Agonists of proteinase‐activated receptor 1 induce plasma extravasation by a neurogenic mechanism

Abstract

1 Thrombin, generated in the circulation during injury, cleaves proteinase-activated receptor 1 (PAR1) to stimulate plasma extravasation and granulocyte in®ltration. However, the mechanism of thrombin-induced in¯ammation in intact tissues is unknown. We hypothesized that thrombin cleaves PAR1 on sensory nerves to release substance P (SP), which interacts with the neurokinin 1 receptor (NK1R) on endothelial cells to cause plasma extravasation. 2 PAR1 was detected in small diameter neurons known to contain SP in rat dorsal root ganglia by immunohistochemistry and in situ hybridization. 3 Thrombin and the PAR1 agonist TFLLR-NH 2 (TF-NH 2 ) increased [Ca 2+ ] i 450% of cultured neurons (EC 50 s 24 mu ml 71 and 1.9 mM, respectively), assessed using Fura-2 AM. The PAR1 agonist completely desensitized responses to thrombin, indicating that thrombin stimulates neurons through PAR1. 4 Injection of TF-NH 2 into the rat paw stimulated a marked and sustained oedema. An NK1R antagonist and ablation of sensory nerves with capsaicin inhibited oedema by 44% at 1 h and completely by 5 h. 5 In wild-type but not PAR1 7/7 mice, TF-NH 2 stimulated Evans blue extravasation in the bladder, oesophagus, stomach, intestine and pancreas by 2 ± 8 fold. Extravasation in the bladder, oesophagus and stomach was abolished by an NK1R antagonist. 6 Thus, thrombin cleaves PAR1 on primary spinal a erent neurons to release SP, which activates the NK1R on endothelial cells to stimulate gap formation, extravasation of plasma proteins, and oedema. In intact tissues, neurogenic mechanisms are predominantly responsible for PAR1-induced oedema.

Neurogenic Inflammation in Stress-Induced Termination of Murine Hair Growth Is Promoted by Nerve Growth Factor

“…These inflammatory effects are, at least in part, mediated by cleavage and activation of proteinase-activated receptors (PARs), 68,69 indicating that, in neurogenic inflammation, proteinases may activate PARs on sensory neurons to stimulate release of SP, which, in turn, additionally enhances the inflammatory response. Moreover, the release of other neuropeptides, eg, calcitonin gene related peptide (CGRP) may also be up-regulated on stress exposure with subsequent PAR activation (Kuhlmei A, unpublished observations).…”

Gene Expression Profiling of Mouse Bladder Inflammatory Responses to LPS, Substance P, and Antigen-Stimulation

“…37 Tryptase responses are modulated by proteinase-activated receptors (PAR) coupled to a G-protein. These receptors are present in bladder afferent neurons 38 and mediate plasma extravasation induced by tryptase and thrombin. 38 PA receptors are also present in normal human kidneys, 39 and mediate the response of human proximal tubular cells to thrombin.…”

“…These receptors are present in bladder afferent neurons 38 and mediate plasma extravasation induced by tryptase and thrombin. 38 PA receptors are also present in normal human kidneys, 39 and mediate the response of human proximal tubular cells to thrombin. 39 Others have reported that activation of PAR induced detectable levels of IL-6 production in a dose-dependent fashion.…”

Epithelial effects of proteinase-activated receptors in the gastrointestinal tract

“…In contrast, other studies have shown that PAR-1 activation can cause plasma extravasation in the stomach (De Garavilla et al 2001), suggestive of a pro-inflammatory effect of PAR-1. The difference may lie in the model used, with one being an assessment of the effect of PAR-1 activation on HClethanol-induced damage in the rat (Kawabata et al 2004) and one being an assessment of PAR-1 effects in normal mouse stomach (De Garavilla et al 2001). The stimulation of plasma exudation by PAR-1 activation in the mouse is dependent upon sensory afferent nerves.…”

“…Related to this is the recognition that PAR-2 can mediate hyperalgesia of the intestine (Coelho et al 2002). Both of these situations point to a relationship between PAR-1 and capsaicin-sensitive afferent activation and indeed this relationship has been demonstrated experimentally , De Garavilla et al 2001. We have evidence that capsaicin-sensitive extrinsic sensory afferent neurons can, through local axon reflexes, stimulate chloride secretion in guinea pig ileum in vitro (Vanner & MacNaughton 1995).…”