Molecular and cellular mediators in radiation-induced lung injury

Radiation-induced lung injury is a common adverse effect in patients receiving thoracic irradiation and for which, there is currently no effective therapy. Using a murine model of thoracic irradiation, we found that mice deficient in either the chemokine CCL3 or one of its receptors, CCR1, are significantly protected from radiation lung injury. This protected phenotype includes improved survival, virtually no pneumonitis or fibrosis, and preserved lung function when compared to wild-type mice. We further showed that a specific CCR1 inhibitor, BX471 provided similar protection. Therefore, CCR1 is a promising target for reducing radiation lung injury. To investigate the mechanisms by which CCL3/CCR1 signalling mediates radiation lung injury, we evaluated their influence on lung inflammation after irradiation. When compared with irradiated WT mice, irradiated CCL3- and CCR1-deficient mice had less lung infiltration of CD4+ and CD8+ T cells; however, CD4-deficient mice showed only partial protection, while CD8-deficient mice had slightly worse fibrosis. We further analyzed inflammatory cytokines and different subsets of CD4+ lymphocytes, TH1, TH2, TH17 and Treg cells, in our model. We found no differences in lung Foxp3+ Treg cells between WT and CCR1-deficient mice. Notably however, irradiated CCR1-deficient mice had less mRNA expression of the TH2 cytokines, IL-4 and IL-13, suggesting that TH2 cells may mediate radiation lung injury. In addition, the TH2-enhanced IL-10/12 double knockout mice (IL-10/12-/-) have increased expression of IL-13 and IL-4 with an associated earlier onset and enhanced degree of lung fibrosis. Even more striking was our finding that irradiated IL-10/12-/- mice had an earlier onset of increased IL-17 mRNA expression, as well as increased lung infiltration of TH17 cells, suggesting that IL-17 cells may also be important mediators in radiation lung injury. In summary, our studies show that CCL3 and its receptor, CCR1, are key mediators of radiation lung injury that act at least in part by recruiting TH17 and TH2 cells into the irradiated lungs. Furthermore, our findings suggest that the specific inhibitor of CCR1, BX471, looks promising as a potential therapeutic agent for ameliorating radiation lung injury