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Influenza‐induced cardiopulmonary dysfunction and alveolar fluid clearance inhibition are attenuated in F508del CFTRheterozygous mice
Author(s) -
Davis Ian Christopher,
Aeffner Famke,
Abdulrahman Basant,
HickmanDavis Judy Marie,
Janssen Paul,
Hayes Don,
Amer Amal,
Bedwell David,
Sorscher Eric
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.913.7
Subject(s) - bronchoalveolar lavage , lung , immunology , influenza a virus , medicine , nasal administration , pulmonary edema , secretion , chemistry , virus , endocrinology
Influenza virus inhibits bronchoalveolar epithelial ENaC‐mediated Na + absorption and stimulates Cl − secretion via CFTR, resulting in significant impairment of alveolar fluid clearance (AFC). To determine the contribution of CFTR to influenza pathogenesis, adult C57BL/6‐congenic F508del CFTR‐heterozygous mice (HETs) and wild‐type (WT) littermate controls were mock‐infected intranasally with 50 μl virus diluent (0.1% FCS in PBS) or infected with 10,000 FFU/mouse influenza A/WSN/33 (H1N1). Infection‐induced hypoxemia and bradycardia were attenuated in HETs at 2–6 days post‐infection (d.p.i.), although weight loss and viral replication did not differ from WT controls. Pulmonary edema (increasing lung wet:dry weight) developed over the course of infection in WT mice, but was absent in HETs at both 2 and 6 d.p.i. Influenza significantly inhibited AFC in live, mechanically‐ventilated WT mice at 2–6 d.p.i. In HETs, influenza had no effect on AFC at 2 d.p.i. and caused significantly less AFC inhibition at 6 d.p.i. Higher HET AFC rates were associated with greater bronchoalveolar lavage fluid TGF‐β at 2 d.p.i. and a 10‐fold increase in IL‐6 at 6 d.p.i. Systemic antibody‐mediated neutralization of TGF‐β or IL‐6 did not alter outcomes in WT mice, but increased cardiopulmonary dysfunction to WT levels in HETs. Our findings indicate that CFTR activity is an important host determinant of lung dysfunction in influenza.