Collagen content and types in the intestinal strictures of Crohn's disease

Graham, Martin F.; Diegelmann, Robert F.; Elson, Charles O.; Lindblad, William J.; Gotschalk, Nancy

doi:10.1016/0016-5085(88)90411-8

Cited by 301 publications

(188 citation statements)

References 21 publications

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“…The smooth muscle cells of the intestinal muscularis are a major contributor of collagen to the extracellular matrix in normal and fibrotic human intestine (11). Therefore, in vitro studies were performed to test the above hypothesis utilizing procollagen secreted by human intestinal smooth muscle cells.…”

mentioning

confidence: 99%

Cleavage of Type I Procollagen by Human Mast Cell Chymase Initiates Collagen Fibril Formation and Generates a Unique Carboxyl-terminal Propeptide

Kofford

Schwartz

Schechter

et al. 1997

Journal of Biological Chemistry

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181

116

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The ability of human mast cell chymase and tryptase to process procollagen was examined. Purified human intestinal smooth muscle cell procollagen was incubated with human mast cell tryptase or human mast cell chymase. Purified chymase, but not tryptase, exhibited procollagen proteinase activity in the presence of EDTA. Addition of purified porcine heparin over a range of 0.1-100 g/ml did not affect either the rate or the products of procollagen chymase cleavage. The cleavage site of chymase on the pro-␣1(I) collagen carboxyl terminus was found to be in the propeptide region at Leu-1248-Ser-1249. Cleavage at this site suggested that the collagen products would form fibrils and confirmed the production of a unique carboxyl-terminal propeptide. Turbidometric fibril formation assay demonstrated de novo formation of chymase-generated collagen fibrils with characteristic lag, growth, and plateau phases. When observed by dark field microscopy, these fibrils were similar to fibrils formed by the action of procollagen proteinases. Thus, mast cell chymase, but not tryptase, exhibits procollagen peptidase-like activity as evidenced by its ability to process procollagen to fibrilforming collagen with concurrent formation of a unique carboxyl-terminal propeptide. These data demonstrate that mast cell chymase has a potential role in the regulation of collagen biosynthesis and in the pathogenesis of fibrosis.Mast cells are abundant in connective tissues of skin, lung, and intestine (1, 2). Increased numbers (or increased activity) of mast cells are associated with fibrotic disorders such as scleroderma, pulmonary fibrosis, and Crohn's disease (3-5). The precise role for mast cells in connective tissue biology and fibrosis is not known. One potential mechanism for mast cell involvement in these processes is through the production of unique proteolytic enzymes that may act on matrix proteins. Mast cell enzymes include the neutral proteases tryptase, chymase, cathepsin G, and a zinc-dependent carboxypeptidase (6). Although chymase and tryptase cleave fibronectin (7-9) and chymase cleaves vitronectin (10), no direct effect of these enzymes on procollagen or collagen has been demonstrated.Because procollagen (the precursor of collagen) requires proteolytic cleavage in the extracellular space prior to normal collagen fibril formation, we have speculated that newly secreted procollagen may be a substrate for mast cell proteolytic enzymes. The smooth muscle cells of the intestinal muscularis are a major contributor of collagen to the extracellular matrix in normal and fibrotic human intestine (11). Therefore, in vitro studies were performed to test the above hypothesis utilizing procollagen secreted by human intestinal smooth muscle cells. MATERIALS AND METHODSPurification of Procollagen-Human intestinal smooth muscle cells (12) were grown to confluence in Dulbecco's modified Eagle's medium containing 200 units/ml penicillin, 0.2 mg/ml streptomycin, 50 units/ml Nystatin, and 10% fetal bovine serum. Cell monolayers were then rinsed wit...

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mentioning

confidence: 99%

Cleavage of Type I Procollagen by Human Mast Cell Chymase Initiates Collagen Fibril Formation and Generates a Unique Carboxyl-terminal Propeptide

Kofford

Schwartz

Schechter

et al. 1997

Journal of Biological Chemistry

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181

116

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“…At the same time, CS proteoglycan was shown to inhibit proteolytic degradation of collagen and Aβ (19,20). CS-E binds type V collagen, which is increased in submucosa of CD patients (21)(22)(23)(24), suggesting that matrix CS-E strengthens CS-E-collagen interaction thereby solid fibrotic formation which is an obstacle of tissue repair.…”

Section: Mechanism Of Chst15/cs-e-mediated Fibrosismentioning

confidence: 99%

New endoscopic approach of anti-fibrotic therapy for inflammatory bowel disease

Suzuki

Yoneyama

2017

Ann. Transl. Med.

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Fibrosis continues to be paid a great attention in not only basic research but also clinical practice, especially for the development of novel therapeutics in various fibrotic diseases. However, there remain several obstacles to translation in developing anti-fibrosis therapy. The present review documents our translational practice from target discovery to first-in-patient studies in the development of anti-fibrosis therapy for inflammatory bowel disease (IBD). First topic is a target selection. We have focused on the target that has an ability to regulate multifactorial cascades of fibrosis. Carbohydrate sulfotransferase 15 (CHST15) synthesizes matrix proteoglycan that regulates various pathogenic mediators and contributes to tissue remodeling during injury. Small interfering RNA (siRNA) targeting CHST15 inhibited activation of fibroblasts in vitro and reduced fibrosis in vivo. Second topic is a clinically feasible application. We established a safe and novel pancolonic delivery of siRNA, which is achieved by direct injection to extracellular matrix (ECM) through endoscope. Third topic is an endpoint for both nonclinical and clinical studies. We have focused on tissue-specific findings for co-existence of fibrosis in ulcerative lesions in IBD and investigated whether the balance of mucosal healing (MH) and fibrosis, which is evaluated by endoscopy and histology respectively, can be used for study endpoints. Phase 1 clinical trial of STNM01, a synthesized CHST15 siRNA, by a single dose endoscopic submucosal injection for non-healer patients with Crohn's disease showed high rates of MH. Analyses of biopsy specimens revealed that STNM01 reduced CHST15 expression at local lesions, repressed pre-existing fibrosis and repaired the damaged crypts. Thus, blockade of multifactorial modulator CHST15 in ECM showed a potential to treat tissue remodeling and skew fibrosis toward mucosal repair. Our practice suggests that target-and tissue-specific findings-based strategy would be a key to translation in developing anti-fibrosis therapy.

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“…Tissue sections were stained with standard hematoxylin-eosin 6 and Masson' s trichrome. 7 Immunohistochemistry was performed using the labeled Streptavidin-biotin technique 8 (Dako, Carpinteria, CA) on paraffin-embedded sections with the following primary mouse monoclonal antibodies: anti-smooth muscle ␣ actin (SMA) (Sigma Chemical Co., St. Louis, MO), CD 31 and CD 34 (Becton Dickinson, Mountainview, CA), factor VIII-related antigen (endothelial cell markers), and proliferating cell nuclear antigen (PCNA) (Dako) (markers for proliferating cells 9 ).…”

Section: Histological Studiesmentioning

confidence: 99%

“…The identity of type III collagen bands was then demonstrated by delayed reduction with dithiothreitol before electrophoresis. 6 Gels were enhanced in 1 mol/L Na salicylate and exposed to photographic film. Procollagen and collagen bands were quantitated by scanning laser densitometry.…”

Section: Procollagen and Collagen Synthesis And Secretion By Culturedmentioning

confidence: 99%

Development of pseudointima and stenosis after transjugular intrahepatic portasystemic shunts: Characterization of cell phenotype and function

et al. 1998

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The clinical utility of transjugular intrahepatic portasystemic shunts (TIPS) is frequently complicated by the ingrowth of tissue into the stent lumen, causing stent stenosis. These studies were undertaken to define the cellular and matrix components of the pseudointima, define the phenotype and function of the mesenchymal cells in the pseudointima and maintain them in culture, and to study the differences between stenotic and nonstenosed stents. A total of 35 stents were evaluated. TIPS pseudointima were examined histologically, by immunohistochemistry and in situ hybridization to determine the cellular and connective tissue constituents. Mesenchymal cells were grown from tissue within the TIPS and around it, and their phenotype was studied and compared with control smooth muscle cells and fibroblasts. Transjugular intrahepatic portasystemic shunt (TIPS) involves creation of a low-resistance tract between the hepatic and portal veins that is kept patent by deployment of an expandable metal stent using radiologic techniques. The ability of TIPS to decompress the portal vein without surgery has led to its widespread use as a treatment for variceal hemorrhage and ascites. However, TIPS is limited by the frequent recurrence of portal hypertension in 70% to 90% 1 of subjects, with recurrent hemorrhage in about 20%. 2 This is primarily due to the development of narrowing of the stent lumen, which presents as either isolated narrowing at the hepatic venous end of the stent or as diffuse narrowing of the stent caused by the ingrowth of tissue (pseudointima) into the stent lumen.To date, only limited data exist on the biology of pseudointima formation and TIPS stenosis. It has been suggested that the mesenchymal cells in TIPS pseudointima are myofibroblasts 3-5 ; however, the phenotype of these cells has not been characterized. Such characterization would be an important first step in understanding the basic mechanism(s) by which pseudointima is formed and how TIPS stenosis develops. It has also been suggested that biliary-TIPS fistulae are important in the genesis of TIPS stenosis. 3,5 However, such fistulae are not always seen, 4 and the pathophysiological abnormalities causing TIPS stenosis have not been identified.The studies presented here were undertaken to: 1) define the time-course of development of TIPS pseudointima; 2) define the cellular and connective tissue components of the TIPS pseudointima in vivo; 3) isolate, characterize, and maintain in culture the mesenchymal cells from TIPS pseudointima; 4) to define the ability of these mesenchymal cells to synthesize and secrete collagen; and 5) to compare and contrast stenotic versus nonstenotic shunts with respect to their clinical and radiologic features, as well as their morphology, mesenchymal cell phenotype, and function. MATERIALS AND METHODS Sources of Tissue and Tissue HandlingTIPS were retrieved from livers either explanted at the time of orthotopic liver transplantation (n ϭ 30) or at the time of autopsy (n ϭ 5). Clinical information and radiographs fro...

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Collagen content and types in the intestinal strictures of Crohn's disease

Cited by 301 publications

References 21 publications

Cleavage of Type I Procollagen by Human Mast Cell Chymase Initiates Collagen Fibril Formation and Generates a Unique Carboxyl-terminal Propeptide

Cleavage of Type I Procollagen by Human Mast Cell Chymase Initiates Collagen Fibril Formation and Generates a Unique Carboxyl-terminal Propeptide

New endoscopic approach of anti-fibrotic therapy for inflammatory bowel disease

Development of pseudointima and stenosis after transjugular intrahepatic portasystemic shunts: Characterization of cell phenotype and function

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