title: Lipoxin A4 and platelet activating factor are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice.
abstract: CFTR (cystic fibrosis transmembrane conductance regulator) is expressed by both neutrophils and platelets. Lack of functional CFTR could lead to severe lung infection and inflammation. Here, we found that mutation of CFTR (F508del) or inhibition of CFTR in mice led to more severe thrombocytopenia, alveolar neutrocytosis and bacteriosis, and lower lipoxin A4/MIP-2 (macrophage inhibitory protein-2) or lipoxin A4/neutrophil ratios in the BAL (bronchoalveolar lavage) during acute E. coli pneumonia. In vitro, inhibition of CFTR promotes MIP-2 production in LPS-stimulated neutrophils; however, lipoxin A4 could dose-dependently suppress this effect. In LPS-induced acute lung inflammation, blockade of PSGL-1 (P-selectin glycoprotein ligand-1) or P-selectin, antagonism of PAF by WEB2086, or correction of mutated CFTR trafficking by KM11060 could significantly increase plasma lipoxin A4 levels in F508del relevant to wildtype mice. Concurrently, F508del mice had higher plasma platelet activating factor (PAF) levels and PAF-AH activity compared to wildtype under LPS challenge. Inhibiting hydrolysis of PAF by a specific PAF-AH (PAF-acetylhydrolase) inhibitor, MAFP, could worsen LPS-induced lung inflammation in F508del mice compared to vehicle treated F508del group. Particularly, depletion of platelets in F508del mice could significantly decrease plasma lipoxin A4 and PAF-AH activity and deteriorate LPS-induced lung inflammation compared to control F508del mice. Taken together, lipoxin A4 and PAF are involved in E. coli or LPS-induced lung inflammation in CFTR-deficient mice, suggesting that lipoxin A4 and PAF might be therapeutic targets for ameliorating CFTR-deficiency deteriorated lung inflammation.
authors.affiliation: Key Laboratory of Molecular Virology & Immunology, Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Haiya
authors.initials: H
authors.lastname: Wu
authors.affiliation: Department of Entomology, University of California Davis, Davis, California, United States of America.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.affiliation: Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Emily M
authors.initials: EM
authors.lastname: Su
authors.affiliation: Key Laboratory of Molecular Virology & Immunology, Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Li
authors.affiliation: Key Laboratory of Molecular Virology & Immunology, Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Caiqi
authors.initials: C
authors.lastname: Zhao
authors.affiliation: Key Laboratory of Molecular Virology & Immunology, Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Yang
authors.affiliation: Key Laboratory of Molecular Virology & Immunology, Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Zhaowei
authors.initials: Z
authors.lastname: Gao
authors.affiliation: Key Laboratory of Molecular Virology & Immunology, Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Mengyao
authors.initials: M
authors.lastname: Pan
authors.affiliation: Key Laboratory of Molecular Virology & Immunology, Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Peiyu
authors.initials: P
authors.lastname: Sun
authors.affiliation: Key Laboratory of Molecular Virology & Immunology, Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Sun
authors.affiliation: Key Laboratory of Molecular Virology & Immunology, Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Yiyi
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Key Laboratory of Molecular Virology & Immunology, Unit of Respiratory Infection and Immunity, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, China; Cardiovascular Research Institute, University of California San Francisco, San Francisco, California, United States of America.
authors.forename: Xiao
authors.initials: X
authors.lastname: Su
mesh_terms: D000818:Animals; D018893:Bronchoalveolar Lavage; D054426:Chemokine CXCL2 / Q000378:metabolism; D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000172:deficiency* / Q000378:metabolism; D004926:Escherichia coli; D008070:Lipopolysaccharides; D044045:Lipoxins / Q000097:blood / Q000378:metabolism*; D018181:Mice, Inbred CFTR; D009154:Mutation / Q000235:genetics; D019007:P-Selectin / Q000378:metabolism; D010972:Platelet Activating Factor / Q000378:metabolism*; D010976:Platelet Count; D011014:Pneumonia / Q000097:blood / Q000378:metabolism* / Q000473:pathology; D013921:Thrombocytopenia / Q000235:genetics
chemical_list: D054426:Chemokine CXCL2; C404915:Cxcl2 protein, mouse; D008070:Lipopolysaccharides; D044045:Lipoxins; D019007:P-Selectin; D010972:Platelet Activating Factor; C040527:lipoxin A4; D019005:Cystic Fibrosis Transmembrane Conductance Regulator