Agonists of proteinase-activated receptor 1 induce plasma extravasation by a neurogenic mechanism
Agonists of proteinase-activated receptor 1 induce plasma extravasation by a neurogenic mechanism
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DOI：
10.1038/sj.bjp.0704152
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发表时间：
2001-08-01
影响因子：
7.3
通讯作者：
Bunnett, NW
中科院分区：
文献类型：
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作者：
de Garavilla, L;Vergnolle, N;Bunnett, NW
1凝血酶，在损伤过程中在循环中产生，切割蛋白酶激活受体I（PAR 1）以刺激血浆外渗和粒细胞浸润。然而，在完整组织中凝血酶诱导炎症的机制尚不清楚。我们假设凝血酶切割感觉神经上的PAR 1以释放P物质（SP），其与内皮细胞上的神经激肽I受体（NK 1 R）相互作用以引起血浆外渗。2通过免疫组织化学和原位杂交在大鼠背根神经节中已知含有SP的小直径神经元中检测到PAR 1。3凝血酶和PAR 1激动剂TFLLR-NH 2（TF-NH 2）增加[Ca 2 +]（i），使用Fura-2 AM评估，> 50%的培养神经元（EC（50）分别为24 μ ml（-1）和1.9 μ M）。PAR 1激动剂完全脱敏对凝血酶的反应，表明凝血酶通过PAR1.4将TF-NH 2注射到大鼠爪中刺激神经元，刺激了显著和持续的水肿。NK 1 R拮抗剂和用辣椒素消融感觉神经在1小时时抑制水肿44%，在5小时时完全抑制水肿。5在野生型但不是PAR 1（-/-）小鼠中，TF-NH 2刺激膀胱、食管、胃、肠和胰腺中的伊文思蓝外渗2-8倍。膀胱、食管和胃中的外渗被NK 1 R拮抗剂消除。6因此，凝血酶切割初级脊髓传入神经元上的PARI以释放SP，其激活内皮细胞上的NKIR以刺激间隙形成、血浆蛋白外渗和水肿。在完整组织中，神经原性机制主要负责PAR 1诱导的水肿。
1 Thrombin, generated in the circulation during injury, cleaves proteinase-activated receptor I (PAR1) to stimulate plasma extravasation and granulocyte infiltration. However, the mechanism of thrombin-induced inflammation in intact tissues is unknown. We hypothesized that thrombin cleaves PAR1 on sensory nerves to release substance P (SP), which interacts with the neurokinin I 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-NH2 (TF-NH2) increased [Ca2+](i), > 50% of cultured neurons (EC(50)s 24 mu ml(-1) and 1.9 muM, 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-NH2 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(-/-) mice, TF-NH2 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 PARI on primary spinal afferent neurons to release SP, which activates the NKIR 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.