Singh Kameshwar P, Gerard Herve C, Hudson Alan P, Boros Dov L
Department of Immunology and Microbiology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, USA.
Immunology. 2004 Mar;111(3):343-52. doi: 10.1111/j.0019-2805.2004.01817.x.
Schistosomiasis mansoni is a tropical helminthic disease characterized by parasite egg-induced granulomatous inflammation and cumulative fibrosis. Because fibrosis is influenced by the imbalance between degradative matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), we analysed the resorption of fibrous tissue and MMP/TIMP expression in the livers of S. mansoni-infected and praziquantel-cured mice. Worm elimination significantly enhanced survival rate, ameliorated the granulomatous pathology and reduced collagen I, III and IV gene expression at 6 and 12 months post-treatment. Compared to 6 months infected, untreated controls, liver fibrous tissue was resorbed by 71.4% at 12 months after treatment. At 3 months post-treatment, expression of the MMP-2, -3, -8, -10, -13, -14 and -16 genes decreased compared with untreated controls. By 6 months, a highly significant increase in MMP-10 gene expression was manifest. At 12 months, messages for all MMP genes decreased in relation to untreated controls. TIMP-1, -2 and -3 gene expression drastically decreased between 3 and 6 months. At 1 year, only TIMP-1 expression was significantly diminished. Overall, profibrogenic tumour necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta and inducible nitric oxide synthase (iNOS) gene expression decreased. Antigen-stimulated splenocytes secreted significantly higher levels of interleukin (IL)-4, IL-5, IL-10 and IL-13 cytokines between 3 and 12 months after treatment. Production of interferon (IFN)-gamma was higher than in untreated controls 3 and 6 months after treatment. In conclusion, praziquantel-treated mice showed a slow resorption of liver fibrous tissue. Resorption is attributed to the precipitous drop in TIMP-1 gene expression level, which shifted the balance in favour of MMP message expression and presumed enhanced collagenase activity.
曼氏血吸虫病是一种热带蠕虫病，其特征为寄生虫卵引起的肉芽肿性炎症和累积性纤维化。由于纤维化受降解性基质金属蛋白酶（MMPs）与金属蛋白酶组织抑制剂（TIMPs）之间失衡的影响，我们分析了曼氏血吸虫感染及吡喹酮治疗后的小鼠肝脏中纤维组织的吸收情况以及MMP/TIMP的表达。驱虫显著提高了生存率，改善了肉芽肿病理状况，并在治疗后6个月和12个月时降低了I、III和IV型胶原基因的表达。与感染6个月未治疗的对照组相比，治疗后12个月肝脏纤维组织吸收了71.4%。治疗后3个月，与未治疗的对照组相比，MMP-2、-3、-8、-10、-13、-14和-16基因的表达下降。到6个月时，MMP-10基因表达显著增加。在12个月时，所有MMP基因的信息相对于未治疗的对照组均下降。TIMP-1、-2和-3基因表达在3至6个月间急剧下降。在1年时，只有TIMP-1表达显著降低。总体而言，促纤维化的肿瘤坏死因子（TNF）-α、转化生长因子（TGF）-β和诱导型一氧化氮合酶（iNOS）基因表达下降。抗原刺激后的脾细胞在治疗后3至12个月间分泌的白细胞介素（IL）-4、IL-5、IL-10和IL-13细胞因子水平显著更高。治疗后3个月和6个月时，干扰素（IFN）-γ的产生高于未治疗的对照组。总之，吡喹酮治疗的小鼠肝脏纤维组织吸收缓慢。吸收归因于TIMP-1基因表达水平的急剧下降，这使平衡向有利于MMP信息表达的方向转变，并推测增强了胶原酶活性。
