Gas exchange disturbances regulate alveolar fluid clearance during acute lung injury

Abstract

Disruption of the alveolar-capillary barrier and accumulation of pulmonary edema, if not resolved, result in poor alveolar gas exchange leading to hypoxia and hypercapnia, which are hallmarks of acute lung injury and the acute respiratory distress syndrome (ARDS). Alveolar fluid clearance (AFC) is a major function of the alveolar epithelium and is mediated by the concerted action of apically-located Na+ channels [epithelial Na+ channel (ENaC)] and the basolateral Na,K-ATPase driving vectorial Na+ transport. Importantly, those patients with ARDS who cannot clear alveolar edema efficiently have worse outcomes. While hypoxia can be improved in most cases by O2 supplementation and mechanical ventilation, the use of lung protective ventilation settings can lead to further CO2 retention. Whether the increase in CO2 concentrations has deleterious or beneficial effects have been a topic of significant controversy. Of note, both low O2 and elevated CO2 levels are sensed by the alveolar epithelium and by distinct and specific molecular mechanisms impair the function of the Na,K-ATPase and ENaC thereby inhibiting AFC and leading to persistence of alveolar edema. This review discusses recent discoveries on the sensing and signaling events initiated by hypoxia and hypercapnia and the relevance of these results in identification of potential novel therapeutic targets in the treatment of ARDS. A major function of the alveolar epithelium is to maintain alveolar fluid balance resulting in minimal epithelial lining fluid, thus providing optimal gas exchange (1). However, during acute lung injury (ALI) and the clinical acute respiratory distress syndrome (ARDS) the alveolar-capillary barrier fails, which leads to flooding of the alveolar space and causes a severe impairment of gas exchange (2). It is well established that clearance of alveolar edema is markedly impaired in most patients with ARDS and that this impairment is associated with worse outcomes (3). Thus, removal of the excess alveolar fluid is of significant clinical importance. The primary mechanism driving fluid reabsorption from the alveolar space is the active vectorial flux of sodium from the airspaces into the lung interstitium and the pulmonary circulation (1). Sodium, in exchange to potassium, is pumped out of the alveolar epithelial cells (AEC) basolaterally by the Na,K-ATPase, whereas Na+ enters the cells apically through the amiloride-sensitive and -insensitive epithelial Na+ channel (ENaC) (1, 4). This vectorial sodium transport process creates an osmotic gradient that drives clearance of fluid from the alveolar space (1). Failure of the alveolar-capillary barrier function leads to alveolar edema and thus to alveolar hypoventilation, resulting in hypoxemia and often elevated CO2 concentrations in the blood (hypercapnia) in patients with ARDS (1, 4). This is of particular importance, as several studies have shown that these conditions are not only consequences of alveolar edema but also further exacerbate alveolar fluid dysbalance by promoting formation and inhibiting reabsorption of the edema fluid (5-7). In this review, we will focus on the mechanisms by which hypoxia and hypercapnia impair alveolar fluid clearance (AFC), concentrating on the regulation of the Na,K-ATPase and ENaC in the context of ALI.