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.
Highlights
Our previous studies have shown that CFTR expressed by neutrophils and platelets plays an important role in mediating LPS-induced acute lung inflammation [1,2,3]
We found that blockade of PSGL-1, P-selectin, or platelet activating factor (PAF), and correction of mutated CFTR trafficking Fig. 5D) significantly increased plasma lipoxin A4 levels in the LPSchallenged F508del mice compared to the vehicle-treated LPSchallenged F508del mice
Correction of thrombocytopenia by anti-platelet aggregation, blockade of PSGL-1 or PAF receptor, or rectifying of mutated CFTR trafficking is associated with a better outcome of acute lung inflammation [2]
Summary
Our previous studies have shown that CFTR expressed by neutrophils and platelets plays an important role in mediating LPS-induced acute lung inflammation [1,2,3]. Patients with cystic fibrosis (CF, caused by CFTR gene mutation) suffer from recurrent lung infection and inflammation manifested by higher neutrophils and other inflammatory profiles and lower lipoxin A4 levels in the lung [4]. We approached an E. coli pneumonia F508del mouse model to test whether mutation of CFTR would affect blood platelet counts, lung bacterial titers, and inflammatory profiles. Two different specific CFTR inhibitors (MalH-2 and CFTRinh-172) were used to test whether inhibition of CFTR would worsen lung infection and inflammation, especially reduce lung lipoxin A4 levels as seen in F508del mice
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