Impact of ENaC downregulation in transgenic mice on the outcomes of acute lung injury induced by bleomycin.

New Findings: What is the central question of this study? How does the downregulation of ENaC, the major driving force for alveolar fluid clearance, impact acute lung injury outcomes induced by bleomycin, featuring alveolar damage, as observed during ARDS exudative phase? What is the main finding and its importance? ENaC downregulation in αENaC(-/-)Tg+ mice did not elicit a substantial worsening impact on the main bleomycin outcomes. In ARDS patients, both ENaC alteration and alveolar damage are observed. Thus, novel therapeutic avenues, favouring alveolar integrity restauration, in addition to lung oedema resolution capacity, mainly driven by ENaC, would be essential.

Abstract: The exudative phase of acute respiratory distress syndrome (ARDS) is characterized by extended alveolar damage, resulting in accumulation of protein-rich inflammatory oedematous fluid in the alveolar space. Na reabsorption through ENaC channels is a major driving force for alveolar fluid clearance (AFC) in physiological and pathological conditions. It has previously been shown that partial αENaC impairment in transgenic (αENaC(-/-)Tg+) mice results in reduced AFC in basal conditions and increased wet/dry ratio after thiourea-induced lung oedema, a model in which the integrity of the alveolar epithelium is preserved. The goal of this study was to further investigate the impact of αENaC downregulation in αENaC(-/-)Tg+ mice using an experimental model of acute lung injury induced by bleomycin. A non-significant trend in enhanced weight loss and mortality rates was observed after the bleomycin challenge in αENaC(-/-)Tg+ compared to wild-type (WT) mice. Bronchoalveolar lavage analyses revealed increased TNFα levels and protein concentrations, as indexes of lung inflammation and alveolar damage, in αENaC(-/-)Tg+ mice, compared to WT, at day 3 post-bleomycin, although a statistical difference was no longer measured at day 7. Differential immune cell counts were similar in WT and αENaC(-/-)Tg+ mice challenged with bleomycin. Moreover, lung weight measurements indicated similar oedema levels in WT mice and in transgenic mice with impaired ENaC channels. Altogether, our data indicated that change in ENaC expression does not elicit a significant impact on lung oedema level/resolution in the bleomycin model, featuring alveolar damage.