Early Structural Changes in Sheep Lung Following Thoracic Irradiation

Abstract

Using a large animal model of radiation lung injury--the sheep exposed to bilateral thoracic irradiation--we have recently shown the development of sustained pulmonary hypertension during the first 4 weeks following radiation. This is the period prior to the onset of pneumonitis and pulmonary fibrosis. In the present study, we have examined biopsy and autopsy lung tissue from these same sheep and assessed the sequential changes in lung morphology. Six unanesthetized sheep received bilateral thoracic irradiation (a total of 15 Gy); control sheep were sham irradiated. Lung biopsy tissue was taken prior to and at weekly or biweekly intervals during the 4 weeks immediately following radiation. The lungs were also removed at autopsy for light and electron microscopic examination. Our results show early (Week 1) interstitial and progressive intraalveolar edema accompanied by endothelial and epithelial injury. A gradual increase in number of interstitial mononuclear cells was evident from Week 1, both in the lung tissue and in perivascular cuffs. The number of peripheral lung interstitial mononuclear cells was twice baseline from Week 3 and included accumulation of lymphocytes, fibroblasts, and intravascular macrophages. The increased numbers of mononuclear cells paralleled the development of chronic pulmonary hypertension, perhaps suggesting their involvement in the pathogenesis of this disease. Alternatively, it may be that increased mononuclear cell number represents a stage of lung repair.

Correlation between Increased Airway Responsiveness and Severity of Pulmonary Edema

“…Detailed analysis of the sheep's response to purified Though only speculation, it is of interest to relate PK demonstrates histologic 19 and physiologic evidence the alterations in airway wall area observed in our consistent with pulmonary edema formation being sheep models of cardiogenic and non-cardiogenic pulsecondary to relatively pure increases in pulmonary monary edema to the inflammation and restructuring microvascular permeability. 8,9,15,19 Increases in left observed in asthma in humans. Currently, asthma is atrial pressure and pulmonary microvascular presinterpreted as a disease in which airway inflammation sures are not observed following treatment with PK.…”

Histological and ultrastructural analyses of mole rats lung cells exposed to ultraviolet radiation

“…This deformation could be formed as a direct toxic effect of radiation on some constituent of interstitial tissue, resulting in elevated osmotic pressure and increasing in the ground substances (Bernard et al, 2012;Davis et al, 1992;Guerry-Force, Perkett, Brigham, & Meyrick, 1988;Kononenko, 1985;Kurus et al, 2013).…”

Epidermal growth factor receptor-tyrosine kinase inhibitor (gefitinib) augments pneumonitis, but attenuates lung fibrosis in response to radiation injury in rats

“…Radiation-induced lung disorder is characterized by interstitial edema, interstitial and alveolar inflammatory cell infiltration (11,12), and subsequent fibrotic reaction characterized by the proliferation of fibroblasts and deposition of extracellular matrix (13). The recruitment and activation of inflammatory cells, such as neutrophils and lymphocytes, are central elements in the development of radiationinduced interstitial pneumonitis (22,23,29).…”

“…However, TRT also induces injury to normal lung tissue, causing radiation pneumonitis (inflammation of the lungs due to radiation) (9). The injury of capillary endothelial cells and epithelial cells, which have the highest mitotic rate and are the most susceptible cells in the lung to radiation, is believed to initiate alveolar edema, exudation, and vascular congestion (10,11). Radiation fibrosis is a sequel of radiation pneumonitis, as an excessive and detrimental over-healing (12,13).…”