Expression of transforming growth factor-ß1 by pancreatic stellate cells and its implications for matrix secretion and turnover in chronic pancreatitis

Pancreatic stellate cells mediate fibrosis in chronic pancreatitis. Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs)-1 and -2 are crucial modulators of fibrosis. Transforming growth factor-ß (TGF-ß) is a key regulator of extracellular matrix production and myofibroblast proliferation. We have examined MMP and TIMP synthesis by transformed cultured pancreatic stellate cells and their regulation by TGF-ß1. By Northern analysis they expressed mRNAs for procollagen 1, TIMP-1, TIMP-2, and MMP-2. Expression of membrane type-1 MMP was confirmed by Western blotting. By immunohistochemistry these enzymes localized to fibrotic areas in human chronic pancreatitis. Active TGF-ß1 constitutes 2 to 5% of total TGF-ß1 secreted by pancreatic stellate cells; they express TGF-ß receptors I and II. Exogenous TGF-ß1 (10 ng/ml) significantly increased procollagen-1 mRNA by 69% and collagen protein synthesis by 34%. Similarly TGF-ß1 at 0.1, 1, and 10 ng/ml significantly reduced cellular proliferation rate by 37%, 44%, and 44%, respectively, whereas pan-TGF-ß-neutralizing antibody increased proliferation by 40%. TGF-ß1 (10 ng/ml) down-regulated MMP-9 by 54% and MMP-3 by 34% whereas TGF-ß1-neutralizing antibody increased MMP-9 expression by 39%. Pancreatic stellate cells express both mediators of matrix remodeling and the regulatory cytokine TGF-ß1 that, by autocrine inhibition of MMP-3 and MMP-9, may enhance fibrogenesis by reducing collagen degradation

Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury.

Inhibitory extracellular matrices form around mature neurons as perineuronal nets containing chondroitin sulfate proteoglycans that limit axonal sprouting after CNS injury. The enzyme chondroitinase (Chase) degrades inhibitory chondroitin sulfate proteoglycans and improves axonal sprouting and functional recovery after spinal cord injury in rodents. We evaluated the effects of Chase in rhesus monkeys that had undergone C7 spinal cord hemisection. Four weeks after hemisection, we administered multiple intraparenchymal Chase injections below the lesion, targeting spinal cord circuits that control hand function. Hand function improved significantly in Chase-treated monkeys relative to vehicle-injected controls. Moreover, Chase significantly increased corticospinal axon growth and the number of synapses formed by corticospinal terminals in gray matter caudal to the lesion. No detrimental effects were detected. This approach appears to merit clinical translation in spinal cord injury

Chondroitinase improves anatomical and functional outcomes after primate spinal cord injury.

Inhibitory extracellular matrices form around mature neurons as perineuronal nets containing chondroitin sulfate proteoglycans that limit axonal sprouting after CNS injury. The enzyme chondroitinase (Chase) degrades inhibitory chondroitin sulfate proteoglycans and improves axonal sprouting and functional recovery after spinal cord injury in rodents. We evaluated the effects of Chase in rhesus monkeys that had undergone C7 spinal cord hemisection. Four weeks after hemisection, we administered multiple intraparenchymal Chase injections below the lesion, targeting spinal cord circuits that control hand function. Hand function improved significantly in Chase-treated monkeys relative to vehicle-injected controls. Moreover, Chase significantly increased corticospinal axon growth and the number of synapses formed by corticospinal terminals in gray matter caudal to the lesion. No detrimental effects were detected. This approach appears to merit clinical translation in spinal cord injury.This work was supported by the National Institutes of Health (NIH, grant no. NS042291 to M.H.T.) and Acorda Therapeutics. Core infrastructure support for the primate spinal cord research facility was provided by the Veterans Administration (Gordon Mansfield Spinal Cord Injury Collaborative Consortium grant nos. IP50RX001045 and RR&D B7332R to M.H.T. and grant no. RR&D 1I01RX002245 to A.R.F.). The California National Primate Research Center is funded by the NIH (grant no. NCRR P51 OD011107-56). Funding was also provided by the Craig H. Neilsen Foundation (M.H.T.), the Bernard and Anne Spitzer Charitable Trust (M.H.T.), the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation (M.H.T.), the British Medical Research Council (J.W.F.) and the Christopher & Dana Reeve Foundation (J.W.F.)

Results of the 5th scientific workshop of the ECCO (II): Pathophysiology of perianal fistulising disease

The fifth scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of fistulas to the disease course of patients with Crohn's disease (CD). The objectives were: a better understanding of the pathophysiological mechanisms underlying the formation of CD fistulas; identification of future topics in fistula research that could provide insights into pathogenesis; the development of novel therapeutic approaches; and a review of current therapeutic strategies (with clarification of existing approaches to prevention, diagnosis and treatment).The results of the workshop are presented in two separate manuscripts. This manuscript describes current state-of-the-art knowledge about fistula pathogenesis, including the roles of epithelial-to-mesenchymal-transition and cytokine matrix remodelling enzymes, and it highlights the common association between fistulas and stenosis in CD. Further, the review considers the possible roles that genetic predisposition and intestinal microbiota play in fistula development. Finally, it proposes future directions and needs for fistula research that might substantially increase our understanding of this complex condition and help unravel novel therapeutic strategies and specific targets for treatment. Overall, it aims to highlight unanswered questions in fistula research and to provide a framework for future research work