Hypoxia‐inducible factor (HIF)‐1α‐induced regulation of lung injury in pulmonary aspiration is mediated through NF‐kB

Abstract

Abstract Aspiration‐induced lung injury is a common grievance encountered in the intensive care unit (ICU). It is a significant risk factor for improving ventilator‐associated pneumonia (VAP) and acute respiratory distress syndrome (ARDS). Hypoxia‐inducible factor (HIF)‐1α is one of the primary transcription factors responsible for regulating the cellular response to changes in oxygen tension. Here, we sought to determine the role of HIF‐1α and specifically the role of type 2 alveolar epithelial cells in generating the acute inflammatory response following acid and particles (CASP) aspiration. Previous studies show HIF‐1 α is involved in regulating the hypoxia‐stimulated expression of MCP‐1 in mice and humans. The CASP was induced in C57BL/6, ODD‐Luc, HIF‐1α (+/+) control, and HIF‐1α conditional knockout (HIF‐1α (−/−) mice). Following an injury in ODD mice, explanted organs were subjected to IVIS imaging to measure the degree of hypoxia. HIF‐1α expression, BAL albumin, cytokines, and histology were measured following CASP. In C57BL/6 mice, the level of HIF‐1α was increased at 1 h after CASP. There were significantly increased levels of albumin and cytokines in C57BL/6 and ODD‐Luc mice lungs following CASP. HIF‐1α (+/+) mice given CASP demonstrated a synergistic increase in albumin leakage, increased pro‐inflammatory cytokines, and worse injury. MCP‐1 antibody neutralized HIF‐1α (+/+) mice showed reduced granuloma formation. The NF‐κB expression was increased substantially in the HIF‐1α (+/+) mice following CASP compared to HIF‐1α (−/−) mice. Our data collectively identify that HIF‐1α upregulation of the acute inflammatory response depends on NF‐κB following CASP.

Keywords

• CASP
• HIF‐1α
• IVIS
• NF‐kB
• Type II AEC