Cardiotrophin-1 attenuates endotoxin-induced acute lung injury

Cardiotrophin-1 (CT-1) is a recently discovered member of the gp130 cytokin e family, which includes IL-6, IL-11, leukemia inhibitory factor, ciliary n eurotrophic factor, and oncostatin M. Recent evidence suggests that, like o ther members of this family, CT-1 may possess anti-inflammatory properties. We hypothesized that in vivo CT-1 administration would attenuate endotoxin (ETX)-induced acute lung injury. We studied the effects of CT-1 (100 mu g/ kg ip, 10 min prior to ETX) in a rat model of ETX-induced acute lung injury (Salmonella typhimurium lipopolysaccharide, 20 mg/kg ip). Six hours after ETX, lungs were harvested for determination of neutrophil accumulation (mye loperoxidase, MPO, assay) and lung edema (wet-to-dry weight ratio). Mechani sms of pulmonary vasorelaxation were examined in isolated pulmonary artery rings at 6 h by interrogating endothelium-dependent (response to acetylchol ine) and endothelium-independent (response to sodium nitroprusside) relaxat ion following alpha-adrenergic (phenylephrine)stimulated preconstriction. C T-1 abrogated the endotoxin-induced lung neutrophil accumulation: 2.3 +/- 0 .2 units MPO/g wet lung (gwl) vs 6.3 +/- 0.3 units MPO/gwl in the ETX group (P < 0.05 vs ETX, P > 0.05 vs control). Similarly, CT-1 prevented ETX-indu ced lung edema: wet-to-dry-weight ratio, 4.473 +/- 0.039 vs 4.747 +/- 0.039 in the ETX group (P < 0.05 vs ETX, P > 0.05 vs control). Endotoxin caused significant impairment of both endothelium-dependent and-independent pulmon ary vasorelaxation, and CT-1 attenuated this injury. Thus, cardiotrophin-1 possesses significant anti-inflammatory properties in a model of endotoxin- induced acute lung injury. (C) 1999 Academic Press.