title: Serine protease inhibition reduces post-ischemic granulocyte recruitment in mouse intestine.
abstract: 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.
authors: INSERM, U1043, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France.
authors: Thomas
authors: T
authors: Gobbetti
authors: Nicolas
authors: N
authors: Cenac
authors: Jean-Paul
authors: JP
authors: Motta
authors: Corinne
authors: C
authors: Rolland
authors: Laurence
authors: L
authors: Martin
authors: Patricia
authors: P
authors: Andrade-Gordon
authors: Martin
authors: M
authors: Steinhoff
authors: Elisabetta
authors: E
authors: Barocelli
authors: Nathalie
authors: N
authors: Vergnolle
mesh_terms: D000818:Animals; D001550:Benzamidines; D018925:Chemokines / Q000378:metabolism; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D006098:Granulocytes / Q000201:enzymology / Q000502:physiology*; D006146:Guanidines / Q000494:pharmacology; D007421:Intestine, Small / Q000098:blood supply*; D007511:Ischemia / Q000201:enzymology* / Q000473:pathology; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000378:metabolism; D044464:Receptor, PAR-2 / Q000378:metabolism; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D014357:Trypsin / Q000378:metabolism; D000511:alpha-Macroglobulins / Q000378:metabolism
chemical_list: D001550:Benzamidines; D018925:Chemokines; D015853:Cysteine Proteinase Inhibitors; D006146:Guanidines; D011480:Protease Inhibitors; D044463:Receptor, PAR-1; D044464:Receptor, PAR-2; D015842:Serine Proteinase Inhibitors; D000511:alpha-Macroglobulins; D009195:Peroxidase; D014357:Trypsin; D007930:Leucine; C024974:E 64; C032855:nafamostat