Alveolar fluid accumulation can be an accompanying factor and/or the cause of acute respiratory failure. Hallmarks of the acute respiratory distress syndrome (ARDS) include both impairments of alveolar epithelial integrity and active ion/fluid-reabsorption. Levels of coagulation factors (e.g. thrombin) and unsaturated fatty acids (e.g. oleic acid (OA)) were found to be elevated in plasma and bronchoalveolar lavage fluid of patients suffering from ARDS. In recent studies the impact of intravascularly applied a-thrombin and of OA -given in concentrations comparable to levels found in ARDS patients-were investigated in experimental lung models to elucidate by which mechanism these substances may influence alveolar epithelial barrier function. In essence, a-thrombin induced lung edema formation by increasing endothelial permeability, and concomitantly inhibiting active alveolar epithelial sodium transport via blockade of the Na⁺,K⁺-ATPase function. OA on the other hand was covalently bound to both epithelial sodium channel and the Na⁺,K⁺-ATPase and directly inhibited the catalytic activity of purified Na⁺,K⁺-ATPase. In conclusion, both thrombin and OA contribute to the impairement of sodium- and fluid-reabsorption by the alveolar epithelium. Thus, in acute lung injury and ARDS, treatment strategies targeting the coagulation system (e.g. alveolar or systemic fibrinolysis) as well as the level of circulating fatty acids (e.g. replacing W-6/9 with W-3 fatty acids in parenteral nutrition solutions) should be considered.