Cyclosporin A protects lung function from hyperoxic damage.
Cyclosporin A (CsA), an inhibitor of protein phosphatase 2B (calcineurin), has been shown to play a role in exocytosis and neutrophil mobility. Hyperoxia (>95% oxygen for 72 h) causes lung injury and reduces lung compliance. This model is indicative of deficiencies in surfactant and elicits a vigorous immune response leading to further damage. We examined the effects of CsA on surfactant-secreting lung alveolar type II cells. CsA enhances ATP-stimulated increases in whole cell capacitance in the presence of 2 mM extracellular Ca2+. This measurement corresponds with increases in exocytosis. Because of its effect on the immune system and exocytosis from type II cells, CsA was examined for its protective effects against hyperoxia-induced lung damage in mice. We found that CsA (50 mg. kg-1. day-1) attenuated hyperoxia-induced reductions in lung compliance when administered before or during 72 h of >95% oxygen (P < 0.05). CsA (10 mg. kg-1. day-1) also had a protective effect against hyperoxia-induced changes in neutrophil infiltration, capillary congestion, edema, and hyaline membrane formation. Wet lung weight-to-dry lung weight ratios did not show any significant changes after hyperoxia or hyperoxia plus CsA (P < 0. 05). CsA may be useful to treat patients undergoing prolonged high-oxygen therapy and possibly other lung injuries.
D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D065095:Calcineurin Inhibitors; D002478:Cells, Cultured; D016572:Cyclosporine / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D005089:Exocytosis; D005260:Female; D018496:Hyperoxia / Q000150:complications*; D008168:Lung / Q000737:chemistry / Q000473:pathology; D008170:Lung Compliance / Q000187:drug effects; D008171:Lung Diseases / Q000209:etiology* / Q000517:prevention & control*; D051379:Mice; D009504:Neutrophils / Q000473:pathology; D011510:Proteolipids / Q000032:analysis; D011650:Pulmonary Alveoli / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism; D011663:Pulmonary Surfactants / Q000032:analysis / Q000378:metabolism; D014018:Tissue Distribution