Impaired defenses of neonatal mouse alveolar macrophage with deletion are modulated by glutathione and TGF1.

Our understanding of the intrinsic effects of cystic fibrosis (CF) transmembrane conductance regulator () deletion on resident neonatal alveolar macrophage (AM) remains limited. We previously demonstrated that diminished glutathione (GSH) or excessive AM transforming growth factor beta one (TGF1) contributes to AM dysfunction in a variety of disease states. In this study, using a gut-corrected neonatal knockout (KO) mouse model and a siRNA-manipulated macrophage-like cell line (THP-1 cell), we hypothesized (1) that mutation alone increases neonatal AM oxidant stress and cellular TGF1 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 ( ≤ 0.05) and oxidized GSSG ( ≤ 0.05) without concurrent inflammation compared to WT littermates. KO AM demonstrated diminished AM thiols ( ≤ 0.05), increased AM mitochondrial ROS ( ≤ 0.05), increased AM TGF1 ( ≤ 0.05) with increased TGF1 signaling ( ≤ 0.05), and impaired phagocytosis ( ≤ 0.05). KO AM mitochondrial ROS was modulated by exogenous GSH ( ≤ 0.05). Conversely, TGF1 was reduced ( ≤ 0.05) and impaired phagocytosis was rescued ( ≤ 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.