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.

DOI: 10.1371/journal.pone.0093003

Extracted Key Phrases

7 Figures and Tables

0204060201520162017
Citations per Year

Citation Velocity: 7

Averaging 7 citations per year over the last 3 years.

Learn more about how we calculate this metric in our FAQ.

Cite this paper

@inproceedings{Wu2014LipoxinAA, title={Lipoxin A4 and Platelet Activating Factor Are Involved in E. coli or LPS-Induced Lung Inflammation in CFTR-Deficient Mice}, author={Haiya Wu and Jun Yang and Emily M. Su and Ling Li and Caiqi Zhao and Xi Yang and Zhaowei Gao and Mengyao Pan and Peiyu Sun and Wei Sun and Yiyi Jiang and Xiao Su}, booktitle={PloS one}, year={2014} }