Bleomycin primes monocytes-macrophages for superoxide production.
Bleomycin (BLM) induces lung inflammation and subsequent fibrosis in humans and animal models. We hypothesized that monocytes-macrophages represent target cells for BLM toxicity and participate in the initial stages of pulmonary inflammation. We developed an animal model of early lung lesions using systemic administration of BLM (2 U.100 g-1 body weight over 5 days) (BLM-rats). We observed a significant decrease in body weight and in serum angiotensin converting enzyme activity in BLM-rats as compared to matched controls rats, but no evidence of fibrosis was seen in optic microscopy of the lungs from BLM-rats. In contrast, electron microscopy revealed accumulation of intracapillary polymorphonuclear leucocytes and unusual presence of eosinophils. We then investigated the in vivo effects of BLM on the respiratory burst of monocytes-macrophages. As compared to control rats, production of superoxide (O2-) by alveolar macrophages from BLM-rats was increased upon stimulation with either phorbol myristate acetate (21.04 +/- 2.78 versus 11.45 +/- 2.26 nmol.10(6) cells.20 min-1, p less than 0.05) or opsonized zymosan (9.35 +/- 0.87 versus 7.03 +/- 0.66 nmol.10(6) cells.20 min-1, p less than 0.05). We also found in BLM-rats an increased number of circulating monocytes and an increased production of O2- by these cells. Monocytes-macrophages may represent a target cell in the early events of BLM toxicity in vivo and the increased production of O2- by these cells participates in tissue injury in pulmonary fibrosis.
Nuclear Medicine Division, Hôpital Cantonal Universitaire, Geneva, Switzerland.
D O
DO
Slosman
P M
PM
Costabella
M
M
Roth
G
G
Werlen
B S
BS
Polla
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology / Q000633:toxicity*; D004195:Disease Models, Animal; D005609:Free Radicals; D008264:Macrophages / Q000187:drug effects* / Q000648:ultrastructure; D008297:Male; D009000:Monocytes / Q000187:drug effects* / Q000648:ultrastructure; D007703:Peptidyl-Dipeptidase A / Q000502:physiology; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000276:immunology / Q000648:ultrastructure; D051381:Rats; D011919:Rats, Inbred Strains; D013481:Superoxides / Q000378:metabolism*
D005609:Free Radicals; D001761:Bleomycin; D013481:Superoxides; D007703:Peptidyl-Dipeptidase A