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

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.

Pulmonary Fibrosis as a Result of Acute Lung Inflammation: Molecular Mechanisms, Relevant In Vivo Models, Prognostic and Therapeutic Approaches

“…Today, gastric contents aspiration is one of the most important risk factors of ALI development, especially in ICU patients [ 305 , 306 ]. Since the main characteristic of gastric contents is their low pH, the primary inductor of this model is a hydrochloric acid solution with pH value of 1.2–1.5, administered to lab animals through the trachea and leading to damage of the airways and alveolar epithelium, as well as disruption of the lung transport functions [ 307 ].…”

Polymer Lung Surfactants Attenuate Direct Lung Injury in Mice

“…Under anesthesia, mice were injected with 30 μL of acid (HCl in normal saline (NS), pH 1.25) or NS (pH 5.3, vehicle control) by deep oral pharyngeal injection. 10 For pharyngeal injection, mice were placed on a custom-designed angled platform with their incisors hung on a wire. The tongue was pulled out of the mouse using forceps, and the liquid was directly dropped into the opening of the trachea using a micropipette.…”

“…The acid component of gastric aspirates was modeled with strong HCl. Under anesthesia, mice were injected with 30 μL of acid (HCl in normal saline (NS), pH 1.25) or NS (pH 5.3, vehicle control) by deep oral pharyngeal injection . For pharyngeal injection, mice were placed on a custom-designed angled platform with their incisors hung on a wire.…”

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

“…In our recent study, we studied C57BL/6 mice, hypoxia reporter mice (oxygen-dependent degradation [ODD] domain within HIF-1α [ODD-Luc]), and HIF-1α triple transgenic cKO mice specific in Type II AEC to confirm and characterize the fate of hypoxic AEC in the pathogenesis of acid aspiration–induced lung injury ( 9 ). We found that HIF-1α is critical in regulating the inflammatory response following acid aspiration–induced lung injury ( 9 , 12 , 13 ).…”

“…Based on these previous findings, we set out to determine the role of Type II AEC in the mitochondrial TCA and glycolysis processes in the presence and absence of HIF-1α following LC and acid aspiration ( 8 , 9 , 13 ). We conclude that hypoxia in mice following direct lung injury promoted the accumulation of succinate.…”