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Vitamin D3 improved hypoxia-induced lung injury by inhibiting the complement and coagulation cascade and autophagy
Chongyang Dai1, Xue Lin2, Yinglian Qi3
1Qinghai University, Xining, Qinghai Province, 810016, People's Republic of China.
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.
Insights
Vitamin D3 (VD3) treatment effectively reduced lung injury caused by hypoxia in rats. VD3 alleviates pulmonary edema by inhibiting complement, coagulation, and autophagy pathways.
Area of Science:
- Pulmonary Medicine
- Pharmacology
- Molecular Biology
Background:
- Hypoxia-induced lung injury is a significant clinical challenge with limited therapeutic options.
- Pulmonary metabolic dysfunction contributes to lung tissue damage.
- Developing novel treatments for hypoxia-induced lung injury is crucial.
Purpose of the Study:
- To investigate the protective effects of vitamin D3 (VD3) against hypoxia-induced lung injury.
- To elucidate the molecular mechanisms underlying VD3's therapeutic action.
Main Methods:
- A rat model of hypoxia was established and treated with VD3.
- Lung injury was assessed via H&E staining, lung water content, and permeability index.
- Transcriptome analysis and in vitro cell models were used to explore molecular pathways.
Main Results:
- VD3 treatment attenuated lung edema, inflammation, and permeability disruption in hypoxia-exposed rats.
- VD3 inhibited complement and coagulation cascades, evidenced by reduced expression of key genes like Fga and Fgb.
- VD3 suppressed hypoxia-induced autophagy in lung cells and tissues.
Conclusions:
- Vitamin D3 alleviates hypoxia-induced pulmonary edema.
- The protective effects of VD3 are mediated by the inhibition of complement and coagulation cascades and autophagy pathways.
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