAPE. Rat type II alveolar epithelial cells (RLE-6TN) were used to investigate the effects and mechanism of DPSCsHiSOD1 on hypoxia injury. We found that DPSCs could treat HAPE, and the effect was better than that of dexamethasone treatment. SOD1 modification could enhance the function of DPSCs in improving the structure of lung tissue, decreasing pulmonary arterial pressure and LWC, and reducing the total lung protein content of BALF and lung homogenates, through anti-oxidative stress and anti-inflammatory effects. Furthermore, we found that DPSCsHiSOD1 could protect RLE-6TN from hypoxic injury by reducing the accumulation of reactive oxygen species (ROS) and activating the Nrf2/HO-1 pathway. Our findings confirm that SOD1 modification could enhance the anti-oxidative stress ability of DPSCs through the Nrf2/HO-1 signalling pathway. DPSCs, especially DPSCsHiSOD1, could be a potential treatment for HAPE. Schematic diagram of the antioxidant stress mechanism of DPSCs in the treatment of high-altitude pulmonary edema. DPSCs can alleviate oxidative stress by releasing superoxide dismutase 1, thereby reducing ROS production and activating the Nrf2/HO-1 signalling pathway to ameliorate lung cell injury in HAPE.
other
2025-08-03 | Elevated cytokine levels in patients with High-altitude pulmonary edema.
Immunomodulation is integral to the body's adaptation to varying altitudes. Nevertheless, the effects of immune regulation on the onset of high-altitude pulmonary edema (HAPE) are not well understood. This research aimed to explore the influence of immune regulation on HAPE pathogenesis through the assessment of cytokine levels. We analyzed the cytokine profiles of 28 HAPE patients at high altitudes and compared them to 25 healthy individuals who had successfully acclimatized. The levels of seven cytokines released by T helper cells (Th)1/2/17, alongside monocyte chemoattractant protein-1 (MCP-1), interleukin (IL)-8, and IL-1β in serum, were quantified using cytometric bead array (CBA) technology. Our findings revealed significantly higher concentrations of IL-2, IL-10, and tumor necrosis factor (TNF) in the peripheral blood of HAPE patients when contrasted with those of healthy individuals (P < 0.001). A comprehensive analysis of these cytokines indicated a robust diagnostic capability for predicting HAPE, achieving an area under the curve (AUC) of 0.98. Conversely, no significant differences were observed in the levels of IL-6, IL-8, interferon-γ (IFN-γ), IL-4, IL-17 A, MCP-1, and IL-1β between the two cohorts. Elevated IL-2, IL-10, and TNF in HAPE patients underscore immune dysregulation as a disease driver. Clinically, these cytokines may guide risk prediction (IL-2-hypoxemia link) and targeted therapies (anti-TNF for vascular leakage). Future work should define hypoxia-specific cytokine networks, validate interventions in altitude cohorts, and integrate multi-omics to map immune-vascular crosstalk.
2023-09-20 | NLRC3 deficiency promotes hypoxia-induced pulmonary hypertension development via IKK/NF-κB p65/HIF-1α pathway.
Hypoxia-induced pulmonary hypertension is a subgroup of type 3 pulmonary hypertension (PH) with the recommended treatment limited to oxygen therapy and lacks potential therapeutic targets. To investigate the role of NLRC3 in hypoxia-induced PH and its potential mechanism, we first collected lung tissues of high-altitude pulmonary hypertension (HAPH) patients. Immunohistochemistry and immunofluorescence showed that NLRC3 was downregulated and was mainly co-localized with the smooth muscle cells of the pulmonary vessels in HAPH patients. Besides, we found that NLRC3 was also expressed in endothelial cells in HAPH patients for the first time. Then, wild type (WT) and NLRC3 knockout (NLRC3-/-) mice were used to construct hypoxia models and primary pulmonary arterial smooth muscle cells (PASMCs) of rats and endothelial cells were cultured for verification. Right heart catheterization and echocardiography suggested that NLRC3 knockout promoted right ventricular systolic pressure (RVSP) up-regulation, right ventricular hypertrophy and fibrosis in hypoxia-induced mice. This study first demonstrated that NLRC3 deficiency promoted hypoxia-stimulated PASMCs proliferation, Human umbilical vein endothelial cells (HUVECs) apoptosis, migration and inflammation through IKK/NF-κB p65/HIF-1α pathway in vitro and in vivo, further promoted vascular remodeling and PH progression, which provided a new target for the treatment of hypoxia-induced PH.
2004-12-01 | Pathogenesis of High Altitude Pulmonary Edema: Does Alveolar Epithelial Lining Fluid Vascular Endothelial Growth Factor Exacerbate Capillary Leak?
Kaner, Robert J., and Ronald G. Crystal. Pathogenesis of high altitude pulmonary edema: Does alveolar epithelial lining fluid vascular endothelial growth factor exacerbate capillary leak? High Alt. Med. Biol. 5:399–409, 2004.—Vascular endothelial growth factor (VEGF) is a potent mediator of capillary leak if it gains access to its receptors on the capillary endothelium. We have observed that there are high levels of VEGF compartmentalized in the alveolar epithelial lining fluid of normal humans at levels 500-fold greater than plasma. The potential for high altitude to result in compromise of alveolar epithelial tight junctions and experimental animal studies in which pulmonary edema is induced when VEGF is overexpressed in the alveolar epithelium, suggest a mechanism. We hypothesize that when the epithelial barrier is compromised at high altitude the normally high level of VEGF in the alveolar epithelial fluid has access to the pulmonary endothelium, where it acutely alters permeability, markedly exacerbating the high permeability pulmonary edema that characterizes high altitude pulmonary edema. If correct, this paradigm opens the possibility of testing available anti-VEGF therapies to treat this potentially fatal disorder.
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Drug Discovery Landscape
2 orphan drug designations for High altitude pulmonary edema.
2 orphan drug designations for High altitude pulmonary edema.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Cyclo-Cys-Gly-Gln-Arg-Glu-Thr-Pro-Glu-Gly-Ala-Glu-Ala-Lys-Pro-Trp-Tyr-Cys | small molecules | EMA | 2013-02-08 | — | Apeptico Forschung und Entwicklung GmbH |
synthetic peptide; cyclo-Cys-Gly-Gln-Arg-Glu-Thr-Pro-Glu-Gly-Ala-Glu-ALA-Lys-Pro-Trp-Tyr-Cys | peptides | FDA | 2013-01-16 | — | Apeptico Forschung und Entwicklung GmbH |
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