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

Abstract

BackgroundThe 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.MethodsInbred 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.ResultsThoracic 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.ConclusionSpecific 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13014-015-0359-y) contains supplementary material, which is available to authorized users.

The Role of Lymphocytes in Radiotherapy-Induced Adverse Late Effects in the Lung

“…For example, Paun et al analyzed the primary radiation injury response of the lung at 6 h, 1, and 7 days after 18 Gy whole thorax irradiation in different mouse strains and characterized infiltrating T cell populations and their cytokine profile in the lung tissue and in the bronchoalveolar lavage fluid (BALF). The authors reveal lower T cell levels in the BALF and increased numbers of infiltrating T H 1 and T H 2 cells in the lung at day 1 and 7 (140). Another murine study from Zheng et al uncovered a more delayed reconstitution of CD4 + T cells compared to that of CD8 + T cells upon low dose total body irradiation (2.5 Gy); furthermore, T H 1 reconstitution was also impaired, whereas T H 17 and T reg cells were elevated (141).…”

“…In this context, a recent murine study described that the radiation-induced early lung inflammation was accelerated by induction of the inflammasome (Nlrp3, caspase 1, IL-1α, and IL-1β), highlighting the contribution of an early innate response (156). Exposure of lung tissue to IR triggered an increased influx of lymphocytes (30, 39, 140, 157). One of the driving forces of lymphocyte infiltration into the lung is the chemokine (C-C motif) ligand 18 (CCL18).…”

A survey of changing trends in modelling radiation lung injury in mice: bringing out the good, the bad, and the uncertain

“…They are also almost entirely performed on C57BL/6 mice, which brings uncertainties in linking such changes to meaningful and relevant end points of delayed lung injury that can be extrapolated to humans. 61,62 The latter obstacles imposed by using C57BL/6 mice apply to many other early subclinical findings during the latent period including those that have reported cytokine-mediated T-cell and macrophage immune modulation, [63][64][65] increased apoptosis, 66 and indices of oxidative stress. 67 Studies on other mouse strains that are closer to humans in being more susceptible to latent pneumonitis can, however, yield more conclusive interpretations.…”

“…This intrusion therefore compromises those studies in which pleural effusions are neither considered nor documented yet still depend on histological criteria to define genetic determinants of radiation lung damage among different recombinant mouse strains. 64,82,92,93,111 The actual origin of radiation-induced pleural effusions remains elusive in spite of its high recorded frequency in mice but some possibilities can be proposed and used as a basis for future investigations. First, pleural effusions can be circumvented by shielding the left hemithorax and allow the full spectrum of pathologies to develop unhindered in the irradiated right lung and reveal a slower progression of pneumonitis in male C57BL/6 as compared with CBA mice.…”

Effects of traditional oriental medicines as anti-cytotoxic agents in radiotherapy

“…IL-1α, IL-1β, IL-6 and IL-12) that are upregulated by radiation exposure cause radiation-induced inflammation in normal tissues. Chronic inflammation occurring as a late effect of radiation is primarily responsible for the induction of fibrosis, which is an irreversible disease (29)(30)(31). In this setting, sufficient amounts of antioxidants as radioprotectors may neutralize the toxic effects of these free radicals and protect normal tissues against ROS-induced damage during radiation exposure (Fig.…”