Molecular Medicine Reports
The cholinergic antiinflammatory pathway is considered an attractive approach for the alleviation of inflammatory diseases. Sepsis is characterized by systemic inflammation and widespread organ injury, especially that in the lung. In the present study, we explored the effects of an 7nAChR agonist, PNU282987, on sepsisinduced lung injury and investigated the mechanisms of PNU282987 in response to lipopolysaccharide (LPS) stimulation in peritoneal macrophages. Sepsis was induced in C57BL/6 mice via cecal ligation puncture (CLP). Fifty mice were randomly divided into five groups: The sham group treated with vehicle, the sham group treated with PNU282987, the CLP group treated with vehicle, and the CLP group treated with PNU282987 (1 mg/kg) 1 h before or 2 h after surgery. All mice were sacrificed at 12 or 24 h after CLP. Both pre and postCLP treatment with PNU282987 significantly attenuated sepsisinduced lung injury and the release of IL6 in the bronchoalveolar lavage fluid (BALF). Pretreatment with PNU282987 also inhibited sepsisincreased TNF and IL6 production, while postCLP treatment only inhibited IL6 production in the lung tissue. Neither pre nor postCLP treatment with PNU282987 affected IL6 release in the serum. Furthermore, pretreatment with PNU282987 resulted in reductions in TNF and IL6 release in a dose and timedependent manner and decreased the phosphorylation levels of p38, JNK and ERK under LPS conditions in peritoneal macrophages. Our results demonstrate that activation of 7nAChR alleviates sepsisinduced lung injury; this effect is associated with the suppression of inflammatory responses via the MAPK pathway, suggesting that 7nAChR is a potential therapeutic target for the treatment of sepsis.