Na,K-ATPase expression is increased in the lungs of alcohol-fed rats.

The acute respiratory distress syndrome (ARDS) is a severe form of acute edematous lung injury characterized by noncardiogenic pulmonary edema and flooding of the alveolar airspaces with proteinaceous fluid. ARDS develops in response to inflammatory stresses including sepsis, trauma, gastric aspiration, pneumonia and massive blood transfusions (Ware and Matthay, 2000). Originally described in 1967 (Ashbaugh et al., 1967), ARDS is characterized by alveolar epithelial and endothelial barrier disruption, surfactant dysfunction, and intense inflammation that, in concert, produce profound derangements in gas exchange and severe respiratory failure. Although a great deal has been learned about the underlying pathophysiology of this syndrome in the past four decades, our treatment remains essentially supportive and despite aggressive ICU care and mechanical ventilation, the mortality rate for ARDS remains unacceptably high at 40–60% (Rubenfeld et al., 2005;Ware and Matthay, 2000). An important clue to which patients are at greater risk for developing ARDS has been uncovered in recent epidemiologic studies demonstrating a link between alcohol abuse and acute lung injury (ALI), including the landmark study in 1996 that first identified an independent connection between alcohol abuse and ARDS (Moss et al., 1996). A more recent study confirmed those initial findings and determined that in individuals with septic shock, the relative risk of ARDS in alcoholic patients versus nonalcoholic patients was 3.7:1 (Moss et al., 2003). If these findings are extrapolated to the population at large, then alcohol abuse contributes to the development of ARDS in tens of thousands of patients in the U.S. each year. Alveolar epithelial barrier dysfunction is a prominent feature of ARDS. The maintenance of a fluid-free alveolar space is critical for facilitating normal gas exchange. A pathological hallmark of ALI/ARDS is heterogeneous damage of the alveolar epithelium, with complete loss of the epithelial surface in some areas but with other alveoli relatively intact. Therefore, at a cellular level the extent of the alveolar epithelial damage may not be as widespread or as uniform as the chest radiograph might suggest, and preservation and repair of the alveolar epithelium are keys to survival. In fact, patients with impaired alveolar epithelial fluid clearance are three times more likely to die from ALI/ARDS than patients with a maximal ability to clear lung fluid (Sznajder, 2001; Ware and Matthay, 2001). However, more than 85% of patients with ALI/ARDS have at least a partial defect in lung fluid clearance (Ware and Matthay, 2001). The ability of the lung to clear fluid away from the alveolar space and into the pulmonary circulation is largely dependent on active Na+ transport by the alveolar epithelium; for review, see (Morty et al., 2007). Na+ uptake at the apical side of the alveolar epithelium is mediated by amiloride-sensitive Na+ channels (ENaC), whereas Na+ is pumped out of the epithelial cells at the basolateral side by the Na,K-ATPase. The Na,K-ATPase belongs to the family of P-type ATPases and the functional enzyme consists of α and β subunits (Lingrel et al., 1994a–c; Sweadner, 1989). Multiple isoforms of both the α and β subunits have been reported (Lingrel et al., 1994b; Therien and Blostein, 2000). The catalytic α subunit contains binding sites for ATP as well as the Na,K-ATPase inhibitor, ouabain; for review, see (Kaplan, 2002). The alveolar epithelium expresses both α1 and α2 subunits (Borok et al., 2002; Ridge et al., 1997, 2003). The β subunit regulates activity and proper membrane localization of the α subunit (Factor et al., 1998; Geering, 1991; Kaplan, 2002; Therien and Blostein, 2000; Thome et al., 2001). Chronic alcohol ingestion increases ENaC density on the apical side of alveolar epithelial cells (Guidot et al., 2000b), and acute alcohol administration (a single dose) to rats decreases Na,K-ATPase activity (Aytacoglu et al., 2006; Rodrigo et al., 2002). However, to our knowledge the effects of chronic alcohol ingestion on the expression of Na,K-ATPase in the lung has not been determined. This critical evidence is necessary to support the aforementioned explanation as to why the otherwise healthy alcoholic lung is not edematous at baseline. Therefore, in this current study we sought to determine whether or not chronic alcohol ingestion increased the expression of Na,K-ATPase within the lung.