Expression of matrix metalloproteinases and their inhibitors during the resorption of schistosome egg-induced fibrosis in praziquantel-treated mice.
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.
Department of Immunology and Microbiology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201, USA.
Kameshwar P
KP
Singh
Herve C
HC
Gerard
Alan P
AP
Hudson
Dov L
DL
Boros
D000818:Animals; D000871:Anthelmintics / Q000627:therapeutic use*; D001835:Body Weight; D002452:Cell Count; D002478:Cells, Cultured; D003094:Collagen / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D005260:Female; D015870:Gene Expression; D006909:Hydroxyproline / Q000032:analysis; D008099:Liver / Q000276:immunology / Q000473:pathology; D008103:Liver Cirrhosis / Q000276:immunology* / Q000473:pathology; D020782:Matrix Metalloproteinases / Q000032:analysis* / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D009929:Organ Size; D011223:Praziquantel / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012555:Schistosomiasis mansoni / Q000188:drug therapy / Q000276:immunology*; D013154:Spleen / Q000276:immunology; D019714:Tissue Inhibitor of Metalloproteinases / Q000032:analysis* / Q000276:immunology
D000871:Anthelmintics; D016207:Cytokines; D019714:Tissue Inhibitor of Metalloproteinases; D011223:Praziquantel; D003094:Collagen; D020782:Matrix Metalloproteinases; D006909:Hydroxyproline