Role of succinate in airway epithelial cell regulation following traumatic lung injury.

Lung contusion and gastric aspiration (LC and GA) are major risk factors for developing acute respiratory distress following trauma. Hypoxia from lung injury is mainly regulated by hypoxia-inducible factor 1α (HIF-1α). Published data from our group indicate that HIF-1α regulation in airway epithelial cells (AEC) drives the acute inflammatory response following LC and GA. Metabolomic profiling and metabolic flux of Type II AEC following LC revealed marked increases in glycolytic and TCA intermediates in vivo and in vitro that were HIF-1α dependent. GLUT-1/4 expression was also increased in HIF-1α+/+ mice, suggesting that increased glucose entry may contribute to increased intermediates. Importantly, lactate incubation in vitro on Type II cells did not significantly increase the inflammatory byproduct IL-1ß. Contrastingly, succinate had a direct proinflammatory effect on human small AEC by IL-1ß generation in vitro. This effect was reversed by dimethylmalonate, suggesting an important role for succinate dehydrogenase in mediating HIF-1α effects. We confirmed the presence of the only known receptor for succinate binding, SUCNR1, on Type II AEC. These results support the hypothesis that succinate drives HIF-1α-mediated airway inflammation following LC. This is the first report to our knowledge of direct proinflammatory activation of succinate in nonimmune cells such as Type II AEC in direct lung injury models.

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.