Lacombe, Domingos Lourenco Penna; (1994) Matrix metalloproteinases in experimental colonic healing. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Indirect evidence has suggested that collagenase, an enzyme that specifically degrades collagen is responsible for colonic dehiscence. This protease is only one member of a family of enzymes, the matrix metalloproteinases (MMPs), which between them degrade all the components of the extracellular matrix. The aim of this thesis is to investigate the distribution of MMPs and their inhibitor, tissue inhibitor of metalloproteinases, TIMP-1, in colonic anastomosis in rabbit models using immunohistochemistry. Anastomotic healing in three different conditions has been investigated following; (i) transection of normal colon; (ii) colonic obstruction for 24h then resection; and (iii) ischaemia for 12h then resection; all carried out in the distal colon. To study different phases of the healing process, tissue from rabbits killed 12h, 1, 3 and 7 days following anastomosis was examined by indirect immunofluorescence. Sections were stained with haematoxylin and eosin and with antisera to collagenase, stromelysin, gelatinase and TIMP-1. In normal healing the distribution of the MMPs was limited to the suture line with TIMP-1 always present at the same site. In an anastomosis following ischaemia MMPs and TIMP-1 were not restricted to the suture line but spread out proximally and distally. In an anastomosis following obstruction a similar pattern was observed but there was also extensive expression of MMPs beyond the anastomotic segment involving the entire colon. The distribution of MMPs was related to the extent of histological damage with extracellular MMPs, mainly collagenase earlier and stromelysin later after injury usually CO-localised with TIMP-1. In the normal healing model the co-existence of TIMP-1 with the MMPs demonstrated a controlled remodelling healing process. Lack of TIMP-1 in relation to MMPs, in the early period after anastomosis, suggests that uncontrolled degradation of the matrix may occur. This may be of relevance in obstruction and ischaemia where the wider distribution of MMPs with relative absence of TIMP-1 persists for longer.

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