Department of Pharmacology and Physiology, Medical School, Université de Sherbrooke, Sherbrooke, Québec, Canada (L.D., C.L., L.G., M.G., L.V., D.G., P.D'.O.J.); Department of Medical Biochemistry and Microbiology, Uppsala University BMC, Uppsala, Sweden (G.P.); and Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden (G.P.).
Department of Pharmacology and Physiology, Medical School, Université de Sherbrooke, Sherbrooke, Québec, Canada (L.D., C.L., L.G., M.G., L.V., D.G., P.D'.O.J.); Department of Medical Biochemistry and Microbiology, Uppsala University BMC, Uppsala, Sweden (G.P.); and Department of Anatomy, Physiology and Biochemistry, Swedish University of Agricultural Sciences, Uppsala, Sweden (G.P.)
J Pharmacol Exp Ther. 2019 Sep;370(3):437-446. doi: 10.1124/jpet.118.256016. Epub 2019 Jun 27.
Multiple sclerosis is a neurodegenerative disease affecting predominantly female patients between 20 and 45 years of age. We previously reported the significant contribution of mouse mast cell protease 4 (mMCP-4) in the synthesis of endothelin-1 (ET-1) in healthy mice and in a murine model of experimental autoimmune encephalomyelitis (EAE). In the current study, the cardiovascular effects of ET-1 and big endothelin-1 (big-ET-1) administered systemically or intrathecally were assessed in the early preclinical phase of EAE in telemetry instrumented/conscious mice. Chymase-specific enzymatic activity was also measured in the lung, brain, and mast cell extracts in vitro. Finally, the impact of EAE immunization was studied on the pulmonary and brain mRNA expression of different genes of the endothelin pathway, interleukin-33 (IL-33), and monitoring of immunoreactive tumor necrosis factor- (TNF-). Systemically or intrathecally administered big-ET-1 triggered increases in blood pressure in conscious mice. One week post-EAE, the pressor responses to big-ET-1 were potentiated in wild-type (WT) mice but not in mMCP-4 knockout (KO) mice. EAE triggered mMCP-4-specific activity in cerebral homogenates and peritoneal mast cells. Enhanced pulmonary, but not cerebral preproendothelin-1 and IL-33 mRNA were found in KO mice and further increased 1 week post-EAE immunization, but not in WT animals. Finally, TNF- levels were also increased in serum from mMCP-4 KO mice, but not WT, 1 week post-EAE. Our study suggests that mMCP-4 activity is enhanced both centrally and systemically in a mouse model of EAE.
多发性硬化症是一种影响主要为 20 至 45 岁女性患者的神经退行性疾病。我们之前报道过，小鼠肥大细胞蛋白酶 4（mMCP-4）在健康小鼠和实验性自身免疫性脑脊髓炎（EAE）的小鼠模型中对内皮素-1（ET-1）的合成有重要贡献。在本研究中，在遥测仪器化/清醒的 EAE 早期临床前阶段，评估了 ET-1 和大内皮素-1（big-ET-1）全身或鞘内给药对心血管的影响。还在体外测量了肺、脑和肥大细胞提取物中的糜酶特异性酶活性。最后，研究了 EAE 免疫接种对不同内皮素途径、白细胞介素-33（IL-33）的肺和脑 mRNA 表达以及免疫反应性肿瘤坏死因子-（TNF-）的监测的影响。全身或鞘内给予 big-ET-1 可引起清醒小鼠血压升高。EAE 后 1 周，野生型（WT）小鼠对 big-ET-1 的升压反应增强，但 mMCP-4 敲除（KO）小鼠则没有。EAE 触发了大脑匀浆和腹腔肥大细胞中 mMCP-4 的特异性活性。在 KO 小鼠中发现增强的肺前内皮素-1 和 IL-33 mRNA，但在脑内未发现，并且在 EAE 免疫接种后 1 周进一步增加，但在 WT 动物中未发现。最后，在 EAE 后 1 周，来自 mMCP-4 KO 小鼠的血清中 TNF-水平也升高，但 WT 小鼠则没有。我们的研究表明，在 EAE 的小鼠模型中，mTCP-4 活性在中枢和全身都增强。
