PDF《bowel disease》

15 years ago had a major impact on the treatment of IBD patients. Therapeutic goals evolved from symptomatic remission to mucosal healing and lowered hospitalization and surgery rates. However, up to one third of patients become therapy-resistant and, consequently, new pharmacological targets are needed. Within the matrix metalloproteinase (MMP) family, gelatinase B or MMP-9 is suggested as a novel therapeutic target for the treatment of IBD, because MMP-9 expression is associated with disease development and is reduced by ef?cient treatment, as recently reviewed3. Moreover, the covalent complex of MMP-9 with neutrophil gelatinase B-associated lipocalin is a serum marker of mucosal healing in UC4 and CD5. Animal studies have been conducted to investigate the causal role of MMP-9 in experimental colitis. Single MMP-9? / ? and double MMP-2? / ? /MMP-9? / ? mice were claimed to be resistant to the development of acute colitis induced by dextran sodium sulphate (DSS)6C8 and monoclonal antibodies against MMP-9 were used to block acute DSS-induced colitis in mice9,10. On these bases, clinical phase

1 studies in UC patients were completed with an MMP-9 inhibitory antibody (GS-5745, Gilead Sciences)11. However, recently, phase 2/3 clinical studies in UC patients (TRIUMPH Study GS-US-326C1100) were terminated after futility and ef?cacy analyses. In the present study, we revert and complement published data on MMP-9 gene de?ciency in three animal models of colitis: an acute and a chronic DSS-mediated model of colonic in?ammation mimicking various aspects of UC and an acute 2,4,6-trinitrobenzenesulfonic acid (TNBS)-mediated model that more closely resembles CD. In addition, we use two peptide inhibitors with proven ef?cacy towards MMP-9 in an acute DSS-induced colitis model in three different set-ups: multiple dose prophylactic and therapeutic schemes, and continuous infusion via osmotic pumps. We ?nd no differences in clinical or histopathological parameters after genetic or pharmacological inhibition of MMP-9. Therefore, our ?ndings suggest that MMP-9 upregulation is a consequence of the in?ammatory process and unlikely represents a therapeutic target in IBD. Results Genetic background and microbiota of MMP-9? / ? and WT mice. MMP-9? / ? mice and their wild type (WT;

C57BL/6J) littermates were backcrossed for

13 generations and reared under speci?c pathogen-free (SPF) conditions for more than

15 years within the same insulator (Supplementary Fig. 1). Genetic background characterization was performed on a panel of 1,449 single nucleotide polymorphisms (SNPs) in both MMP-9? / ? and WT mice. MMP-9? / ? and WT mice were 99.86% and 99.97% of C57BL/6J recipient genome, respectively. Two SNPs (rs3664408 and rs13476889) of 129S6/Sv background could be discriminated in the MMP-9? / ? mice at chromosome 2, related to the region of genetic modi?cation for Mmp9. Over a period of

15 years, no differe........