Inhibition of FABP4 attenuates hyperoxia-induced lung injury and fibrosis via inhibiting TGF-β signaling in neonatal rats.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease characterized by interrupted alveologenesis and alveolar simplification caused by oxygen therapy in premature infants. Metabolic dysfunction is involved in the pathogenesis of BPD. Fatty acid-binding protein 4 (FABP4) is significantly increased in specific lung tissues in patients with BPD. Therefore, we investigated whether BMS309403, an FABP4 inhibitor that can mitigate tissue fibrosis, can regulate pulmonary fibrotic processes in newborn rats exposed to hyperoxia. Newborn rat pups were exposed to room air (RA; 21% O₂ ) or 85% O₂ from 5 to 14 days of age and were then allowed to recover in RA until 29 days of age. They received intraperitoneal injection with placebo (phosphate-buffered saline [PBS]) or BMS 309403 (0.5 mg or 1.0 mg kg^-1 d^-1 ) every other day from 4 to 14 days of age then were divided into O₂ plus PBS or low dose or high dose and RA plus PBS or low dose or high dose groups. We assessed lung histology and evaluated lung collagen I, FABP4 as well as TGF-β1 expression at 14 and 29 days of age. In the hyperoxia injury-recovery model, prophylactic BMS309403 treatment reduced mean linear intercept values and FABP4 expression (p < 0.001). Prophylactic BMS309403 treatment mitigated pulmonary fibrosis and TGF-β1 expression immediately after hyperoxia exposure (p < 0.05). The attenuation of hyperoxia-induced alveolar developmental impairment and pulmonary fibrosis by FABP4 inhibition indicated that such inhibition has potential clinical and therapeutic applications.