Abstract
Author SummaryAcute lung injury is a devastating lung disease caused by injuries or acute infections to the lung. In patients it manifests itself as acute respiratory distress syndrome. Severe pulmonary edema and uncontrolled lung inflammation are typical symptoms of acute lung injury, which make it hard for patients to breath efficiently. In the clinical course of the disease, patients require mechanical ventilation to support their lung function and to provide sufficient oxygen levels to vital organs such as the brain, the heart, or the kidneys. We hypothesized that stretch conditions—such as those that occur during mechanical ventilation—result in transcriptional adaptation of alveolar epithelial cells—the innermost lining of the lungs. In this study we identified an unexpected involvement of the transcription factor hypoxia-inducible factor HIF1A in lung protection. We observed that during acute lung injury, stabilization of HIF1A is mediated by increased levels of succinate, an intermediate product of the citrate cycle. Interestingly, we show that HIF1A in alveolar epithelia functions to induce a transcriptional program that improves the efficiency of carbohydrate metabolism by injured lungs, thereby helping to adapt to the injurious conditions of mechanical stretch and to reduce lung inflammation. These preclinical findings highlight the potential for pharmacological HIF1A stabilization in the treatment of acute lung injury.
Highlights
Acute lung injury (ALI) is an inflammatory disease of the lungs that is characterized by hypoxemic respiratory failure with bilateral pulmonary infiltrates, not attributable to left heart failure [1,2,3,4]
These studies reveal a surprising role for hypoxia-inducible factor 1A (HIF1A) in lung protection during acute lung injury (ALI), where normoxic HIF1A stabilization and HIF-dependent control of alveolar-epithelial glucose metabolism function as an endogenous feedback loop to dampen lung inflammation
Subsequent studies of Calu-3 pulmonary epithelia exposed to different timeperiods of stretch (Figure 1B) or studies utilizing a HIF reporter plasmid transfected into pulmonary epithelia (A549) and exposed to stretch conditions revealed stabilization of HIF1A—the key transcription factor for hypoxia adaptation (Figure 1C) [30]
Summary
Acute lung injury (ALI) is an inflammatory disease of the lungs that is characterized by hypoxemic respiratory failure with bilateral pulmonary infiltrates, not attributable to left heart failure [1,2,3,4]. Alveolar epithelial injury plays a key role in the pathogenesis of ALI, leading to disruptions of the alveolarcapillary barrier function, resulting in extensive pulmonary edema, attenuated gas exchange, and uncontrolled lung inflammation [2]. It is important to point out that ALI is among the leading causes of morbidity and mortality of patients requiring critical care medicine. While acute lung injury (ALI) contributes significantly to critical illness, it resolves spontaneously in many instances. The majority of patients experiencing ALI require mechanical ventilation. We hypothesized that mechanical ventilation and concomitant stretch-exposure of pulmonary epithelia could activate endogenous pathways important in lung protection
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