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Matrilysins-1 and -2 (MMP-7 and -26) and Metalloelastase (MMP-12), Unlike MMP-19, are Up-Regulated in Necrotizing Enterocolitis

Bister, Ville*; Salmela, Mikko T.*; Heikkilä, Päivi†; Anttila, Annaleena‡; Rintala, Risto‡; Isaka, Keichi§; Andersson, Sture‡; Saarialho-Kere, Ulpu*¶

Journal of Pediatric Gastroenterology & Nutrition: January 2005 - Volume 40 - Issue 1 - pp 60-66
Original Articles: Gastroenterology

Objectives: Necrotizing enterocolitis (NEC) is the most common gastrointestinal disease of premature infants characterized histologically by extensive tissue injury and inflammation. Matrix metalloproteinases (MMP) are involved in tissue remodeling and cell migration, both being important aspects of inflammatory disease. The aim of this study was to investigate whether MMPs play a role in the pathogenesis of NEC.

Methods: Expression of MMP-1, -7, -9, -10, -12, -19 and -26 was studied using in situ hybridization/immunohistochemistry in samples intestinal tissue removed from 15 patients with NEC; in 7 of them control samples were obtained at closure of stomas. Six intestinal samples from patients with intestinal atresia and four samples of necrosis were also included in the material examined. Laminin-5 was immunostained to find migrating enterocytes and cytokeratin to delineate mucosal epithelium.

Results: MMP-7 protein was upregulated in the epithelium of 12/18 NEC samples. MMP-26 was induced in stromal cells of 12/17 NEC specimens. Stromal expression was found for MMP-1 and -12 mRNAs in 7/18 samples. MMP-1 was also detected in the epithelium of regenerating areas. Both NEC and stoma samples expressed MMP-9 in inflammatory cells. Epithelial MMP-19 was downregulated in NEC.

Conclusions: Our results suggest that several MMPs may be major factors in tissue destruction and remodeling in NEC. Targeted inhibition of matrilysins, using synthetic MMP inhibitors or blockers of their signal transduction pathways, may represent a novel therapeutic option for the treatment of intestinal inflammation associated with NEC.

Departments of *Dermatology and †Pathology, Helsinki University Central Hospital; ‡Hospital for Children and Adolescents, University of Helsinki, Helsinki, Finland; §Department of Obstetrics and Gynecology, Tokyo Medical University, Tokyo, Japan; and ¶Department of Dermatology, Karolinska Institutet at Stockholm Soder Hospital, Stockholm, Sweden

Received February 10, 2004; accepted August 16, 2004.

Address all correspondence and requests for reprints to Dr. Ulpu Saarialho-Kere, Department of Dermatology, Karolinska Institutet, Stockholm Soder Hospital, SE-11883 Stockholm, Sweden (e-mail: ulpu.saarialho-kere@helsinki.fi).

© 2005 Lippincott Williams & Wilkins, Inc.