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Matrix-Metallo-Proteinases and their tissue inhibitors in radiation-induced lung injury
Kunyu Yang1, Jan Palm, Jochem König
1Department of Radiotherapy and Radiooncology, Saarland University, Homburg/Saar, Germany.
Purpose:
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.
Material And 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.
Conclusion:
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.
Insights
Irradiation increases matrix metalloproteinases (MMPs) in lung tissue, contributing to inflammation. However, in transgenic mice with high TGF-beta1, tissue inhibitors of metalloproteinases (TIMPs) increase, potentially reducing fibrosis.
Area of Science:
- Pulmonary medicine
- Radiology
- Biochemistry
Background:
- Extracellular matrix (ECM) remodeling after lung damage involves Matrix-Metallo-Proteinases (MMPs) and Tissue-Inhibitors of Metallo-Proteinases (TIMPs).
- Transforming growth factor (TGF)-beta1 is implicated in radiation-induced lung fibrosis, affecting fibroblast proliferation and collagen synthesis.
- Elevated TGF-beta1 plasma levels are common in lung cancer patients.
Purpose of the Study:
- To investigate the effect of thoracic irradiation on the MMP/TIMP system in lung tissue.
- To compare the response in normal (wild-type) mice and transgenic mice overexpressing TGF-beta1.
Main Methods:
- Thoracic irradiation (12 Gy) or sham-irradiation was administered to wild-type (WT) and TGF-beta1 transgenic (TG) mice.
- Lung tissue was analyzed 4 and 8 weeks post-irradiation using Western blot for TGF-beta1, TIMP-1/-2/-3, zymography for MMP-2/MMP-9 activity, and immunohistochemistry for cellular localization.
- Groups included TG 12 Gy, TG 0 Gy, WT 12 Gy, and WT 0 Gy.
Main Results:
- Irradiation significantly increased MMP-2 and MMP-9 expression in lung tissue.
- In TG mice, TIMP-1/-2/-3 expression was elevated, and MMP-9 activity was decreased.
- Immunohistochemistry revealed that parenchymal and inflammatory cells express MMPs and TIMPs.
Conclusions:
- Overexpression of MMP-2 and MMP-9 is associated with the inflammatory response in radiation-induced lung injury.
- MMP-2 and MMP-9 degrade collagen IV, impacting lung tissue structural integrity.
- In TG mice, increased TIMP expression and diminished MMP-9 activity may reduce ECM degradation, potentially mitigating lung fibrosis.
