Summary.
Background: Fibrotic disease occurs in most tissues. Transforming growth factor (TGF)‐β is the major inducer of fibrosis. The fibrinolytic system is considered to play an important role in the degradation of extracellular matrices. However, the detailed mechanism of how this system affects fibrosis remains unclear. Methods and results: We examined experimental fibrosis in mice with a deficiency of α2‐antiplasmin (α2AP), which is a potent and specific plasmin inhibitor. We found that the lack of α2AP attenuated bleomycin‐induced TGF‐β1 synthesis and fibrosis. In addition, the production of TGF‐β1 from the explanted fibroblasts of α2AP−/− mice decreased dramatically as compared to that in wild‐type mice. Moreover, we found that α2AP specifically induces the production of TGF‐β1 in fibroblasts. Conclusion: The lack of α2AP attenuated TGF‐β1 synthesis, thereby resulting in attenuated fibrosis. This is the first report to describe the crucial role that α2AP plays in TGF‐β1 synthesis during the process of fibrosis. Our results provide new insights into the role of α2AP in fibrosis.
The fibrinolytic system is considered to play an important role in the degradation of extracellular matrices (ECM). However, the detailed mechanism regarding how this system affects fibrosis remains unclear. Urokinase-type plasminogen activator receptor (uPAR) not only functions as a proteinase receptor but also plays a role in cellular adhesion, differentiation, proliferation, and migration through intracellular signaling. To investigate the effect of uPAR on dermal fibrosis, the skin of wild-type mice was compared with uPAR-deficient (uPAR(-/-)) mice. The results showed that the absence of uPAR increases dermal thickness. In addition, collagen synthesis as well as the number of myofibroblasts was greater in the skin of uPAR(-/-) mice than in the skin of uPAR(+/+) mice. Moreover, we showed that the absence of uPAR attenuates the activity of matrix metalloproteinases (MMP)-2, 9 in the skin. In conclusion, this study suggests that the absence of uPAR not only regulates fibrosis-related gene expression and MMP activity but also results in ECM deposition. Therefore, the absence of uPAR induces dermal fibrosis. These findings provide new insights into the role of uPAR on dermal fibrosis.
We focused on dynamic responses to acute heat stress between 34 degrees C and 38.5 degrees C. Physiological and neuroendocrinological changes between 34 degrees C and 38.5 degrees C were studied in mice. The influence of humid conditions, 85% relative humidity (RH), on these changes was also investigated. Rectal temperatures increased above 34 degrees C and hematocrit levels increased at 38.5 degrees C 85% RH for 60 min. Food consumption and body weight gains decreased after a daily 60 min exposure to 34, 37 and 38.5 degrees C for 2 weeks. The corticosterone and vasopressin levels in the blood, and catecholamine and serotonin metabolite levels in the hypothalamus were not changed at 34 degrees C, but increased when above 37 degrees C for 60 min. Above 37 degrees C, these physiological and neuroendocrinological changes were accelerated by humid conditions. These results indicated that food consumption and body weight gains decreased above 34 degrees C, and the neuroendocrinological changes, which were accelerated by humid conditions, were induced above 37 degrees C. In comparison with restraint and water immersion stress, heat stress at 37 degrees C 85% RH showed a slower increase in serum corticosterone levels, smaller changes in plasma dopamine and dihydroxyphenylacetic acid levels, and, after repeated exposure, larger decreases in food consumption and body weight gains. This study clarified the relationships between temperature and humidity conditions and physiological and neuroendocrinological changes, along with the characteristics of responses in acute heat stress.
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