Treatment of Pulmonary Edema by ENaC Activators/Stimulators

Martin      Fronius

Abstract

Lungs contain a particular amount of fluid that is crucial for proper lung function. This fluid content is tightly controlled within certain limits. Fluid accumulation in the alveolar airspace impairs gas exchange and represents a lifethreatening condition referred to as pulmonary edema. Ion transport processes by pulmonary epithelia represent a mechanism, responsible for fluid absorption from the airspace. Thus, it is obvious to consider ion transport processes as target for therapeutic interventions in pulmonary edema. The principle mechanism responsible for fluid absorption from the airspace is: Na⁺ diffuses through luminal Na⁺ channels into epithelial cells and is extruded by Na⁺/K⁺-ATPases at the basolateral side. This process generates an osmotic gradient that represents the driving force for fluid absorption. The rate of Na⁺ absorption is limited by the number/activity of Na+ channels in the luminal membrane of alveolar epithelial cells. Although different Na+ channels have been identified, the epithelial Na+ channel (ENaC) is a major player that participates in Na⁺-driven fluid absorption and thus a suitable target for the treatment of pulmonary edema.

This article reviews cellular mechanisms by which ENaC activity can be increased in alveolar epithelia (lectins, proteases, β-adrenoceptors, mineralo-/glucocorticoid-receptors). These mechanisms are involved in regulating ENaC-dependent fluid absorption under physiological conditions. Additionally, pre-clinical as well as some preliminary clinical studies revealed that “ENaC-activators/stimulators” (β2-adrenoceptor agonists and mineralo-/glucocorticoid-receptor agonists) could be beneficial for therapeutic interventions in patients with pulmonary edema. However, the outcome of subsequently performed multicenter clinical trials with “ENaC-activators/stimulators” for treatment of patients with pulmonary edema was disappointing.

Keywords: Alveolar epithelium, β-adrenoceptor, ENaC, epithelial Na+ channel, fluid absorption, mineralo-/glucocorticoid, lectin, proteolytic cleavage.