Identification of matrix metalloproteinase-2 and -9 activities within the intestinal mucosa of dogs with chronic enteropathies

Mohsen Hanifeh,Laura Mäkitalo,Minna Marjaana Rajamäki,Susanne Kilpinen,Pernilla Syrjä,Thomas Spillmann

doi:10.1186/s13028-018-0371-y

Abstract

BackgroundMatrix metalloproteinases (MMPs) 2 and 9 are zinc- and calcium-dependent endopeptidases involved in the breakdown and reconstitution of extracellular matrix under both physiological and pathological conditions. Mucosal MMP-2 and -9 activities have been reported to be upregulated in the intestine of humans with inflammatory bowel disease (IBD), and in animal models of IBD. However, their involvement in the pathogenesis of canine chronic enteropathies (CE) is unknown. This study investigated mucosal pro- and active MMP-2 and -9 activities in dogs with CE and healthy dogs using gelatin zymography, and also to determine the association of their activities in dogs with CE with the canine IBD activity index (CIBDAI), histopathologic findings, the clinical outcome, and hypoalbuminemia. Intestinal mucosal samples from duodenum, ileum, colon, and cecum were collected from 40 dogs with CE and 18 healthy Beagle dogs.ResultsIn dogs with CE, the number of samples positive for mucosal pro- and active MMP-2 was significantly higher in the duodenum (P < 0.0001 and P = 0.011, respectively), ileum (P = 0.002 and P = 0.018, respectively), and colon (P < 0.0001 and P = 0.002, respectively), compared with healthy controls. Mucosal pro-MMP-9-positive samples in the duodenum and colon were significantly more frequent in dogs with CE than in healthy dogs (P = 0.0004 and P = 0.001, respectively). Despite the presence of mucosal samples positive for active MMP-9 in the intestinal segments of dogs with CE, the difference compared to healthy controls did not reach statistical significance. None of the intestinal mucosal samples in healthy dogs showed gelatinolytic activity corresponding to the control bands of active MMP-2 and -9. Mucosal active MMP-9 activities displayed a significant positive association with the severity of neutrophil infiltration in the duodenum (P = 00.040), eosinophils in the cecum (P = 00.037), and the CIBDAI score for ileum samples (P = 0.023). There was no significant association of pro- and active MMP-2 and -9 levels with the clinical outcome or hypoalbuminemia.ConclusionsThis study is the first to demonstrate upregulation of mucosal pro- and active MMP-2 and pro-MMP-9 in the intestine of dogs with CE compared to healthy dogs. The results provide supporting evidence for the possible involvement of MMP-2 and -9 in the pathogenesis of canine CE.

Highlights

Matrix metalloproteinases (MMPs) 2 and 9 are zinc- and calcium-dependent endopeptidases involved in the breakdown and reconstitution of extracellular matrix under both physiological and pathological conditions
The number of samples positive for pro- and active MMP-2 and proMMP-9 was higher in the mucosa of dogs with chronic enteropathies (CE) compared to healthy dogs in all intestinal segments when determined using gelatin zymography
We found a positive correlation between active MMP-9 activities in the ileal mucosa and the canine inflammatory bowel disease (IBD) activity index (CIBDAI) score before treatment in dogs with CE, which is similar to the relationship between mucosal MMP-9 and the disease activity index in a rat model of colitis [31], and between fecal MMP-9 and clinical activities of ulcerative colitis in humans [32]

Summary

Introduction

Matrix metalloproteinases (MMPs) 2 and 9 are zinc- and calcium-dependent endopeptidases involved in the breakdown and reconstitution of extracellular matrix under both physiological and pathological conditions. Mucosal MMP-2 and -9 activities have been reported to be upregulated in the intestine of humans with inflammatory bowel disease (IBD), and in animal models of IBD. Their involvement in the pathogenesis of canine chronic enteropathies (CE) is unknown. Chronic enteropathy (CE) is a term used to describe a group of inflammatory conditions of the intestinal tract of unknown cause in dogs [1]. Synonymous for CE, the term inflammatory bowel disease (IBD) has been used in dogs, for example in a review determining canine IBD/CE according to the response to treatment [3]. The occurrence of an aberrant immune response to antigens derived from endogenous microbiota is likely to play an important role in CE pathogenesis; the specific pathways leading to tissue injury and intestinal inflammation are not fully understood [3, 8, 9]

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