Vascular injury after whole thoracic x-ray irradiation in the rat

Abstract

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.

Fig. 1

Body weight of rats given 5 or 10 Gy X-rays compared to age-matched controls measured at the indicated time points (mean ± sem). There was a significant reduction in body weight in rats irradiated with 10 Gy compared to age-matched controls at 2 and 12 months (*/τ p ≤ 0.02 vs age-matched controls).

Fig. 2

Total lung angiotensin converting enzyme activity was measured by means of a spectrophotometric assay using FAPGG as a substrate. The values represent total ACE activity in the lungs of rats irradiated with 5 or 10 Gy at the 6 different time points up to 1 year (mean ± sem). Significant reduction in ACE activity was observed 2, 5 and 12 months after 10 Gy compared to age-matched controls and at 12 months after 5 Gy. (/^τ/^ξ/^γ p ≤ 0.02 vs age-matched controls).

Fig. 3

Pulmonary Vascular Resistance values independent of hematocrit and blood volume in rats irradiated with 5 or 10 Gy X-rays compared to age matched controls at the indicated time points (mean ± sem). Pulmonary vascular resistance that developed at a constant flow rate of 100 ml/min/kg was found to be significantly elevated at 1, 2 and 5 months following 10 Gy compared to age-matched controls, with resolution by 12 months. No significant differences were noted between the rats irradiated with 5 Gy and their age-matched controls at any of the time points (*/^ψ/^Θ p ≤ 0.02 vs age-matched controls).

Fig. 4

The ratio of the weight of the right ventricle versus the sum of the left ventricle and septum (RV/LV+S) calculated in rats irradiated with 5 or 10 Gy of X-rays compared to age matched controls at the time points indicated (mean ± sem). There was a modest but significant increase in this ratio in rats irradiated with 5 Gy compared to age matched controls at 5 months, with resolution by 12 months. A significant elevation was also noted at 2 months after 10 Gy of X-rays compared to age matched controls with resolution by 5 months (*/^#p ≤ 0.02 vs age-matched controls).

Fig. 5

Dry lung weight normalized to body weight recorded for rats irradiated with 5 or 10 Gy compared to age-matched controls (mean ± sem). A significant elevation in this index was observed 1, 2, 5 and 12 months after 10 Gy of X-rays compared to age-matched controls (*/^τ/^ξ/^γ p ≤ 0.02 vs age-matched controls).

Fig. 6

Low-magnification (top) and high-magnification (bottom) pulmonary arterial angiograms in lungs isolated from a rat 2 months after a dose of 10 Gy (right) and an age-matched control rat (left) in which intravascular pressure was at 30 mmHg and airway pressure at 6 mmHg. In low-magnification images, the pulmonary artery cannula is 1.67 mm in diameter. In the high-magnification images, the scale bar (lower-left image) indicates approximately 500 microns.

Fig. 7

Pulmonary microvascular density measured in rats after 10 Gy compared to age-matched controls at the indicated time points (mean ± sem). Vascular density was significantly decreased at 1,2,5 and 12 months following irradiation with 10 Gy (/^{^}/^</# p ≤ 0.02 vs age-matched controls).

Fig. 8

Pulmonary arterial distensibility at 2 wks, 1, 2, 5 and 12 months following 10 Gy of X-rays compared to age-matched controls (mean ± sem). Vascular diameters were obtained from corresponding angiograms and the distensibility (change in diameter for unit changes in pressure) was computed for each group. A significant reduction in distensibility was observed at 2 months and persisted at 5 and 12 months following irradiation with 10 Gy (*/^/^$ p ≤ 0.02 vs age-matched controls).