Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice

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Acute adaptive immune response correlates with late radiation-induced pulmonary fibrosis in mice Alexandra Paun1, Amit Kunwar1 and Christina K Haston1,2*

Abstract Background: The lung response to radiation exposure can involve an immediate or early reaction to the radiation challenge, including cell death and an initial immune reaction, and can be followed by a tissue injury response, of pneumonitis or fibrosis, to this acute reaction. Herein, we aimed to determine whether markers of the initial immune response, measured within days of radiation exposure, are correlated with the lung tissue injury responses occurring weeks later. Methods: Inbred strains of mice known to be susceptible (KK/HIJ, C57BL/6J, 129S1/SvImJ) or resistant (C3H/HeJ, A/J, AKR/J) to radiation-induced pulmonary fibrosis and to vary in time to onset of respiratory distress post thoracic irradiation (from 10–23 weeks) were studied. Mice were untreated (controls) or received 18 Gy whole thorax irradiation and were euthanized at 6 h, 1d or 7 d after radiation treatment. Pulmonary CD4+ lymphocytes, bronchoalveolar cell profile & cytokine level, and serum cytokine levels were assayed. Results: Thoracic irradiation and inbred strain background significantly affected the numbers of CD4+ cells in the lungs and the bronchoalveolar lavage cell differential of exposed mice. At the 7 day timepoint greater numbers of pulmonary Th1 and Th17 lymphocytes and reduced lavage interleukin17 and interferonγ levels were significant predictors of late stage fibrosis. Lavage levels of interleukin-10, measured at the 7 day timepoint, were inversely correlated with fibrosis score (R = −0.80, p = 0.05), while serum levels of interleukin-17 in control mice significantly correlated with post irradiation survival time (R = 0.81, p = 0.04). Lavage macrophage, lymphocyte or neutrophil counts were not significantly correlated with either of fibrosis score or time to respiratory distress in the six mouse strains. Conclusion: Specific cytokine and lymphocyte levels, but not strain dependent lavage cell profiles, were predictive of later radiation-induced lung injury in this panel of inbred strains. Keywords: Fibrosis, Strain-dependent radiation response, Inbred strains, Cytokines, Late effects

Introduction The radiation-induced lung injury is thought to occur through the ionizing radiation producing reactive oxygen species which induce lesions in DNA leading to damage of the alveolar epithelium [1] and capillary endothelium [2]. The inflammatory reaction to cell damage, including lymphocyte [3] and neutrophil [4] recruitment, if excessive or sustained, likely through epithelial [5] and leukocyte cell [3] derived cytokine signalling, can lead to the overwhelming inflammatory response of alveolitis/ pneumonitis. The tissue response to injury can also be * Correspondence: [email protected] 1 Department of Human Genetics, Meakins-Christie Laboratories, McGill University, Montreal, QC, Canada 2 Department of Medicine, Meakins-Christie Laboratories, McG