PULMONARY ENDOTHELIAL DYSFUNCTION IN THE PRESENCE OR ABSENCE OF INTERSTITIAL INJURY INDUCED BY INTRATRACHEALLY INJECTED BLEOMYCIN IN RABBITS

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Abstract
Repeated s.c. administration of bleomycin (BLM) to rabbits was previously shown to produce functional and structural endothelial damage with no evidence interstitial fibrosis. Here, rabbits received intratracheally a single injection of BLM (6 U/kg, n = 6: low dose or 11 U/kg, n = 4: high dose); 6 additional animals received intratracheally an injection of saline and served as controls. Four weeks after BLM administration, the low-dose group demonstrated significant reduction in the single-pass pulmonary removal of 14C-5-hydroxytryptamine (5-HT) (P < 0.05; n = 4); 3H-norepinephrine (NE) removal and 3H-benzoyl-phe-ala-pro (BPAP) substrate for lung angiotension converting enzyme (ACE) metabolism in vivo, as well as lung and serum ACE activity in vitro remained at control levels. No morphologic or biochemical evidence of fibrosis was observed. The high-dose BLM group exhibited significant reductions in 14C-5-HT and 3H-NE removal and 3H-BPAP metabolism in vivo but no significant changes in lung or serum ACE activity in vitro. There was evidence of fibrosis, as revealed by 59% increase in lung hydroxyproline content and by light microscopic examination of lung tissue. Intratracheal administration of BLM to rabbits can produce endothelial dysfunction in the presence or absence of interstitial injury.