TGF-betal transgenic mouse model of thoracic irradiation: modulation of MMP-2 and MMP-9 in the lung tissue

Abstract

To investigate the effects of TGF-beta1 on the two gelatinases (MMP-2 and MMP-9), and their roles in lung remodeling after irradiation-induced lung injury. Expressions of TGF-beta1 were measured with western blot, and expressions of MMP-2 and MMP-9 were analyzed with zymography in a -TGF-beta1 transgenic mouse model after thoracic irradiation with 12 Gy. We found expressions of TGF-beta1 in the lung from the transgenic mice were three folds as compared to those from control mice. With densitometrical analysis, we found a significant decrease in MMP-9 activity in lung homogenates from the transgenic mice as compared with those from non-transgenic control mice 8 weeks after sham-irradiation (relative MMP-9 activity: C: 1.000 0.1091; TG: 0.4772 +/- 0.470 (n = 8, P < 0.05). But MMP-2 was constitutively expressed in the lung homogenates from the transgenic mice as compared to those from control mice 8 weeks after sham-irradiation (relative MMP-2 activity 8 weeks after sham-irradiation: C: 1.000 +/- 0.1556, TG: 1.0075 +/- 0.1472). Eight weeks after thoracic irradiation with 12 Gy, we observed a significant increase of MMP-2 and MMP-9 activity in lung homogenates from both transgenic and normal mice. In TGF-beta1 transgenic mice relative MMP-9 activity was increased to 1.5321 +/- 0.2217 folds 8 weeks after thoracic irradiation with 12 Gy as compared to those after sham-irradiation (1.000 +/- 0.2153), and relative MMP-2 activity was increased to 1.7142 +/- 0.4231 folds. Our results show that TGF-beta1 itself down-regulates activity of MMP-9, thereby decreases ECM degradation in lungs of TGF-beta1 transgenic mice. Also we find that ionizing irradiation upregulates both MMP-2 and MMP-9 activity. Over-expressions of MMP-9 and MMP-2 after lung irradiation are involved in the inflammatory response associated with radiation-induced lung injury, and maybe further in radiation-induced lung fibrosis.