Angiotensin converting enzyme inhibitors mitigate collagen synthesis induced by a single dose of radiation to the whole thorax.
Our long-term goal is to use angiotensin converting enzyme (ACE) inhibitors to mitigate the increase in lung collagen synthesis that is induced by irradiation to the lung, which could result from accidental exposure or radiological terrorism. Rats (WAG/RijCmcr) were given a single dose of 13 Gy (dose rate of 1.43 Gy/min) of X-irradiation to the thorax. Three structurally-different ACE inhibitors, captopril, enalapril and fosinopril were provided in drinking water beginning 1 week after irradiation. Rats that survived acute pneumonitis (at 6-12 weeks) were evaluated monthly for synthesis of lung collagen. Other endpoints included breathing rate, wet to dry lung weight ratio, and analysis of lung structure. Treatment with captopril (145-207 mg/m(2)/day) or enalapril (19-28 mg/m(2)/day), but not fosinopril (19-28 mg/m(2)/day), decreased morbidity from acute pneumonitis. Lung collagen in the surviving irradiated rats was increased over that of controls by 7 months after irradiation. This increase in collagen synthesis was not observed in rats treated with any of the three ACE inhibitors. Analysis of the lung morphology at 7 months supports the efficacy of ACE inhibitors against radiation-induced fibrosis. The effectiveness of fosinopril against fibrosis, but not against acute pneumonitis, suggests that pulmonary fibrosis may not be a simple consequence of injury during acute pneumonitis. In summary, three structurally-different ACE inhibitors mitigate the increase in collagen synthesis 7 months following irradiation of the whole thorax and do so, even when therapy is started one week after irradiation.
Department of Radiation Oncology, MFRC 4072-76, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Lakhan
L
Kma
Feng
F
Gao
Brian L
BL
Fish
John E
JE
Moulder
Elizabeth R
ER
Jacobs
Meetha
M
Medhora
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D002216:Captopril / Q000494:pharmacology / Q000627:therapeutic use*; D003094:Collagen / Q000096:biosynthesis*; D004307:Dose-Response Relationship, Radiation; D004353:Drug Evaluation, Preclinical; D004656:Enalapril / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D005355:Fibrosis; D017328:Fosinopril / Q000494:pharmacology / Q000627:therapeutic use*; D005786:Gene Expression Regulation / Q000528:radiation effects*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000528:radiation effects; D011658:Pulmonary Fibrosis / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D017564:Radiation Pneumonitis / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D012084:Renin-Angiotensin System / Q000502:physiology; D013909:Thorax / Q000528:radiation effects*
D000806:Angiotensin-Converting Enzyme Inhibitors; D004656:Enalapril; D003094:Collagen; D002216:Captopril; D017328:Fosinopril