Modulation of HIF1α/CXCR4 by CDDP, acetazolamide, and salidroside in early lung injury caused by acute high-altitude hypoxia

Background

The inflammatory response of pulmonary vascular endothelial cells is critical in the pathogenesis of hypobaric hypoxia-induced acute lung injury. Elucidation of the underlying mechanisms and potential therapeutic interventions is crucial for both medical professionals and individuals exposed to high altitudes.

Methods

A murine model of acute lung injury was established by subjecting mice to hypobaric hypoxia at an altitude equivalent to 6000 m for 8 and 72 h. Histopathological and immunohistochemical analyses were performed using hematoxylin-eosin staining and immunohistochemistry to assess inflammation. Western blotting for Endothelial Nitric Oxide Synthase (eNOS) phosphorylation was used to evaluate endothelial injury. High-throughput RNA sequencing was employed to identify early inflammatory regulators, and the protein expression of Hypoxia inducible factor-1 (HIF1α), C-X-C chemokine receptor 4 (CXCR4) and Phospho-Endothelial Nitric Oxide Synthase (p-eNOS) was examined via western blotting. Additionally, the expression level of CXCR4 and selected cytokines were quantified by real-time Polymerase Chain Reaction.

Results

Lung tissues demonstrated marked inflammatory infiltration and lung injury after 8 h of hypobaric hypoxia exposure, peaking at 24 h. HIF1α expression was significantly upregulated at 8 h and gradually decreased thereafter. CXCR4, identified as a target gene of HIF1α, exhibited a similar expression pattern. Preventive treatment with compound Danshen dripping pills, acetazolamide and salidroside accelerated the suppression of HIF1α and CXCR4 expression compared to the natural response following 8 h of hypobaric hypoxia. Furthermore, these agents demonstrated enhanced protective effects against endothelial dysfunction and inflammation.

Conclusions

These findings indicate that the endothelial HIF1α/CXCR4 axis plays a pivotal role in the early phase of hypobaric hypoxia-induced acute lung injury. The downregulation of HIF1α/CXCR4 by compound Danshen dripping pills, acetazolamide and salidroside suggests promising therapeutic strategies for managing acute high-altitude hypoxic lung injury.