Obreja Otilia, Rukwied Roman, Steinhoff Martin, Schmelz Martin
Department of Anaesthesiology and Intensive Care, Faculty of Clinical Medicine Mannheim, University of Medicine Heidelberg, Mannheim, Germany.
Exp Dermatol. 2006 Jan;15(1):58-65. doi: 10.1111/j.0906-6705.2005.00392.x.
Activation of protease-activated receptors (PAR) can induce vasodilation (VD) and increase of vascular permeability either directly by stimulating endothelial cells or indirectly via activation of nociceptors and subsequent release of neuropeptides (neurogenic inflammation). We aimed to estimate the relative contribution of the two pathways for stimulation with endogenous activators of PAR-2 (trypsin) and of PAR-1, 3 and 4 (thrombin) using in vivo dermal microdialysis in rats. Protein extravasation (PE) was assessed by increase of protein concentration in the dialysate, and VD was quantified by laser Doppler scanning. Both trypsin (10(-8)-10(-4) M) and thrombin (10(-6), 10(-5.5) and 10(-5) M) provoked PE and local VD in a dose-dependent manner. Trypsin (10(-4) M)-induced PE was inhibited by 87.2 +/- 21% due to the substance P (SP) NK1 receptor antagonist SR140333. VD was blocked by 58.15 +/- 10.1% in response to the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP(8-37). By contrast, CGRP(8-37) did not affect thrombin-induced VD, while blockade of SP receptors prevented the PE elicited only by low doses of thrombin (10(-6) M), being ineffective at higher thrombin concentrations. In conclusion, intradermal trypsin elicits a neurogenic inflammation in rat, probably mediated via PAR-2 activation on nociceptors and subsequent SP and CGRP release. Thrombin-induced PE and VD are mediated mainly by a non-neurogenic mechanism.
蛋白酶激活受体（PAR）的激活可通过刺激内皮细胞直接诱导血管舒张（VD）和增加血管通透性，或通过激活伤害感受器并随后释放神经肽（神经源性炎症）间接实现。我们旨在通过大鼠体内真皮微透析，评估PAR-2（胰蛋白酶）以及PAR-1、3和4（凝血酶）的内源性激活剂刺激时这两种途径的相对贡献。通过透析液中蛋白质浓度的增加评估蛋白质外渗（PE），并通过激光多普勒扫描对VD进行定量。胰蛋白酶（10⁻⁸ - 10⁻⁴ M）和凝血酶（10⁻⁶、10⁻⁵.⁵和10⁻⁵ M）均以剂量依赖性方式引发PE和局部VD。由于P物质（SP）NK1受体拮抗剂SR140333，胰蛋白酶（10⁻⁴ M）诱导的PE被抑制了87.2±21%。响应降钙素基因相关肽（CGRP）受体拮抗剂CGRP(8 - 37)，VD被阻断了58.15±10.1%。相比之下，CGRP(8 - 37)不影响凝血酶诱导的VD，而阻断SP受体仅能预防低剂量凝血酶（10⁻⁶ M）引发的PE，在较高凝血酶浓度时无效。总之，皮内注射胰蛋白酶在大鼠中引发神经源性炎症，可能是通过伤害感受器上的PAR-2激活以及随后的SP和CGRP释放介导的。凝血酶诱导的PE和VD主要由非神经源性机制介导。
