Blockade of p38 Mitogen-Activated Protein Kinase Inhibits Murine Sclerodermatous Chronic Graft-versus-Host Disease.
Blockade of p38 Mitogen-Activated Protein Kinase Inhibits Murine Sclerodermatous Chronic Graft-versus-Host Disease.
复制标题
阻断 p38 丝裂原激活蛋白激酶可抑制小鼠硬皮病慢性移植物抗宿主病。
DOI：
10.1016/j.ajpath.2016.12.016
复制
发表时间：
2017
期刊：
影响因子：
6
通讯作者：
Takehara K.
中科院分区：
文献类型：
--
作者：
Matsushita T;Date M;Kano M;Mizumaki K;Tennichi M;Kobayashi T;Hamaguchi Y;Hasegawa M;Fujimoto M;Takehara K.
B10.D2小鼠骨髓移植(BMT)是研究人类硬皮病型慢性移植物抗宿主病(SCL-cGVHD)和系统性硬化症(SSC)的有效动物模型。P38丝裂原活化蛋白激酶(MAPK)通路是炎症和细胞因子产生的关键调节因子。此外，p38MAPK的激活在SSC的胶原合成中起着重要作用。我们研究了p38 MAPK抑制剂VX-702对SCL-cGVHD小鼠的影响。给SCL-cGVHD小鼠于骨髓移植后第7天至35天灌胃VX-702。我们比较了VX-702治疗组和对照组SCL-cGVHD小鼠的皮肤纤维化。同种异体骨髓移植可增加皮肤中p38MAPK的磷酸化。与对照组相比，注射VX-702可减轻SCL-cGVHD小鼠的皮肤纤维化。免疫组织化学染色显示，与对照组相比，VX-702抑制了CD8+T细胞、CD11+T细胞和CD11b+细胞在SCL-cGVHD小鼠真皮中的渗透。VX-702可降低SCL-cGVHD小鼠皮肤细胞外基质和致纤维化细胞因子IL-6、IL-13的mRNA表达。此外，VX-702在体外可直接抑制成纤维细胞素胶原的产生。VX-702被证明是治疗SCL-cGVHD和SSc患者的有前途的候选药物。
Bone marrow transplantation (BMT) of B10.D2 mice into sublethally irradiated BALB/c mice across minor histocompatibility loci is a well-established animal model for human sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) and systemic sclerosis (SSc). The p38 mitogen-activated protein kinase (MAPK) pathway is a key regulator of inflammation and cytokine production. Furthermore, the activation of p38 MAPK plays an important role in collagen production in SSc. We investigated the effects of p38 MAPK inhibitor, VX-702, on Scl-cGVHD mice. VX-702 was orally administered to Scl-cGVHD mice from day 7 to 35 after BMT. We compared skin fibrosis of Scl-cGVHD mice between the VX-702–treated group and control group. Allogeneic BMT increased the phosphorylation of p38 MAPK in the skin. The administration of VX-702 attenuated the skin fibrosis of Scl-cGVHD compared to the control mice. Immunohistochemical staining showed that VX-702 suppressed the infiltration of CD4+T cells, CD8+T cells, and CD11b+cells into the dermis of Scl-cGVHD mice compared to the control mice. VX-702 attenuated the mRNA expression of extracellular matrix and fibrogenic cytokines, such as IL-6 and IL-13, in the skin of Scl-cGVHD mice. In addition, VX-702 directly inhibited collagen production from fibroblastsin vitro. VX-702 was shown to be a promising candidate for use in treating patients with Scl-cGVHD and SSc.
登录
查看更多内容
干扰素-γ对博莱霉素诱导的实验性硬皮病的作用。
影响因子：
3
作者：
T. Yamamoto;S. Takagawa;M. Kuroda;K. Nishioka
通讯作者：
K. Nishioka
影响因子：
56.9
作者：
HAN, J;LEE, JD;ULEVITCH, RJ
通讯作者：
ULEVITCH, RJ
影响因子：
--
作者：
Nishikawa, M;Myoui, A;Yoshikawa, H
通讯作者：
Yoshikawa, H
影响因子：
--
作者：
Cohen, Stanley B.;Cheng, Tien-Tsai;Caulfield, John P.
通讯作者：
Caulfield, John P.
DOI：
10.1172/jci17601
发表时间：
2003-07
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Britt E. Anderson;J. McNiff;Jun Yan;H. Doyle;M. Mamula;M. Shlomchik;W. Shlomchik
通讯作者：
Britt E. Anderson;J. McNiff;Jun Yan;H. Doyle;M. Mamula;M. Shlomchik;W. Shlomchik