Open AccessImpaired defenses of neonatal mouse alveolar macrophage with cftr deletion are modulated by glutathione and TGF β 1
Author(s) -
Gauthier Theresa W.,
Grunwell Jocelyn R.,
Ping XiaoDu,
Harris Frank L.,
Brown Lou Ann S.
Publication year - 2017
Publication title -
physiological reports
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.918
H-Index - 39
ISSN - 2051-817X
DOI - 10.14814/phy2.13086
Subject(s) - glutathione , endocrinology , medicine , inflammation , oxidative stress , cystic fibrosis transmembrane conductance regulator , cystic fibrosis , alveolar macrophage , mitochondrial ros , bronchoalveolar lavage , phagocytosis , macrophage , transforming growth factor beta , transforming growth factor , lung , chemistry , immunology , in vitro , biochemistry , enzyme
Our understanding of the intrinsic effects of cystic fibrosis ( CF ) transmembrane conductance regulator ( cftr ) deletion on resident neonatal alveolar macrophage ( AM ) remains limited. We previously demonstrated that diminished glutathione ( GSH ) or excessive AM transforming growth factor beta one ( TGF β 1) contributes to AM dysfunction in a variety of disease states. In this study, using a gut‐corrected cftr neonatal knockout ( KO ) mouse model and a si RNA ‐manipulated macrophage‐like cell line ( THP ‐1 cell), we hypothesized (1) that cftr mutation alone increases neonatal AM oxidant stress and cellular TGF β 1 signaling via altered GSH , thereby impairing cellular function, and (2) that exogenous GSH attenuates AM alterations and dysfunction in the KO AM . In neonatal KO mice, the baseline bronchoalveolar lavage fluid demonstrated a near doubling in mixed disulfides ( P ≤ 0.05) and oxidized GSSG ( P ≤ 0.05) without concurrent inflammation compared to WT littermates. KO AM demonstrated diminished AM thiols ( P ≤ 0.05), increased AM mitochondrial ROS ( P ≤ 0.05), increased AM TGF β 1 ( P ≤ 0.05) with increased TGF β 1 signaling ( P ≤ 0.05), and impaired phagocytosis ( P ≤ 0.05). KO AM mitochondrial ROS was modulated by exogenous GSH ( P ≤ 0.05). Conversely, TGF β 1 was reduced ( P ≤ 0.05) and impaired phagocytosis was rescued ( P ≤ 0.05) by exogenous GSH in the KO AM . These results suggest that an altered neonatal AM phenotype may contribute to the initiation of lung inflammation/infection in the CF lung. Modulation of the AM in the neonatal CF lung may potentially alter progression of disease.