Retinoic acid induced repair in the lung of adult hyperoxic mice, reducing transforming growth factor-β1 (TGF-β1) mediated abnormal alterations

The aim of the study was to determine the effects of retinoic acid on lung alveolar repair in adult hyperoxic mice and to investigate the relationship between TGF-β1 and retinoic acid during the repair processes. Adult mice were divided into 4 groups. Two groups were given daily intraperitoneal injections of peanut oil/dimethylsulfoxide mixture and retinoic acid (50 mg/kg body weight, 50 μl of volume) dissolved in peanut oil/dimethylsulfoxide mixture for 12 days with a 2-day break on days 6 and 7. Following hyperoxia (100% oxygen) for 72 h the remaining two groups were treated in the same manner as already described: peanut oil/dimethylsulfoxide mixture and retinoic acid. Lung structure was investigated by light microscopy. TGF-β1 and Smad protein expressions in the lung were assayed by biochemical methods. Hyperoxic mice exhibited damage to the alveolar walls, increased cell proliferation and induced Smad3/TGF-β1 signaling. Smad2 and phospho-Smad2 protein expressions were unchanged in all groups. Retinoic acid administration improved the degenerative alterations caused by hyperoxia and helped in alveolar repair. This positive effect of retinoic acid resulted from the inhibition of Smad3/TGF-β1 signaling via reduced Smad4 mRNA and increased Smad7 protein expression. Retinoic acid also induced alveolarization and restricted Smad3/TGF-β1 signaling by decreasing Smad4 mRNA in healthy mice. Thus, retinoic acid helped repair Smad3/TGF-β1-induced lung damage in hyperoxic mice.