Renin-Angiotensin system suppression mitigates experimental radiation pneumonitis.
OBJECTIVE
To find the mitigators of pneumonitis induced by moderate doses of thoracic radiation (10-15 Gy).


METHODS
Unanesthetized WAG/RijCmcr female rats received a single dose of X-irradiation (10, 12, or 15 Gy at 1.615 Gy/min) to the thorax. Captopril (an angiotensin-converting enzyme inhibitor) or losartan (an angiotensin receptor blocker) was administered in the drinking water after irradiation. Pulmonary structure and function were assessed after 8 weeks in randomly selected rats by evaluating the breathing rate, ex vivo vascular reactivity, and histopathologic findings. Survival analysis was undertaken on all animals, except those scheduled for death.


RESULTS
Survival after a dose of 10 Gy to the thorax was not different from that of unirradiated rats for <or=1 year. Survival decreased to <50% by 45 weeks after 12 Gy and by 8-9 weeks after 15 Gy. Captopril (17-56 mg/kg/d) improved survival and reduced radiation-induced increases in breathing rate, changes in vascular reactivity, and histopathologic evidence of injury. Radiation-induced increases in the breathing rate were prevented even if captopril was started 1 week after irradiation or if it was discontinued after 5 weeks. Losartan, although effective in reducing mortality, was not as efficacious as captopril in mitigating radiation-induced increases in the breathing rate or altered vasoreactivity.


CONCLUSIONS
In rats, a moderate thoracic radiation dose induced pneumonitis and morbidity. These injuries were mitigated by captopril even when it was begun 1 week after radiation or if discontinued 5 weeks after exposure. Losartan was less effective in protecting against radiation-induced changes in vascular reactivity or tachypnea.
Ghosh
Swarajit N
SN
Department of Medicine, Division of Pulmonary and Critical Care, Medical College of Wisconsin, Milwaukee, WI 53226, USA. snghosh@mcw.edu
Zhang
Rong
R
Fish
Brian L
BL
Semenenko
Vladimir A
VA
Li
X Allen
XA
Moulder
John E
JE
Jacobs
Elizabeth R
ER
Medhora
Meetha
M
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D002216:Captopril / Q000008:administration & dosage / Q000627:therapeutic use*; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D019808:Losartan / Q000008:administration & dosage / Q000627:therapeutic use*; D008168:Lung / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects; D011651:Pulmonary Artery / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D011829:Radiation Dosage; D011833:Radiation Injuries, Experimental / Q000188:drug therapy / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D017564:Radiation Pneumonitis / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects* / Q000502:physiology; D015656:Respiratory Mechanics / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects
D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D002216:Captopril; D019808:Losartan