Background: Mutation of cystic fibrosis transmembrane conductance regulator (CFTR) in the airway epithelial cells can lead to recurrent airway inflammation in cystic fibrosis (CF). Dysfunction of CFTR in neutrophils could contribute to LPS-induced acute lung inflammation. Deficiency of CFTR could also facilitate platelet aggregation and neutrophil-platelet interaction and promote inflammation.
Aim: To study whether inhibition or mutation of CFTR in alveolar macrophages (AMs) or peritoneal macrophages (PMs) would promote their proinflammatory responses and whether dysfunction of CFTR would deteriorate acute E. coli-induced lung or peritoneal inflammation.
Design: Laboratory study.
Methods: ELISA was used to determine production of proinflammatory cytokines in the CFTR inhibited or mutated macrophages under LPS challenge. Lung or peritoneum lavage was used to analyze proinflammatory parameters and cell differentiation. Excess lung water and lung vascular permeability were measured for evaluating severity of acute lung inflammation.
Results: Escherichia coli LPS simulation in AMs increased CFTR expression. Inhibition or mutation of CFTR in both AMs and PMs enhanced production of tumor necrosis factor alpha (TNF-α) and macrophage inflammatory protein-2 (MIP-2). Mutation of CFTR in macrophages exaggerated production of cytokines through NF-kB and p38 MAPK. Inhibition of CFTR by MalH2 or CFTRinh-172 deteriorates E. coli-induced acute lung inflammation. Deficiency of CFTR promotes migration of monocytes and neutrophils in E. coli pneumonia and peritonitis mouse models.
Conclusions: CFTR expressed by alveolar or peritoneal macrophages regulates acute proinflammatory responses.
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