Angiotensin converting enzyme activity in mice after subacute bleomycin administration

Abstract

Multiple ip or sc injections of bleomycin (BLM) in mice elevated the serum and pulmonary activities of the peptidyl dipeptidase, angiotensin converting enzyme (ACE). ACE activity in lungs of mice treated every 3 days with BLM (9 mg/kg) was elevated 33, 36, and 45 days after the initiation of ip drug administration. After 12 BLM injections the increases in enzyme activities were dose related, with mice receiving the largest cumulative dose (108 mg/kg) having the greatest increase (53%) in lung ACE activity above control values. Mice treated every 3 days sc also had elevated pulmonary ACE activities after 15 injections, although liver and spleen activities were unaltered and the activities in the kidneys were reduced over 70% from control values. In addition to elevated lung ACE activity, serum ACE activity was increased 22 and 26% in mice treated ip and sc, respectively. A marked elevation in lung collagen as measured by lung hydroxyproline content was detected at the time of increased lung and serum ACE activity. Mice injected ip more frequently but with a lower dose of BLM (1.5 mg/kg, 2×/day, 5 days/week × 5 weeks) displayed no change in pulmonary ACE activity and hydroxyproline content even though they had received, over the same time period, a cumulative dose of BLM equal to that achieved by injecting 9 mg/kg of BLM every 3 days × 12. These data indicate that, subacute treatment of mice with BLM leads to an elevation in pulmonary and serum ACE activity and a decrease in renal ACE activity at the time of the development of fibrosis. The increase in lung ACE activity and hydroxyproline content appears to depend not only upon the total cumulative dose but also the dosage schedule. The elevation in serum ACE activity may reflect the loss of kidney enzyme or the shedding of pulmonary enzyme.