gms | German Medical Science

Pneumonitis is a dose-limiting side effect of radiotherapy for any thorax associated neoplasm. Clinically, it may cause an increase in breathing frequency due to respiratory insufficiency and results in a lethality rate up to 10%. Pneumonitis mostly occurs within irradiated areas of the lung but can spread to non irradiated areas, indicating that humoral factors might be involved. However, the underlying mechanisms of irradiation-induced pneumonitis are unclear. The current hypothesis suggests that complex alterations concerning epithelial/endothelial cells, macrophages/monocytes and a perpetual cascade of cytokine expression patterns are of major importance for the induction of pneumonitis. In this scenario several observations suggest an involvement of the CD95/CD95-ligand (CD95-L) system in proinflammatory cytokine responses and attraction of neutrophils. Moreover the expression of CD95 and CD95-L is induced by ionizing radiation. The aim of the present study was to gain insight into a putative involvement of the CD95/CD95-L system in radiation-induced pneumonitis. Mice with a genetically defined deficiency of the CD95 receptor (lpr) or the CD95 ligand (gld) and control mice with an intact CD95/CD95-L system (C57BL6/J) were analysed for their susceptibility to develop radiation-induced pneumonitis. To this end we examined the development of pneumonitis after single irradiation with 0/12,5 Gy to the right hemithorax in CD95 (lpr) or CD95L deficient (gld) and control mice (C57BL/6J) regarding breathing frequency and histopathological alterations. A highly significant increase in breathing frequency occurred in irradiated control mice between days 5 and 70. Furthermore, a clear inflammatory response with increased alveolar wall thickness, interstitial edema and enhanced number of inflammatory cells in the interstitial and peribronchial space was observed at days 21, 42 and 84 post irradiation (right lung > left lung). In contrast, no increase in breathing frequency and no inflammatory response was detectable in irradiated gld and lpr mice. These results suggest that the CD95/CD95L- system plays an essential role in the induction of morphological and functional alterations in the lung characteristic for irradiation-induced pneumonitis. This report demonstrates for the first time that the CD95CD95L system is of major importance for the development of irradiation induced pneumonitis, implicating new perspectives for future therapeutic and preventive strategies.