Matrix-Metallo-Proteinases and their tissue inhibitors in radiation-induced lung injury.
OBJECTIVE
Remodeling of extracellular matrix (ECM) after lung damage depends on collagen degrading Matrix-Metallo-Proteinases (MMP) and their endogenous inhibitors (Tissue-Inhibitors of Metallo-Proteinases, TIMP). Transforming growth factor (TGF)-beta1 has been implicated in the pathogenesis of radiation-induced lung fibrosis upon its effects on fibroblast proliferation and collagen synthesis. Lung cancer patients have often elevated TGF-beta1 plasma levels as a result of increased TGF-beta1 expression in their tumours. On this background, we investigated the effect of irradiation on the MMP/TIMP system in the lung tissue of normal and transgenic TGF-beta1 mice, in which TGF-beta1 is overexpressed in the liver resulting in high TGF-beta1 plasma levels.


METHODS
Transgenic (TG) and wild-type (WT) mice underwent thoracic irradiation with 12 Gy or sham-irradiation. For each study group (TG 12 Gy; TG 0 Gy; WT 12 Gy; WT 0 Gy) 8 mice were sacrificed at 4 and 8 weeks after (sham-) irradiation. The TGF-beta1, TIMP-1/-2/-3 expression in the lung tissue was quantified by Western blot; the MMP-2 and MMP-9 activity was analysed by zymography. The cellular origin of the MMP and TIMP was localised by immunohistochemistry.


RESULTS
Irradiation had no influence on the TIMP-1/-2/-3, but increased significantly the MMP-2 /-9 expression. In the lung tissue of TG mice the TIMP-1/-2/-3 expression was elevated, the MMP-9 activity was decreased. The immunhistochemical study showed that parenchymal and inflammatory cells express these MMP/TIMP.


CONCLUSIONS
Our results provide evidence that the overexpression of MMP-2 and MMP-9 is involved in the inflammatory response of radiation-induced lung injury. MMP-2 and MMP-9 are known to degrade collagen IV of basement membranes, therefore affecting the structural integrity of lung tissue. In contrast, in lung tissue of TG mice the TIMP-1/-2/-3 expression was up-regulated and the MMP-9 activity was diminished, thereby decreasing possibly the ECM degradation leading to lung fibrosis.
Yang
Kunyu
K
Department of Radiotherapy and Radiooncology, Saarland University, Homburg/Saar, Germany.
Palm
Jan
J
König
Jochem
J
Seeland
Ute
U
Rosenkranz
Stephan
S
Feiden
Wolfgang
W
Rübe
Christian
C
Rübe
Claudia E
CE
D000818:Animals; D049109:Cell Proliferation / Q000528:radiation effects; D003094:Collagen / Q000096:biosynthesis; D005109:Extracellular Matrix / Q000473:pathology; D005347:Fibroblasts / Q000166:cytology / Q000473:pathology / Q000528:radiation effects; D005786:Gene Expression Regulation / Q000235:genetics / Q000502:physiology; D007150:Immunohistochemistry; D008171:Lung Diseases / Q000201:enzymology* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011658:Pulmonary Fibrosis / Q000188:drug therapy / Q000473:pathology; D011833:Radiation Injuries, Experimental / Q000201:enzymology* / Q000378:metabolism; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism*
D019715:Tissue Inhibitor of Metalloproteinase-1; D019714:Tissue Inhibitor of Metalloproteinases; D053773:Transforming Growth Factor beta1; D003094:Collagen; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9