Expression of matrix metalloproteinases and their inhibitors during the resorption of schistosome egg‐induced fibrosis in praziquantel‐treated mice

Abstract

SUMMARYSchistosomiasis mansoni is a tropical helminthic disease characterized by parasite egginduced granulomatous in¯ammation and cumulative ®brosis. Because ®brosis is in¯uenced by the imbalance between degradative matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), we analysed the resorption of ®brous tissue and MMP/TIMP expression in the livers of S. mansoni-infected and praziquantel-cured mice. Worm elimination signi®cantly enhanced survival rate, ameliorated the granulomatous pathology and reduced collagen I, III and IV gene expression at 6 and 12 months posttreatment. Compared to 6 months infected, untreated controls, liver ®brous tissue was resorbed by 71Á4% 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 signi®cant 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 signi®cantly diminished. Overall, pro®brogenic tumour necrosis factor (TNF)-a, transforming growth factor (TGF)-b and inducible nitric oxide synthase (iNOS) gene expression decreased. Antigen-stimulated splenocytes secreted signi®cantly 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)-g was higher than in untreated controls 3 and 6 months after treatment. In conclusion, praziquantel-treated mice showed a slow resorption of liver ®brous 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.

Dynamics of collagen, MMP and TIMP gene expression during the granulomatous, fibrotic process induced bySchistosoma mansonieggs

“…They speculated that alternate pathways, mediated by a 1-macroglobulin or plasminogen activator inhibitor 1, could have compensated for the loss of inhibition by TIMP. Singh et al (2004) recently found that praziquantel cure of infected mice strongly diminished TIMP-1 gene expression and promoted absorption of liver fibrosis. Moreover, intrahepatic injections of TIMP-1 antisense oligodeoxynucleotide suppress the expression of the TIMP-1 gene and lower the total collagen content of the livers of infected mice (unpubl.…”

Prevention and treatment of Schistosoma mansoni-induced liver fibrosis in mice

“…The hydroxyproline assay was carried out based on the previously reported methodology (Bergman and Loxley 1963) using base rather than acid hydrolysis for the dissolution of tissue (Singh et al 2004). Briefly, liver tissue was weighed and incubated overnight at 37°C in 5% KOH (6 ml/100 mg tissue weight).…”

Effect of Chemotherapy with Praziquantel on the Production of Cytokines and Morbidity Associated with Schistosomiasis Mansoni

“…Furthermore, there is evidence that treatment with praziquantel induces a change in the immune response that provides partial protection against schistosome infection, thus providing benefits that may extend beyond a transient reduction in levels of infection (21,40,42). Additionally, although the cumulative fibrosis that occurs during infection is mostly irreversible, periportal fibrosis regresses following eradication of the infection by chemotherapy (16,44,48).…”