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Chronic Alcohol Ingestion in Rats Decreases K rüppel‐Like Factor 4 Expression and Intracellular Zinc in the Lung
Author(s) -
CurryMcCoy Tiana V.,
Guidot David M.,
Joshi Pratibha C.
Publication year - 2013
Publication title -
alcoholism: clinical and experimental research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.267
H-Index - 153
eISSN - 1530-0277
pISSN - 0145-6008
DOI - 10.1111/j.1530-0277.2012.01946.x
Subject(s) - metallothionein , endocrinology , in vivo , chemistry , alveolar macrophage , cell culture , in vitro , medicine , zinc , biology , macrophage , biochemistry , genetics , microbiology and biotechnology , organic chemistry
Background Chronic alcohol ingestion alters the dynamic balance between granulocyte‐macrophage colony‐stimulating factor ( GM ‐ CSF ) and transforming growth factor beta1 ( TGF β1) signaling within the alveolar space and, in parallel, impairs alveolar macrophage and epithelial cell function by inhibiting expression of the zinc importer ZIP 4 and decreasing zinc bioavailability in the alveolar compartment. As the transcription factor K rüppel‐like factor 4 ( KLF 4 ) binds to ZIP 4 , we hypothesized that alcohol exposure and consequent perturbations in GM ‐ CSF and TGF β1 signaling could decrease cellular KLF 4 expression and/or binding as a mechanism by which it inhibits ZIP 4 expression and decreases cellular zinc levels. Methods and Results Alcohol exposure in vitro or chronic ingestion in vivo decreased KLF 4 expression in alveolar macrophages and epithelial cells. Treatment with GM ‐ CSF or TGF β1 showed an enhancing or dampening effect on KLF 4 expression and binding, respectively. Further, treatment of a rat alveolar macrophage cell line with alcohol in vitro for 4 weeks decreased the expression of the zinc transporters ZIP 4 and ZNT 1, and of the zinc storage protein metallothionein 1. In parallel, treating these macrophages with KLF 4 si RNA decreased ZIP 4 expression and decreased cellular zinc and phagocytic capacity to levels equivalent to those following alcohol exposure. In epithelial monolayers, transepithelial electrical resistance ( TER ) was significantly decreased by alcohol ingestion as compared with control diets, and it was restored by in vitro GM ‐ CSF treatment. In contrast, in vitro TGF β1 treatment of the epithelial monolayers from control‐fed rats significantly decreased TER as compared with untreated control monolayers. Conclusions Taken together, these results suggest that within the alveolar space, chronic alcohol exposure decreases KLF 4 and ZIP 4 expression and consequently decreases zinc transport into cells, which, in turn, impairs their function. Furthermore, the dynamic decrease in the relative influence of GM ‐ CSF versus TGF β1 could mediate the zinc deficiency and consequent cellular dysfunction that characterize the “alcoholic lung” phenotype.