Genetics of High-Altitude Pulmonary Edema

Eichstaedt, Christina A.; Benjamin, Nicola; Cao, Ding; Palevičiūtė, Eglė; Grünig, Ekkehard

doi:10.1016/j.hfc.2022.07.002

Cited by 5 publications

(2 citation statements)

References 52 publications

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“…In addition, if the body experiences severe trauma, infection, shock, acute lung injury, or acute respiratory distress syndrome can be rapidly induced, which can be life-threatening [ 6 ]. It is considered that the occurrence of HAPE is a complex process that involves multiple factors and many genes [ 7 ]. The happening and development of HAPE are related to obvious individual and racial diversity, and it is affected by environmental and genetic factors [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Vitamin D3 improved hypoxia-induced lung injury by inhibiting the complement and coagulation cascade and autophagy pathway

Dai,

Lin,

et al. 2024

BMC Pulm Med

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Background Pulmonary metabolic dysfunction can cause lung tissue injury. There is still no ideal drug to protect against hypoxia-induced lung injury, therefore, the development of new drugs to prevent and treat hypoxia-induced lung injury is urgently needed. We aimed to explore the ameliorative effects and molecular mechanisms of vitamin D3 (VD3) on hypoxia-induced lung tissue injury. Methods Sprague–Dawley (SD) rats were randomly divided into three groups: normoxia, hypoxia, and hypoxia + VD3. The rat model of hypoxia was established by placing the rats in a hypobaric chamber. The degree of lung injury was determined using hematoxylin and eosin (H&E) staining, lung water content, and lung permeability index. Transcriptome data were subjected to differential gene expression and pathway analyses. In vitro, type II alveolar epithelial cells were co-cultured with hepatocytes and then exposed to hypoxic conditions for 24 h. For VD3 treatment, the cells were treated with low and high concentrations of VD3. Results Transcriptome and KEGG analyses revealed that VD3 affects the complement and coagulation cascade pathways in hypoxia-induced rats, and the genes enriched in this pathway were Fgb/Fga/LOC100910418. Hypoxia can cause increases in lung edema, inflammation, and lung permeability disruption, which are attenuated by VD3 treatment. VD3 weakened the complement and coagulation cascade in the lung and liver of hypoxia-induced rats, characterized by lower expression of fibrinogen alpha chain (Fga), fibrinogen beta chain (Fgb), protease-activated receptor 1 (PAR1), protease-activated receptor 3 (PAR3), protease-activated receptor 4 (PAR4), complement (C) 3, C3a, and C5. In addition, VD3 improved hypoxic-induced type II alveolar epithelial cell damage and inflammation by inhibiting the complement and coagulation cascades. Furthermore, VD3 inhibited hypoxia-induced autophagy in vivo and in vitro, which was abolished by the mitophagy inducer, carbonyl cyanide-m-chlorophenylhydrazone (CCCP). Conclusion VD3 alleviated hypoxia-induced pulmonary edema by inhibiting the complement and coagulation cascades and autophagy pathways.

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Section: Introductionmentioning

confidence: 99%

Vitamin D3 improved hypoxia-induced lung injury by inhibiting the complement and coagulation cascade and autophagy pathway

Dai,

Lin,

et al. 2024

BMC Pulm Med

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“…In recent years, evidences for the adaptation genetic basis and the comparing of genetic pro les between high altitude natives and lowlanders emerge 7,8 , in which EPAS1, EGLN1 and PPARA were identi ed as the strong candidate genes for the natural selection at high altitude 3 . There is much interest in whether genetic factors and which molecular signaling play a role in the pathogenesis of HAPE, but no de nitive gene differences and speci c biomarkers for HAPE have been reported so far 3,11,12 .…”

Section: Introductionmentioning

confidence: 99%

TNF-α and RPLP0 driving apoptosis of endothelial cells as the shared molecular mechanism of high altitude pulmonary edema in sojourners and natives: bioinformatic analysis and experimental validation

Ge,

Li,

et al. 2024

Preprint

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High altitude pulmonary edema (HAPE) is a fatal threat for those sojourners who ascend rapidly without sufficient acclimatization. High altitude natives are insusceptible to HAPE resulting from evolved genetic specializations of adaption. In this study, based on GSE52209, the gene expression profile of HAPE patients was compared with acclimatized sojourners and adapted natives, with the common and divergent differential expressed genes (DEGs) and their hub genes being identified, respectively. Bioinformatic methodologies of functional enrichment analysis, immune infiltration, diagnostic model constructing, ceRNAs and drugs predicting, were performed to detect the potential biological functions and molecular mechanisms. Next, an array of in-vivo experiments in HAPE rat model and in-vitro experiments in HUVECs were conducted to verify the results of bioinformatic analysis. Enriched pathways of DEGs and immune landscapes for HAPE exhibited significant differences between sojourners and natives, and the common DEGs were mainly enriched in the pathways of development and immunity. Nomograms found the upregulation of TNF-α and downregulation of RPLP0 exhibited high diagnostic efficiency for HAPE both in sojourners and natives, which was furtherly validated in the HAPE rat model. Treatment of TNF-α and knock-down of RPLP0 activated apoptosis signaling in endothelial cells (ECs) and enhanced endothelial permeability. Conclusively, TNF-α and RPLP0 are identified as the shared biomarkers and molecular basis for HAPE during the acclimatization/adaption/maladaptation processes in sojourners and natives, which inspire new ideas for the prediction and treatment of HAPE.

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TNF-α and RPLP0 drive the apoptosis of endothelial cells and increase susceptibility to high-altitude pulmonary edema

Ge,

Li,

et al. 2024

Apoptosis

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High-altitude pulmonary edema (HAPE) is a fatal threat for sojourners who ascend rapidly without sufficient acclimatization. Acclimatized sojourners and adapted natives are both insensitive to HAPE but have different physiological traits and molecular bases. In this study, based on GSE52209, the gene expression profiles of HAPE patients were compared with those of acclimatized sojourners and adapted natives, with the common and divergent differentially expressed genes (DEGs) and their hub genes identified, respectively. Bioinformatic methodologies for functional enrichment analysis, immune infiltration, diagnostic model construction, competing endogenous RNA (ceRNA) analysis and drug prediction were performed to detect potential biological functions and molecular mechanisms. Next, an array of in vivo experiments in a HAPE rat model and in vitro experiments in HUVECs were conducted to verify the results of the bioinformatic analysis. The enriched pathways of DEGs and immune landscapes for HAPE were significantly different between sojourners and natives, and the common DEGs were enriched mainly in the pathways of development and immunity. Nomograms revealed that the upregulation of TNF-α and downregulation of RPLP0 exhibited high diagnostic efficiency for HAPE in both sojourners and natives, which was further validated in the HAPE rat model. The addition of TNF-α and RPLP0 knockdown activated apoptosis signaling in endothelial cells (ECs) and enhanced endothelial permeability. In conclusion, TNF-α and RPLP0 are shared biomarkers and molecular bases for HAPE susceptibility during the acclimatization/adaptation/maladaptation processes in sojourners and natives, inspiring new ideas for predicting and treating HAPE.

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Genetics of High-Altitude Pulmonary Edema

Cited by 5 publications

References 52 publications

Vitamin D3 improved hypoxia-induced lung injury by inhibiting the complement and coagulation cascade and autophagy pathway

Vitamin D3 improved hypoxia-induced lung injury by inhibiting the complement and coagulation cascade and autophagy pathway

TNF-α and RPLP0 driving apoptosis of endothelial cells as the shared molecular mechanism of high altitude pulmonary edema in sojourners and natives: bioinformatic analysis and experimental validation

TNF-α and RPLP0 drive the apoptosis of endothelial cells and increase susceptibility to high-altitude pulmonary edema

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