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. 1999 Jul;127(5):1083-90.
doi: 10.1038/sj.bjp.0702634.

Characterization of the inflammatory response to proteinase-activated receptor-2 (PAR2)-activating peptides in the rat paw

N Vergnolle  1 , M D Hollenberg, K A Sharkey, J L Wallace
Affiliations

Characterization of the inflammatory response to proteinase-activated receptor-2 (PAR2)-activating peptides in the rat paw

N Vergnolle et al. Br J Pharmacol. 1999 Jul.

Abstract

In the present study, we have observed the development of an inflammatory reaction in the rat hindpaw, following the injection of specific agonists of PAR2 (two PAR2 activating peptides). This inflammation was characterized by oedema and granulocyte infiltration. Two selective PAR2 activating peptides, SLGRL-NH2 and trans-cinnamoyl-LIGRLO-NH2 induced significant oedema in the rat hindpaw from 1-6 h following subplantar injection. Six hours after the PAR2-activating peptide injection, the paw tissues showed a complete disruption of tissue architecture along with an inflammatory cell infiltrate. In the inflamed paw, PAR2-immunoreactivity was expressed on endothelial cells as well as on the infiltrating inflammatory cells. The oedema induced by the injection of the two PAR2 activating peptides was slightly reduced in rats pre-treated with compound 48/80, but was not modified by pre-treatment of rats with cromolyn, a mast cell stabilizer. Pre-treatment of rats with a cyclo-oxygenase inhibitor (indomethacin) or a nitric oxide synthase inhibitor (L-N(omega)-nitro-L-arginine methyl ester) had no effect on the oedema induced by the PAR2-activating peptides. These results demonstrate that the administration of PAR2-activating peptides into the rat paw induced an acute inflammatory response characterized by a persistent oedema (at least 6 h) and granulocyte infiltration. The PAR2-induced inflammatory response occurred through a mechanism largely independent of mast cell activation, and of the production of prostanoids and nitric oxide.

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Figures

Figure 1
Figure 1
Increase in rat hindpaw volume following administration of PAR2-activating peptides (SL-NH2, 500 μg and tc-NH2, 100 and 500 μg), a control peptide (LS-NH2, 100 and 500 μg) or vehicle. Asterisks denote significant differences (P<0.05) between the control peptide groups and the other groups for the same dose.
Figure 2
Figure 2
Histological staining of sections of rat hindpaws, 6 h after the injection of vehicle (A), the control peptide (LS-NH2, 100 μg) (B), the two PAR2-activating peptides SL-NH2, 500 μg (C), and tc-NH2, 100 μg (D). Scale bar: 50 μm. The scale bar in B is for A, B, C and D.
Figure 3
Figure 3
Fluorescence micrographs of PAR2-immunoreactivity in the rat paw from animals injected 6 h earlier with a control peptide (LS-NH2, A and C) and paws injected with a PAR2AP (tc-NH2, B and D). (A) Subdermis from the control paw showing little or no specific labelling. (B) In paws injected with the PAR2AP, there was an extensive infiltration of immunoreactive cells and considerable oedema. (C) On the endothelium of some blood vessels of control tissues (arrow) there was faint PAR2-immunoreactivity. (D) In PAR2AP-treated paws, increased intensity of PAR2-immunoreactivity was found on the endothelium of some blood vessels (mostly venules, arrow). Scale bars: 50 μm. The scale bar in B is for A and B, and the bar in D is for C and D.
Figure 4
Figure 4
(A) Effects of prior depletion of mast cells (through pre-treatment with compound 48/80) on the increase in hindpaw volume following injection of PAR2-activating peptides (tc-NH2, 100 μg or SL-NH2 500 μg) or a control peptide (LS-NH2, 100 μg). Asterisks denote significant differences (P<0.05) from the corresponding group not treated with compound 48/80. (B) Effects of mast cell stabilization (through pre-treatment with cromolyn) on the increase in hindpaw volume following injection of PAR2-activating peptides (tc-NH2, 100 μg or SL-NH2 500 μg) or a control peptide (LS-NH2, 100 μg). Asterisks denote significant differences (P<0.05) from the corresponding group not treated with cromolyn.
Figure 5
Figure 5
Effects of pre-treatment with the cyclo-oxygenase inhibitor, indomethacin, on the increase in hindpaw volume following injection of PAR2-activating peptide (tc-NH2, 100 μg) or a control peptide (LS-NH2, 100 μg). Asterisks denote significant differences (P<0.05) from the corresponding group not treated with indomethacin.
Figure 6
Figure 6
Effects of pre-treatment with the nitric oxide synthase inhibitor, L-NAME, on the increase in hindpaw volume following injection of a PAR2-activating peptide (tc-NH2, 100 μg) or a control peptide (LS-NH2, 100 μg), compared to control treatment with D-NAME. Asterisks denote significant differences (P<0.05) from the corresponding group not treated with L-NAME.
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