DYNAMICS OF TGF-BETA-3 PEPTIDE ACTIVITY DURING RAT ALVEOLAR EPITHELIAL-CELL PROLIFERATIVE RECOVERY FROM ACUTE HYPEROXIA

Hyperoxia causes a reproducible pattern of lung injury and recovery, c haracterized by proliferation of type II alveolar epithelial cells (AE C2) during the recovery phase. We measured TGF-beta peptide production by AEC2 and macrophages from lungs of adult male rats exposed to 100% oxygen for 48 h and then allowed to recover ibr up to 72 h in room ai r, TGF-beta peptide activity levels were measured using the PAI-1 prom oter-luciferase mink lung epithelial cell assay and characterized with peptide specific inhibitory antibodies. Control AEC2 produced 997 +/- 54 Dg active TGF-beta . 10(6) cells(-1). 24 h(-1) (mean +/- SD), of w hich > 70% was TGF-beta 3, while cultured macrophages produced 58 +/- 17 pg active TGF-beta . 10(6) macrophages(-1). 24 h(-1), > 80% of whic h was TGF-beta 1. During hyperoxia and recovery; active TGF-beta 3 pro duction by AEC2 decreased by 75%, with a nadir at 24 h recovery (P < 0 .005). In contrast, TGF-beta peptide activity increased from undetecta ble levels in lung lavage from control rats to a peak of 1,470 +/- 743 pg/rat after 45 h oxygen exposure and 24 h recovery, while lavaged ma crophage TGF-beta production in culture also increased threefold to a peak of 150 +/- 5 pg . 10(6) cells(-1). 24 h(-1) after 48 h oxygen exp osure (P < 0.005). The nadir of active TGF-beta 3 production by AEC2 c oincided with the peak of the AEC2 proliferative phase of repair as de termined by BrdU incorporation and FAGS analysis of freshly isolated A EC2. We conclude that active TGF-beta 3 production by AEC2 is dynamica lly downregulated during the proliferative phase of recovery from acut e hyperoxic injury in rat. We speculate that decreased autocrine negat ive regulation of AEC2 proliferation by TGF-beta 3 may facilitate AEC2 proliferation during recovery from acute hyperoxic injury.