Although all of the classical hallmarks of inflammation, ie, swelling (increased wall thickness), redness (erythema), impaired function, and even pain,
44- Coelho AM
- Vergnolle N
- Guiard B
- Fioramonti J
- Bueno L
Proteinases and proteinase-activated receptor 2: a possible role to promote visceral hyperalgesia in rats.
have been observed after the acute intracolonic administration of a selective PAR-2 agonist, it is also necessary to consider a possible anti-inflammatory role for PAR-2. Several studies have suggested that PAR-2 activation might promote resolution of inflammation.
3- Vergnolle N
- Wallace JL
- Bunnett NW
- Hollenberg MD
Protease-activated receptors in inflammation, neuronal signaling and pain.
In airway epithelia, both PAR-1-AP and PAR-2-AP elicit relaxation through the release of prostaglandin E
2, thus causing a powerful bronchodilatation.
12- Cocks TM
- Fong B
- Chow JM
- Anderson GP
- Frauman AG
- Goldie RG
- Henry PJ
- Carr MJ
- Hamilton JR
- Moffatt JD
A protective role for protease-activated receptors in the airways.
A recent study has shown that systemic treatment with PAR-2-AP inhibits the development of TNBS-induced colitis leading to an increased survival rate, improved macroscopic and histological damage score, and a decrease in the mucosal content of Th1 helper cell type 1 cytokines.
13- Fiorucci S
- Mencarelli A
- Palazzetti B
- Distrutti E
- Vergnolle N
- Hollenberg MD
- Wallace JL
- Morelli A
- Cirino G
Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis.
In that study, the authors also showed that
in vivo treatment with a PAR-2-AP directly inhibited trinitrobenzensulfonic acid-induced interferon-γ secretion and CD44 expression on lamina propria T lymphocytes.
13- Fiorucci S
- Mencarelli A
- Palazzetti B
- Distrutti E
- Vergnolle N
- Hollenberg MD
- Wallace JL
- Morelli A
- Cirino G
Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis.
The apparent discrepancy between our results documenting a proinflammatory role for PAR-2-AP and anti-inflammatory effects of PAR-2-AP observed by Fiorucci and colleagues
13- Fiorucci S
- Mencarelli A
- Palazzetti B
- Distrutti E
- Vergnolle N
- Hollenberg MD
- Wallace JL
- Morelli A
- Cirino G
Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis.
in the TNBS-induced colitis model, may be explained by the nature of inflammation. The TNBS-induced colitis model is a model of chronic intestinal inflammation and the authors have looked at the damage 7 days after the induction of colitis, whereas in our study, an acute exposure to PAR-2-AP provoked an intestinal inflammation that was maximal between 4 and 6 hours after its induction. It is well known that some inflammatory mediators provoke an inflammatory reaction when administered acutely, but can be anti-inflammatory in the setting of chronic inflammation.
45- Peskar BM
- Maricic N
- Gretzera B
- Schuligoi R
- Schmassmann A
Role of cyclooxygenase-2 in gastric mucosal defense.
, 46- Mazelin L
- Theodorou V
- Fioramonti J
- Bueno L
Vagally dependent protective action of calcitonin gene-related peptide on colitis.
, 47Nitric oxide as antiinflammatory agent.
Another explanation for proinflammatory
versus anti-inflammatory effects of PAR-2 activation is that inflammatory response may result from local activation of PAR-2, whereas systemic activation of PAR-2 may lead to an anti-inflammatory effect. In fact, local activation of PAR-2 (intracolonic administration), but not systemic injection (intraperitoneal) was responsible for the proinflammatory effects in the colon, whereas only a systemic injection of PAR-2 agonists induced resolution of TNBS-induced colitis.
13- Fiorucci S
- Mencarelli A
- Palazzetti B
- Distrutti E
- Vergnolle N
- Hollenberg MD
- Wallace JL
- Morelli A
- Cirino G
Proteinase-activated receptor 2 is an anti-inflammatory signal for colonic lamina propria lymphocytes in a mouse model of colitis.
It has been established that the induction of hypotension can be responsible for a decreased inflammation in models such as carrageenan-induced paw inflammation,
48- Torpy DJ
- Webster EL
- Zachman EK
- Aguilera G
- Chrousos GP
Urocortin and inflammation: confounding effects of hypotension on measures of inflammation.
and systemic administration of PAR-2-AP is known to cause hypotension,
8- Damiano B
- Cheung W
- Santulli R
- Fung-Leung P
- Ngo K
- Ye R
- Darrow A
- Derian C
- De Garavilla L
- Andrade-Gordon P
Cardiovascular responses mediated by proteinase-activated receptor-2 (PAR-2) and thrombin receptor (PAR-1) are distinguished in mice deficient in PAR-2 or PAR-1.
, 49- Cicala C
- Pinto A
- Bucci M
- Sorrentino R
- Walker B
- Harriot P
- Cruchley A
- Kapas S
- Howells GL
- Cirino G
Protease-activated receptor-2 involvement in hypotension in normal and endotoxemic rats in vivo.
, 50- Emilsson K
- Wahlestedt C
- Sun MK
- Nystedt S
- Owman C
- Sundelin J
Vascular effects of proteinase-activated receptor 2 agonist peptide.
it is thus possible that hypotension induced by a chronic and systemic treatment with PAR-2-AP is responsible for the anti-inflammatory effects observed in the model of TNBS-induced colitis. Systemic
versus local administration of PAR-2-AP activates different target cells expressing PAR-2 and these cells might be implicated differently in the inflammatory cascade. For example, it has been shown that endothelial activation of PAR-2, which might occur after systemic injection of PAR-2-AP, reduced tissue damage induced by ischemia-reperfusion injuries
14- Napoli C
- Cicala C
- Wallace JL
- de Nigris F
- Santagada V
- Caliendo G
- Franconi F
- Ignarro LJ
- Cirino G
Protease-activated receptor-2 modulates myocardial ischemia-reperfusion injury in the rat heart.
and cardiac inflammation,
51- Napoli C
- de Nigris F
- Cicala C
- Wallace JL
- Caliendo G
- Condorelli M
- Santagada V
- Cirino G
Protease-activated receptor-2 activation improves efficiency of experimental ischemic preconditioning.
whereas PAR-2 activation on epithelial cells has been shown to induce the release of proinflammatory cytokines such as IL-8 and IL-6
52- Asokananthan N
- Graham PT
- Fink J
- Knight DA
- Bakker AJ
- McWilliam AS
- Thompson PJ
- Stewart GA
Activation of protease-activated receptor (PAR)-1, PAR-2, and PAR-4 stimulates IL-6, IL-8, and prostaglandin E2 release from human respiratory epithelial cells.
or the release of arachidonic acid, the precursor of lipid inflammatory mediators, from enterocytes.
26- Kong W
- McConalogue K
- Khitin L
- Hollenberg MD
- Payan D
- Bohm S
- Bunnett N
Luminal trypsin may regulate enterocytes through proteinase-activated receptor-2.
In summary, our study shows that a direct local activation of PAR-2 in the mouse colon leads to intestinal inflammation and a severe impairment of intestinal permeability. Trypsin and tryptase, through the activation of PAR-2, also causes colonic inflammation. Considering the large presence of those two proteinases in the gut, and the increased luminal tryptic activity associated with inflammatory bowel disease, it is likely that trypsin and/or tryptase can locally activate PAR-2, and might then participate in the intestinal pathophysiological changes observed in inflammatory bowel disease patients.