title: CFTR regulates acute inflammatory responses in macrophages.
abstract: 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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: From the Institute of Biology and Medical Sciences, Soochow University, Suzhou 215123, China.
authors.forename: Z
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China and Cardiovascular Research Institute, University of California, San Francisco, CA 94143-0130, USA xsu@ips.ac.cn.
authors.forename: X
authors.initials: X
authors.lastname: Su
mesh_terms: D000208:Acute Disease; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004927:Escherichia coli Infections / Q000378:metabolism / Q000473:pathology; D008070:Lipopolysaccharides; D016676:Macrophages, Alveolar / Q000378:metabolism*; D017737:Macrophages, Peritoneal / Q000378:metabolism*; D018181:Mice, Inbred CFTR; D009000:Monocytes / Q000502:physiology; D009154:Mutation; D016328:NF-kappa B / Q000502:physiology; D009504:Neutrophils / Q000502:physiology; D010538:Peritonitis / Q000378:metabolism / Q000473:pathology; D018410:Pneumonia, Bacterial / Q000378:metabolism / Q000473:pathology*; D048051:p38 Mitogen-Activated Protein Kinases / Q000502:physiology
chemical_list: D016207:Cytokines; D008070:Lipopolysaccharides; D016328:NF-kappa B; D019005:Cystic Fibrosis Transmembrane Conductance Regulator; D048051:p38 Mitogen-Activated Protein Kinases