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Stromelysin-1 and macrophage metalloelastase expression in the intestinal mucosa of Crohn’s disease patients treated with infliximab

Stromelysin-1 and macrophage metalloelastase expression in the intestinal mucosa of Crohn’s disease patients treated with infliximab
Stromelysin-1 and macrophage metalloelastase expression in the intestinal mucosa of Crohn’s disease patients treated with infliximab
Background and aims: the mechanism by which anti-tumor necrosis factor (TNF)-a therapy promotes rapid closure of fistulas and mucosal wound healing in Crohn’s disease (CD) remains unclear. An ex-vivo model of gut T-cell mediated injury indicated that TNF-a blockade prevents tissue damage concomitant with matrix metalloproteinase (MMP) inhibition. We, therefore, hypothesized that the chimeric anti-TNF-a antibody infliximab facilitates wound healing in CD by downregulating tissue degrading MMPs. We focused on MMP-3 (stromelysin-1) and MMP-12 (macrophage metalloelastase) as these two enzymes have been linked to connective tissue destruction in CD.
Methods: endoscopic biopsies were taken from 10 CD patients immediately before and after 10 weeks of treatment with infliximab. Before treatment, biopsies were taken from macroscopically inflamed areas, and after treatment were collected from the same locations as before treatment. The degree of mucosal damage was assessed by using a histological scoring system. MMP transcripts were detected by in-situ hybridization on paraffin sections. MMP proteins were determined by immunoblotting on mucosal homogenates.
Results: six out of 10 patients had a clinical response to infliximab. MMP-3 and MMP-12 transcripts and proteins, which were highly expressed in CD inflamed mucosa, decreased after treatment in those patients who responded to infliximab. MMP-3 and MMP-12 downregulation was accompanied by a concomitant improvement of the histologic score. No change in MMP expression was found in nonresponders.
Conclusion: the downregulation of tissue degrading MMPs in CD mucosa may explain the wound repair capacity of infliximab in healing fistulas and ulcers.
0954-691X
1049-1055
Di Sabatino, Antonio
08cb3ec3-e4a0-423c-aa27-f428979b957d
Saarialho-Kere, Ulpu
d3a10378-4e3e-45ee-86c4-c9ba28dd1522
Buckley, Mark G.
e4abc0c1-8413-4b27-bded-e94312c66424
Gordon, John N.
3f07dd32-289a-46a8-9ad3-d2ad2b1592d3
Biancheri, Paolo
479c256d-187d-4b65-b226-8069299e61b2
Rovedatti, Laura
93ed44df-98f8-4ea2-bc64-de8b0e64d3c7
Corazza, Gina R.
f6c77bfb-9866-449c-882e-f72746f1009e
MacDonald, Thomas T.
a6bde8a9-acc4-4128-851f-dd5dbfe28816
Pender, Sylvia L.F.
62528b03-ec42-41bb-80fe-48454c2c5242
Di Sabatino, Antonio
08cb3ec3-e4a0-423c-aa27-f428979b957d
Saarialho-Kere, Ulpu
d3a10378-4e3e-45ee-86c4-c9ba28dd1522
Buckley, Mark G.
e4abc0c1-8413-4b27-bded-e94312c66424
Gordon, John N.
3f07dd32-289a-46a8-9ad3-d2ad2b1592d3
Biancheri, Paolo
479c256d-187d-4b65-b226-8069299e61b2
Rovedatti, Laura
93ed44df-98f8-4ea2-bc64-de8b0e64d3c7
Corazza, Gina R.
f6c77bfb-9866-449c-882e-f72746f1009e
MacDonald, Thomas T.
a6bde8a9-acc4-4128-851f-dd5dbfe28816
Pender, Sylvia L.F.
62528b03-ec42-41bb-80fe-48454c2c5242

Di Sabatino, Antonio, Saarialho-Kere, Ulpu, Buckley, Mark G., Gordon, John N., Biancheri, Paolo, Rovedatti, Laura, Corazza, Gina R., MacDonald, Thomas T. and Pender, Sylvia L.F. (2009) Stromelysin-1 and macrophage metalloelastase expression in the intestinal mucosa of Crohn’s disease patients treated with infliximab. European Journal of Gastroenterology & Hepatology, 21 (9), 1049-1055. (doi:10.1097/MEG.0b013e3283293d0f).

Record type: Article

Abstract

Background and aims: the mechanism by which anti-tumor necrosis factor (TNF)-a therapy promotes rapid closure of fistulas and mucosal wound healing in Crohn’s disease (CD) remains unclear. An ex-vivo model of gut T-cell mediated injury indicated that TNF-a blockade prevents tissue damage concomitant with matrix metalloproteinase (MMP) inhibition. We, therefore, hypothesized that the chimeric anti-TNF-a antibody infliximab facilitates wound healing in CD by downregulating tissue degrading MMPs. We focused on MMP-3 (stromelysin-1) and MMP-12 (macrophage metalloelastase) as these two enzymes have been linked to connective tissue destruction in CD.
Methods: endoscopic biopsies were taken from 10 CD patients immediately before and after 10 weeks of treatment with infliximab. Before treatment, biopsies were taken from macroscopically inflamed areas, and after treatment were collected from the same locations as before treatment. The degree of mucosal damage was assessed by using a histological scoring system. MMP transcripts were detected by in-situ hybridization on paraffin sections. MMP proteins were determined by immunoblotting on mucosal homogenates.
Results: six out of 10 patients had a clinical response to infliximab. MMP-3 and MMP-12 transcripts and proteins, which were highly expressed in CD inflamed mucosa, decreased after treatment in those patients who responded to infliximab. MMP-3 and MMP-12 downregulation was accompanied by a concomitant improvement of the histologic score. No change in MMP expression was found in nonresponders.
Conclusion: the downregulation of tissue degrading MMPs in CD mucosa may explain the wound repair capacity of infliximab in healing fistulas and ulcers.

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Published date: September 2009

Identifiers

Local EPrints ID: 72614
URI: http://eprints.soton.ac.uk/id/eprint/72614
ISSN: 0954-691X
PURE UUID: c06dfbc8-8292-4f20-abd2-7a09b21379ef
ORCID for Sylvia L.F. Pender: ORCID iD orcid.org/0000-0001-6332-0333

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Date deposited: 18 Feb 2010
Last modified: 14 Mar 2024 02:45

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Contributors

Author: Antonio Di Sabatino
Author: Ulpu Saarialho-Kere
Author: Mark G. Buckley
Author: John N. Gordon
Author: Paolo Biancheri
Author: Laura Rovedatti
Author: Gina R. Corazza
Author: Thomas T. MacDonald

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