Biology Contribution
Vascular Injury After Whole Thoracic X-Ray Irradiation in the Rat

https://doi.org/10.1016/j.ijrobp.2009.01.006Get rights and content

Purpose

To study vascular injury after whole thoracic irradiation with single sublethal doses of X-rays in the rat and to develop markers that might predict the severity of injury.

Methods and Materials

Rats that received 5- or 10-Gy thorax-only irradiation and age-matched controls were studied at 3 days, 2 weeks, and 1, 2, 5, and 12 months. Several pulmonary vascular parameters were evaluated, including hemodynamics, vessel density, total lung angiotensin-converting enzyme activity, and right ventricular hypertrophy.

Results

By 1 month, the rats in the 10-Gy group had pulmonary vascular dropout, right ventricular hypertrophy, increased pulmonary vascular resistance, increased dry lung weights, and decreases in total lung angiotensin-converting enzyme activity, as well as pulmonary artery distensibility. In contrast, irradiation with 5 Gy resulted in only a modest increase in right ventricular weight and a reduction in lung angiotensin-converting enzyme activity.

Conclusion

In a previous investigation using the same model, we observed that recovery from radiation-induced attenuation of pulmonary vascular reactivity occurred. In the present study, we report that deterioration results in several vascular parameters for ≤1 year after 10 Gy, suggesting sustained remodeling of the pulmonary vasculature. Our data support clinically relevant injuries that appear in a time- and dose-related manner after exposure to relatively low radiation doses.

Introduction

Lung injury after exposure to high-dose radiation during cancer treatment has been well described. Although radiation injuries to the kidneys or hematopoietic system can occur at lower doses than pulmonary injuries, better supportive therapies for renal and blood cell disorders are available than for lung failure, potentially leaving impaired pulmonary function as the survival limiting factor. Furthermore, the response of the lung to exposure in the 1–10-Gy range has not been well investigated (1). This dose range assumes importance in the face of the growing threat of nuclear accidents and radiologic terrorism, with exposure possible, to survivable radiation doses. Any attempt to adequately respond to such incidents will require the capability to accurately predict and interpret the expression of radiation injury in different organ systems.

Radiation injury is believed to result from a combination of the direct effects of radiation, the inflammatory process, and abnormal wound healing. Several mediators, including reactive oxygen and nitrogen species, cytokines, growth factors, and intermediates of the renin-angiotensin system, are involved in this complex process (2). The injury of blood vessels is believed to be a primary determinant of the resultant effects of radiation in a variety of organs, including the lungs (3). Clinical studies conducted in the early 1970s examined the relationship between relative pulmonary blood flow and irradiation. Blood flow was found to decrease in regions of the lungs irradiated with 40 Gy, although the mechanism was not clear (4). Recent studies in rats have demonstrated changes in lung perfusion occurring as early as 3 days after hemithoracic irradiation with 28 Gy of X-rays, which initiates the development of hypoxia and chronic oxidative stress that perpetuates injury (5). We have confirmed that the reactivity of pulmonary arteries is attenuated after injury by 10 Gy to the whole thorax. The decrease in reactivity coincided with other structural and functional indexes of pulmonary dysfunction (6). In the present study, we measured several parameters to more completely characterize pulmonary vascular status in rats after single whole thoracic irradiation using sublethal doses. Hemodynamic and structural alterations in pulmonary vasculature are also likely to have an effect on cardiac function. McChesney et al. demonstrated that structural and functional cardiac damage, as well as pulmonary hypertension, were more pronounced in dogs after 12 Gy whole thoracic irradiation compared with irradiation of limited volumes of the lungs and heart 7, 8. In addition to being an important factor in the development, progression, and resolution of radiation-induced cardiopulmonary dysfunction, remodeling in the pulmonary vascular bed could also be a target for therapeutic intervention after radiation exposure.

A suitable animal model with well-defined features is needed to understand further the processes that underlie radiation injury with sublethal doses at the tissue and whole animal level. Such knowledge will be crucial in accurately evaluating the efficacy of radioprotectors and therapeutic agents, as well as in monitoring individuals with survivable radiation injury. We developed a rat model of radiation-induced lung injury (6) and sequentially assessed the changes in cardiopulmonary physiology and morphology that result from whole thoracic irradiation with single doses of 5 or 10 Gy X-rays.

Section snippets

Animals

All the studies were done under approval of the Medical College of Wisconsin and Zablocki Veterans Affairs Medical Center Institutional Animal Care and Use Committee review boards and in compliance with the National Research Council's “Guide for the Care and Use of Laboratory Animals.”

Injury model

Unanesthetized female WAG/Rij/MCW rats (110–170 g, n = 144) were placed in a Plexiglas holding jig and given 5 or 10 Gy of radiation limited to the thorax. A Pantak HF320 orthovoltage system (Therapax, Danbury,

Body weight

The body weight was observed to vary with the dose. No reduction in body weight was observed in rats irradiated with 5 Gy compared with the age-matched controls at any endpoint. However, rats irradiated with 10 Gy had a significant decrease in body weight compared with the age-matched controls at 2 and 12 months (Fig. 1).

Hematocrit

The hematocrit did not vary after the two doses used, and no significant differences were recorded in rats irradiated with either 5 or 10 Gy compared with the age-matched

Discussion

Large-dose radiation injury from fractionated radiation exposure of the thorax has been investigated because of the use of therapeutic radiation for lung tumors or lymphoma. The consequences of a single exposure to lower doses have only recently received attention because of the threat of radiologic terrorism. In addition, pulmonary fibrosis is a well-recognized complication of total body irradiation, including the lungs, developing months to years after total body irradiation with more modest

Conclusion

These data are essential for two purposes. First, they are needed to estimate the risk and presentation of injury, as well as to optimize screening procedures for patients with possible exposure. Second, to test any mitigating or therapeutic interventions, the natural history of a single radiation dose to the thorax must be known.

Additional studies are needed to determine whether the deterioration in pulmonary arterial distensibility and vessel density after whole thoracic irradiation with 5 or

Acknowledgments

The authors would like thank Gretta Schmirler for expert technical assistance. We thank Lynn Gruman of the Histology Core for the sectioning and staining of lung tissues, and Vladimir Semenenko and X. Allen Li in the Irradiation Core for conducting irradiation and dosimetry.

References (26)

  • R.C. Molthen et al.

    Quantitative models of the rat pulmonary arterial tree morphometry applied to hypoxia-induced arterial remodeling

    J Appl Physiol

    (2004)
  • J.H. Linehan et al.

    A simple distensible vessel model for interpreting pulmonary vascular pressure-flow curves

    J Appl Physiol

    (1992)
  • W. Miska et al.

    Proteins of the kallikrein-kinin system in human semen: Isolation and properties of kininase II

    Biol Chem Hoppe Seyler

    (1988)
  • Cited by (58)

    • Pharmacologic ACE-Inhibition Mitigates Radiation-Induced Pneumonitis by Suppressing ACE-Expressing Lung Myeloid Cells

      2022, International Journal of Radiation Oncology Biology Physics
      Citation Excerpt :

      Although genetic and pharmacologic inhibition of ACE is known to improve late injury to multiple organ systems,2,6,8,12 the mechanisms of these actions are unclear. ACE inhibitor treatment has well-established function as a vasodilator and a suppressor of reactive oxygen species production in the vasculature; however, ACE activity falls in the lung perfusate during radiation pneumonitis due to pulmonary vasculature regression.14 These data would suggest ACE inhibitors may have a nonvascular cellular target in the mitigation of radiation pneumonitis.

    • Decreasing irradiated rat lung volume changes dose-limiting toxicity from early to late effects

      2016, International Journal of Radiation Oncology Biology Physics
      Citation Excerpt :

      In general we see a dose dependent biphasic increase in respiratory rate as reported before (5, 6). Next, we assessed the level of known radiation-induced lung pathologies, vascular remodeling, pulmonary inflammation, and fibrosis (3, 6, 7, 9, 11-16) by scoring the histology of lung slides (Fig. 3). Finally, to investigate the role of these different pathologies in the development of late RILD, we correlated the level of early and late lung effects with respiratory rate changes.

    • Biomarkers to Predict Lethal Radiation Injury to the Rat Lung

      2023, International Journal of Molecular Sciences
    • Modeling normal bladder injury after radiation therapy

      2023, International Journal of Radiation Biology
    View all citing articles on Scopus

    Supported by National Institutes of Health/NIAID U19 AI067734-01 and the Department of Veterans Affairs.

    Conflict of interest: none.

    View full text