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

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.