The synthetic hydroxyproline-containing collagen analogue (Gly-Pro-Hyp) ₁₀ ameliorates acute DSS colitis

Abstract

In experimental models of and humans with intestinal inflammation, increased levels of the matrix-degrading gelatinases MMP-2 and -9 in inflamed tissues can be detected. The synthetic collagen analogue (Gly-Pro-Hyp) ₁₀, (GPO) ₁₀, has been identified as a relevant binding structure for proMMP-2/-9 and promotes enzymatic activity of proMMP-2. Since targeted MMP strategies might offer promising anti-inflammatory treatment options, we for the first time studied in vivo actions exerted by (GPO) ₁₀ applying an acute dextrane sulfate sodium (DSS) induced colitis model. Seven-day intraperitoneal (GPO) ₁₀ treatment ameliorated clinical symptoms and histopathological colonic changes as compared to placebo controls with severe colitis. (GPO) ₁₀-treated mice displayed a diminished influx of neutrophils, and T- and B-lymphocytes into their colonic mucosa whereas numbers of regulatory T-cells and regenerative cells were higher as compared to placebo controls. Furthermore, IL-6 secretion was down-regulated in ex vivo colonic biopsies derived from (GPO) ₁₀-treated mice whereas higher concentrations of the anti-inflammatory cytokine IL-10 in extra-intestinal compartments such as MLN and spleen could be detected. Strikingly, influx of inflammatory cells into lungs was abolished following (GPO) ₁₀ application. We therefore propose (GPO) ₁₀ as a promising effective and safe treatment option of intestinal and extra-intestinal inflammatory conditions in humans.