International Journal of Radiation Oncology*Biology*Physics
Biology ContributionLoss of Matrix Metalloproteinase-13 Attenuates Murine Radiation-Induced Pulmonary Fibrosis
Introduction
Pulmonary fibrosis includes a group of disorders of interstitial lung tissue that are either idiopathic or provoked by multiple known causes, including chemotherapy and radiotherapy for lung cancer (1). There are substantial similarities of the pathophysiological events caused by radiation to those that occur after other types of lung injury, including chemotherapy, surgery (2) or idiopathic pulmonary fibrosis (IPF) 3, 4. Fibrogenesis may not be a unique pathologic process but occurs on the basis of the same biological effects that take place in normal tissue repair (5). An excess of matrix deposition and fibroblast replication occurs in the course of persistent and exaggerated wound healing 6, 7, 8, 9, 10. Recently, some promising strategies targeting tumor growth factor-beta, platelet-derived growth factor, integrins, and other pathways have been suggested for the treatment of fibrosis 7, 8, 9, 10, 11.
Potential targets for therapeutic intervention also include matrix metalloproteinases (MMPs), because they are considered to play an important role in fibrogenesis. MMPs constitute a family of extracellular zinc- and calcium-dependent proteases that degrade extracellular matrix (ECM) and other extracellular proteins, the extensive remodeling of which can result in fibrogenesis 12, 13. According to their substrate specificity, MMPs have been structurally classified. Their activity is regulated at numerous levels, including gene transcription, proenzyme activation, and inhibition of their activated form by the tissue inhibitor of matrix metalloproteinases (TIMPs) 14, 15. It has recently been suggested that matrix metalloproteinase 13 (MMP13) is involved in the fibrotic process of the biliary system (13) as well as in the process of hepatic and skin tissue repair 13, 16. MMP13 is an interstitial collagenase of rodents capable of degrading insoluble fibrillar collagens as a highly specific protease (13). Moreover, the involvement of other MMPs such as MMP2 and MMP9 in pulmonary inflammation after radiation has been shown (17).
The role of MMP13 in radiation-induced pulmonary fibrosis has not yet been studied. Hence, in this study, we considered the role of MMP13 in a radiation-induced pulmonary fibrosis model along with longitudinal radiological monitoring using volume computed tomography and MRI using MMP 13-deficient C57Bl/6 mice (18).
Section snippets
Animals
The animal experiments were approved by the internal review board and governmental authorities (Regierungspraesidium Karlsruhe, Germany). We have previously described the genetics of MMP13 knockout mice (19). Briefly, the mice were bred in-house in a consistent genetic background (C57Bl/6). The mice of the cohorts for the study (24× MMP13–/– and 24× MMP13+/+) were age matched (18–20 weeks when radiation was given). The mice used in the cohorts were not F2) littermates. Instead, we performed a
Histological analysis
Histology taken 2 days after irradiation revealed severe acute inflammatory reaction in all methods including Masson's trichrome, Sirius-red, and hematoxylin eosin staining (Fig. 2). A strong infiltration with inflammatory cells with an edematous broadening of the alveolar septa could be detected in all the irradiated populations. The inflammatory cells consisted of mononuclear cells with predominantly lymphocytes, few monocytes, and even fewer macrophages (Figs. 2 and 4 [left panel, Day 2], p
Discussion
Here we investigated the role of MMP13 in the response of lung tissue to ionizing radiation in a mouse knockout model for MMP13. We found that MMP13-deficient C57Bl/6 mice developed less pulmonary fibrosis upon radiation injury than their wildtype counterparts. This partial resistance to radiation induced lung fibrosis was evident in histology and noninvasive radiological imaging studies using VCT and MRI. Moreover, thoracic radiation reduced life span of the mice, which was offset in part in
Acknowledgments
We thank Peter Peschke and Alexandra Tietz for support.
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This work was supported in part by grants from Deutsche Krebshilfe 106997, DFG National Priority Research Program the Tumor-Vessel Interface (Grant No. SPP1190), National Aeronautics and Space Administration Specialized Center of Research (Grant No. NNJ04HJ12G), Bundesminsterium fuer Forschung und Technologie (Grant No. 03NUK004A,C) and Tumorzentrum Heidelberg-Mannheim.
Conflict of interest: none.