Stimulation of alveolar epithelial fluid clearance in human lungs by exogenous epinephrine

Objectives. Because several experimental studies have demonstrated that cyclic adenosine monophosphate generation following beta-adrenoceptor activation can markedly stimulate alveolar fluid clearance, we determined whether the endogenous levels of catecholamines that occur in the pulmonary edema fluid and plasma of patients with acute lung injury are high enough to stimulate alveolar fluid clearance in the human lung. Design: Observational clinical Study. Setting. Academic university hospital and laboratory. Patients: Twenty-one patients with acute pulmonary edema plus ex vivo human lungs. Interventions. Measurements of catecholamine levels in patient samples and controlled laboratory studies of the effects of these catecholamine levels on the rates of alveolar fluid clearance in ex vivo human lungs. Measurements and Main Results. The concentrations of both epinephrine and norepinephrine in the pulmonary edema fluid and plasma were similar to 10(-9) M (range of 1-8 x 10(-9) M) in hydrostatic pulmonary edema (n = 6) and acute lung injury patients (n = 15). We therefore tested whether 10(-9) M epinephrine or norepinephrine stimulated alveolar fluid clearance in isolated human lungs and found that these epinephrine or norepinephrine concentrations did not stimulate alveolar fluid clearance. However, higher concentrations of epinephrine (10(-7) M), but not norepinephrine (10(-7) M), significantly stimulated alveolar fluid clearance by 84% above control. Glibenclamide (10(-5) M) and CFTR(inh)-172 (10(-5) M), cystic fibrosis transmembrane conductance regulator inhibitors, completely inhibited the epinephrine-induced stimulation of alveolar fluid clearance. Conclusions. These results indicate that endogenous catecholamine concentrations in pulmonary edema fluid are probably not sufficient to stimulate alveolar fluid clearance. In contrast, administration of exogenous catecholamines into the distal airspaces can stimulate alveolar fluid clearance in the human lung, an effect that is mediated in part by cystic fibrosis transmembrane conductance regulator. Therefore, exogenous cyclic adenosine monophosphate-dependent stimulation will probably be required to accelerate the resolution of alveolar edema in the lungs of patients with pulmonary edema.