Biology Contribution
Renin-Angiotensin System Suppression Mitigates Experimental Radiation Pneumonitis

https://doi.org/10.1016/j.ijrobp.2009.07.1743Get rights and content

Purpose

To find the mitigators of pneumonitis induced by moderate doses of thoracic radiation (10–15 Gy).

Methods and Materials

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 ≤1 year. Survival decreased to <50% by 45 weeks after 12 Gy and by 8–9 weeks after 15 Gy. Captopril (17–56mg/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.

Conclusion

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.

Introduction

The lung is a sensitive target for injuries that can develop months to years after exposure to ionizing radiation (1). Preclinical research has indicated that radiation-induced injuries might be treatable, although no therapies have yet been approved by the Food and Drug Administration (FDA) (2). Our interest was to develop drugs for the mitigation (agents given after irradiation, but before symptoms manifest) of lung dysfunction that can occur in survivors of radiation accidents or radiologic attacks (3). The relevance of such studies is of increasing value because of the increasing demand for nuclear energy and threats of radiologic terrorism 2, 3. Thus, we have developed a rat model of pulmonary injury after a single nonlethal radiation dose (4). To minimize the effects on other organs (except for the heart), the irradiation was localized to the thorax. The rats were housed in a barrier to minimize infection. These rats developed pneumonitis at 4–12 weeks after a dose of 10 Gy, but not after 5 Gy (4). Structural and functional analyses of the lung revealed histopathologic changes that were accompanied by an increase in the breathing rate and a loss of vascular reactivity (measured ex vivo).

Because radiation exposure to humans at volumes encompassing both lungs is rare, the development of agents to mitigate the effects of such irradiation must be largely restricted to animal models. Free radical scavengers (5), antioxidants (6), blockers of growth factors, and inhibitors of the renin angiotensin system (RAS) (7) have demonstrated efficacy in the mitigation of radiation injuries in animal models 2, 8. These studies were preliminary and did not explicitly address radiation accident or terrorism scenarios 9, 10, 11. For example, in previous studies, the angiotensin-converting enzyme (ACE) inhibitor captopril or enalapril and the AT1 receptor blocker L158,809 were administered before radiation exposure. In addition, the radiation doses were fractionated, rendering them of uncertain relevance to single-dose exposures. The radiation was often applied to the hemithorax, which might not reflect the consequences of simultaneous injury in both lungs. Finally, many of the studies were conducted to evaluate the effect of total body irradiation for bone marrow transplantation, which included a preparatory course of cyclophosphamide. We chose to study two FDA-approved RAS inhibitors in our model of rat radiation pneumonitis: the ACE inhibitor, captopril, and the angiotensin II, type 1, (AT1) blocker, losartan.

Section snippets

Animal model

The Institutional Animal Care and Use Committee at the Medical College of Wisconsin approved all protocols. The rats (female WAG/RijCmcr) were housed in a moderate security barrier. After radiation exposure, the drinking water of preselected groups was supplemented with pharmaceutical grade captopril (Sigma Chemical, St. Louis, MO) or losartan (Merck, Whitehouse Station, NJ) immediately or after a delay of 1 or 2 weeks. The drugs were delivered in the drinking water at concentrations of 100–500

Prosurvival actions of captopril and losartan

We have previously reported that thoracic irradiation with a dose of 10 Gy did not affect the acute survival of rats and also did not generate fibrotic injury to the lung (4). Figure 1A shows the morbidity after whole thoracic doses of 10, 12, and 15 Gy. Survival after 15 Gy was reduced to <50% by 8–9 weeks after irradiation (Fig. 1A), but survival was increased to >80% by treatment with captopril at 56 mg/kg/d started immediately after radiation (Fig. 1B). In additional studies, we used a

Discussion

Our long-term goal was to identify mitigators and treatments of radiation-induced lung injury after a radiologic attack or radiation accident 2, 3, 16.

In the present study, we tested two FDA-approved RAS suppression agents (captopril and losartan) for mitigation efficacy 8 weeks after irradiation when pneumonitis peaked. The drug doses were chosen to match, on a milligram per meter squared per day basis, those used in the clinic. Some of these drug doses have been effective for mitigation and

Conclusion

We have shown that the ACE inhibitor captopril is an effective mitigator of pulmonary dysfunction caused by survivable doses of radiation. To our knowledge, this is the first demonstration that lung injury caused by a single whole-thoracic radiation dose can be mitigated by an FDA-approved agent. At doses (on a milligram per meter squared per day basis) approved by the FDA for use in humans, captopril improves the vascular, functional, and structural derangements that develop in the rat lung by

Acknowledgments

We acknowledge the invaluable technical assistance from Mary Lou Mäder, Amy Irving, and Ying Gao, as well as the support and suggestions from Dr. Robert Molthen and Qingping Wu at the Zablocki Veterans Affairs Medical Center in Milwaukee. Losartan was a kind gift from Merck.

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  • Cited by (0)

    Supported by National Institutes of Health/National Institute of Allergy and Infectious Diseases (Grants U19-AI-67734 and RC-1 AI 81294).

    Conflict of interest: none.

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