Serine Protease Inhibition Reduces Post-Ischemic Granulocyte Recruitment in Mouse Intestine

INSERM, U1043, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
American Journal Of Pathology (Impact Factor: 4.59). 11/2011; 180(1):141-52. DOI: 10.1016/j.ajpath.2011.09.031
Source: PubMed


Proteases and proteinase-activated receptor (PAR) activation are involved in several intestinal inflammatory conditions. We hypothesized that serine proteases and PAR activation could also modulate the intestinal injury induced by ischemia-reperfusion (I-R). C57Bl/6 mice were subjected to 90 minutes of intestinal ischemia followed or not by reperfusion. Sham-operated animals served as controls. After ischemia, plasma and tissue serine protease activity levels were increased compared to the activity measured in plasma and tissues from sham-operated mice. This increase was maintained or further enhanced after 2 and 5 hours of reperfusion, respectively. Trypsin (25 kDa) was detected in tissues both after ischemia and 2 hours of reperfusion. Treatment with FUT-175 (10 mg/kg), a potent serine protease inhibitor, increased survival after I-R, inhibited tissue protease activity, and significantly decreased intestinal myeloperoxidase (MPO) activity and chemokine and adhesion molecule expression. We investigated whether serine proteases modulate granulocyte recruitment by a PAR-dependent mechanism. MPO levels and adhesion molecule expression were significantly reduced in I-R groups pre-treated with the PAR(1) antagonist SCH-79797 (5 mg/kg) and in Par(2)(-/-)mice, compared, respectively, to vehicle-treated group and wild-type littermates. Thus, increased proteolytic activity and PAR activation play a pathogenic role in intestinal I-R injury. Inhibition of PAR-activating serine proteases could be beneficial to reduce post-ischemic intestinal inflammation.

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    • "morphological injury caused by mesenteric I/R [7] [8] [9] [10] [11] [12]. More recently, we focused our attention on 5-HT, a known paracrine mediator and neurotransmitter involved in the physiological regulation of gut motility, perception and secretion [13]. "
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    • "Microscopic histological damage score was evaluated by a person unaware of the treatments and was based on a semiquantitative scoring system in which the following features were graded: extent of destruction of normal mucosal architecture (0, normal; 1, 2, and 3, mild, moderate, and extensive damage, respectively), presence and degree of cellular infiltration (0, normal; 1, 2, and 3, mild, moderate, and transmural infiltration), extent of muscle thickening (0, normal; 1, 2, and 3, mild, moderate, and extensive thickening), presence or absence of crypt abscesses (0, absent; 1, present), and presence or absence of goblet cell depletion (0, absent; 1, present). The scores for each feature were then summed with a maximum possible score of 11 as previously described [9], [10]. "
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