Megan Podowski, Carla Calvi, Shana Metzger, Kaori Misono, Hataya Poonyagariyagorn, Armando Lopez-Mercado, Therese Ku, Thomas Lauer, Sharon McGrath-Morrow, Alan Berger, Christopher Cheadle, Rubin Tuder, Harry C. Dietz, Wayne Mitzner, Robert Wise, Enid Neptune
Losartan and TGF-β–neutralizing antibody inhibit chronic CS-induced TGF-β signaling in the lung and attenuate destructive airspace enlargement.
(A) Morphometric analysis of airspace dimension assessed by mean linear intercept (MLI) in mice subjected to 1 month, 2 months, and 4 months of CS exposure. n = 10–25 mice per treatment group. *P < 0.01. (B) Morphometric analysis of airspace dimension in mice subjected to 2 months of RA with drinking water or 2 months of CS exposure with drinking water, concurrent low-dose losartan (LD, 0.6 g/l), high-dose losartan (HD, 1.2 g/l), control antibody, or TGF-β–neutralizing antibody (TGFNAb) (10 mg/kg/wk). *P < 0.01, RA versus CS or CS versus CS plus other treatments. n = 6–8 mice per treatment group. (C) Representative H&E photomicrographs of lungs from mice subjected to 2 months of CS exposure with or without losartan treatment compared with RA controls. Original magnification, ×20. Scale bar: 200 μm. (D) Airway alveolar attachment count in mice subjected to the designated treatments. n = 6–8 mice per treatment group. BM, basement membrane. (E) Representative photomicrographs of lungs subjected to CS compared with RA controls or CS plus losartan stained for psmad2 (brown), a marker of TGF-β signaling (airspace compartment [top panel], airway compartment [bottom panel]). Original magnification, ×40. Scale bar: 50 μm. (F) Quantitative immunohistochemistry of psmad2 staining of lungs from aforementioned treatment groups. n = 6–8 mice per treatment or condition. CS + Los, CS plus losartan.