Isoforskolin pretreatment attenuates lipopolysaccharide-induced acute lung injury in animal models

Isoforskolin was isolated from Coleus forskohlii native to Yunnan in China. We hypothesize that isuforskolin pretreatment attenuates acute lung injury induced by lipopolysaccharide (endotoxin). Three acute lung injury models were used: situ perfused rat lung, rat and mouse models of endotoxic shock. Additionally, lipopolysaccharide stimulated proinflammatory cytokine production was evaluated in human mononuclear leukocyte. In situ perfused rat lungs, pre-perfusion with isoforskolin (100, and 200 mu M) and dexarrethasone (65 mu M, positive control) inhibited lipopolysaccharide (10 mg/L) induced increases in lung neutrophil adhesion rate, myeloperoxidase activity, lung weight Wet/Dry ratio, permeability-surface area product value, and tumor necrosis factor (TNF)-alpha levels. In rats, pretreatments with isoforskolin (5, 10, and 20 mg/kg, i.p.) and dexamethasone (5 mg/kg, i.p.) markedly reduced lipopolysaccharide (6 mg/kg i.v.) induced increases of karyocyte, neutrophil counts and protein content in bronchoalveolar lavage fluid, and plasma myeloperoxidase activity. Lung histopathology showed that morphologic changes induced by lipopolysaccharide were less pronounced in the isoforskolin and dexamethasone pretreated rats. In mice, 5 mg/kg isoforskolin and dexamethasone caused 100% and 80% survival, respectively, after administration of lipopolysaccharide (62.5 mg/kg, iv., 40% survival if untreated). In human mononuclear leukocyte, isoforskolin (50, 100, and 200 mu M) and dexamethasone (10 mu M) pre-incubation lowered lipopolysaccharide (2 mu g/mL) induced secretion of the cytokine TNF-alpha, and interleukins (IL)-1 beta, IL-6, and IL-8. In conclusion, pretreatment with isoforskolin attenuates lipopolysaccharide-induced acute lung injury in several models, and it is involved in down-regulation of inflammatory responses and proinflammatory cytokines TNF-alpha, IL-1 beta, IL-6, and IL-8. (C) 2011 Elsevier B.V. All rights reserved.