Hypoxia signaling during acute lung injury

Abstract

Acute lung injury (ALI) is an inflammatory lung disease that manifests itself in patients as acute respiratory distress syndrome and thereby contributes significantly to the morbidity and mortality of patients experiencing critical illness. Even though it may seem counterintuitive, as the lungs are typically well-oxygenated organs, hypoxia signaling pathways have recently been implicated in the resolution of ALI. For example, functional studies suggest that transcriptional responses under the control of the hypoxia-inducible factor (HIF) are critical in optimizing alveolar epithelial carbohydrate metabolism, and thereby dampen lung inflammation during ALI. In the present review we discuss functional roles of oxygenation, hypoxia and HIFs during ALI, mechanisms of how HIFs are stabilized during lung inflammation, and how HIFs can mediate lung protection during ALI.

Keywords: HIF1A; LPS; acute lung injury; acute respiratory distress syndrome; carbohydrate metabolism; glycolysis; hypoxia; hypoxia-inducible factor; inflammation; lung protection; mechanical ventilation; sepsis.

Fig. 1.

Definition of acute respiratory distress syndrome (ARDS) and acute lung injury (ALI).

Fig. 2.

Moderate hypoxia improves outcome in polymicrobial ALI. Animals were treated with intratracheal lipopolysaccharide (LPS) and staphylococcal enterotoxin B (SEB) to mimic polymicrobial lung injury. High oxygen concentrations led to decreased survival within 48–60 h after intratracheal injection of toxins as hyperoxia suppresses adenosine A2A receptor-mediated activation of anti-inflammatory pathways.

Fig. 3.

Experimental setup for a murine model of ventilator-induced lung injury. Anesthetized animals are intubated or tracheotomized and then connected to the ventilator. ECG, Sp_O2, and temperature can be monitored continuously. Additionally, a catheter is placed in the carotid artery for blood pressure and blood gas monitoring. Ventilator-induced lung injury is induced by pressure-controlled ventilation (PCV) with a p_max of 45 cmH₂O for various time periods.

Fig. 4.

Mechanisms of HIF1A stabilization during ALI. Patients with ALI frequently require mechanical ventilation. Cyclic mechanical stretch results in HIF1A stabilization. Stretch-induced HIF1A stabilization is mediated by the inhibition of succinate dehydrogenase (SDH), causing normoxic stabilization of alveolar epithelial HIF1A. Studies implicate HIF1A-mediated optimization of carbohydrate metabolism of the injured lungs by increasing glycolytic capacity. Tricarboxylic acid (TCA) cycle flux is associated with increased alveolar epithelial capacity to produce ATP, while concomitantly preventing reactive oxygen species (ROS) accumulation and attenuating lung inflammation (adapted from Ref. with permission).