Loss of matrix metalloproteinase-13 attenuates murine radiation-induced pulmonary fibrosis.
OBJECTIVE
Pulmonary fibrosis is a disorder of the lungs with limited treatment options. Matrix metalloproteinases (MMPs) constitute a family of proteases that degrade extracellular matrix with roles in fibrosis. Here we studied the role of MMP13 in a radiation-induced lung fibrosis model using a MMP13 knockout mouse.


METHODS
We investigated the role of MMP13 in lung fibrosis by investigating the effects of MMP13 deficiency in C57Bl/6 mice after 20-Gy thoracic irradiation (6-MV Linac). The morphologic results in histology were correlated with qualitative and quantitative results of volume computed tomography (VCT), magnetic resonance imaging (MRI), and clinical outcome.


RESULTS
We found that MMP13 deficient mice developed less pulmonary fibrosis than their wildtype counterparts, showed attenuated acute pulmonary inflammation (days after irradiation), and a reduction of inflammation during the later fibrogenic phase (5-6 months after irradiation). The reduced fibrosis in MMP13 deficient mice was evident in histology with reduced thickening of alveolar septi and reduced remodeling of the lung architecture in good correlation with reduced features of lung fibrosis in qualitative and quantitative VCT and MRI studies. The partial resistance of MMP13-deficient mice to fibrosis was associated with a tendency towards a prolonged mouse survival.


CONCLUSIONS
Our data indicate that MMP13 has a role in the development of radiation-induced pulmonary fibrosis. Further, our findings suggest that MMP13 constitutes a potential drug target to attenuate radiation-induced lung fibrosis.
Flechsig
Paul
P
Department of Molecular Pathology, German Cancer Research Center, Heidelberg, Germany.
Hartenstein
Bettina
B
Teurich
Sybille
S
Dadrich
Monika
M
Hauser
Kai
K
Abdollahi
Amir
A
Gröne
Hermann-Josef
HJ
Angel
Peter
P
Huber
Peter E
PE
D000818:Animals; D008136:Longevity / Q000528:radiation effects; D008168:Lung / Q000528:radiation effects; D008279:Magnetic Resonance Imaging; D053509:Matrix Metalloproteinase 13 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011658:Pulmonary Fibrosis / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology*; D017564:Radiation Pneumonitis / Q000000981:diagnostic imaging / Q000209:etiology / Q000473:pathology*; D014057:Tomography, X-Ray Computed
D053509:Matrix Metalloproteinase 13