蛋白酶活化受体对支气管哮喘炎症细胞功能调控的研究进展

蛋白酶活化受体(PAR)为7次跨膜G蛋白耦联受体,广泛分布于参与支气管哮喘(简称哮喘)的各种炎症细胞.内源性和外源性的蛋白酶通过激活PAR可调控炎症细胞的功能,从而影响哮喘气道炎症的发生和发展.本文综述蛋白酶受体对哮喘炎症细胞功能调控的研究进展.     

活化蛋白C治疗感染中毒症及其所致急性肺损伤的研究进展

近来的研究表明活化蛋白C（APC）在感染中毒症中具有抗凝、促纤溶和抗炎作用。重组人活化蛋白C（rhAPC）可显著降低感染中毒症患者的病死率。但rhAPC在临床应用中的适应证及其有效性仍存在争议。细胞学研究提示APC可通过与细胞表面受体结合,激活细胞内的各种蛋白酶,使其磷酸化或去磷酸化,诱导细胞内信号转导,调节炎症相关基因的表达,从而调节参与感染中毒症的多个重要病理生理过程。此外,APC可能对感染中毒症所致急性肺损伤起到保护性作用。     

蛋白酶活化受体-2与心肌缺血再灌注损伤

蛋白酶活化受体-2是一种G蛋白偶联的细胞膜表面受体，广泛分布于心血管以及富含血管的组织器官，能通过溶蛋白性裂解的方式激活受体自身，启动多种细胞效应。近年诸多研究表明该受体与心肌缺血再灌注损伤的关系密切。本文主要就其在心肌缺血再灌注中的作用作一综述。     

尘螨抗原的蛋白酶活性

尘螨抗原除有一般抗原的共同特性外,尚具有蛋白酶水解作用。尘螨蛋白酶抗原能够裂解B细胞和巨噬细胞膜表面某些受体分子如CD23和CD25,酶解上皮细胞间的紧密联接,诱导支气管上皮细胞释放前炎症介质。尘螨抗原的蛋白酶作用在吸入抗原致敏及特应性疾病的病理生理过程中起重要作用。     

尘螨抗原蛋白酶作用的研究进展

尘螨抗原除有一般抗原的共同特性外,尚具有蛋白酶水解作用。尘螨蛋白酶抗原能够裂解B细胞和巨噬细胞膜表面某些受体分子(如CD23和CD25),酶解上皮细胞间的紧密连接,诱导支气管上皮细胞释放前炎症介质。尘螨抗原的蛋白酶作用在吸入抗原致敏及特应性疾病的病理生理过程中起重要作用。     

PPARγ与胰岛素抵抗

过氧化物体增殖物激活受体（PPAR）γ是一类由配体调节的核激素受体，属于核激素受体超家族。新近研究显示PPARγ的超生理活化与活化的中度缺失均与胰岛素抵抗关系密切，由此提出选择性PPARγ激活剂的概念，这很可能为2型糖尿病的治疗提供新的靶向。     

013 尘螨抗原的蛋白酶活性

尘螨抗原除有一般抗原的共同特性外,尚具有蛋白酶水解作用.尘螨蛋白酶抗原能够裂解B细胞和巨噬细胞膜表面某些受体分子如CD23和CD25,酶解上皮细胞间的紧密联接,诱导支气管上皮细胞释放前炎症介质.尘螨抗原的蛋白酶作用在吸入抗原致敏及特应性疾病的病理生理过程中起重要作用.     

尘螨抗原的蛋白酶活性

尘螨抗原除有一航抗原的共同特性外，尚具有蛋白酶水解作用。尘螨蛋白酶蛋白酶抗原能够裂解B细胞和巨噬细胞膜表面某些受体分子和CD23和CD25，酶解上皮细胞间的紧密联接，诱导支气管上皮细胞释放前炎症介质，尘螨抗原的蛋白酶作用在吸入抗原致敏及特应性疾病的病理生理过程中起重要作用。     

过氧化物酶体增殖因子活化受体γ与缺血性卒中

过氧化物酶体增殖因子活化受体(PPARs)属于核受体超家族中的一员,参与许多生理调控如糖代谢、脂肪代谢、细胞生长及分化。PPAR-γ则与细胞葡萄糖摄取、抗动脉粥样硬化和免疫调控有关,PPAR-γ的活化有效减轻了神经变性和脑内的炎性反应。本文就PPAR-γ在缺血性脑卒中病理损伤过程中发挥的神经保护作用相关研究作一综述。     

蛋白酶及其抑制剂与肺疾病

近年来认为许多肺疾病的发生与发展和肺内蛋白酶—抗蛋白酶的平衡失调有关,在慢性支气管炎和肺气肿的研究中已明确了这一概念。[对人肺起作用的弹性蛋白酶的来源] 1.胰脏胰脏分泌的弹性蛋白酶在进入体循环尚未到达肺之前可被血浆蛋白酶抑制剂迅速灭活。已证明,胰弹性蛋白酶原在血清中能与α_1-抗胰蛋白酶(α_1-AT)结合,有可能使弹性蛋白酶在肺内的活化延迟。2.巨噬细胞巨噬细胞可能含有一种具有丝氨酸蛋白酶性质的弹性蛋白酶,该酶可能来自中性粒细胞,通过巨噬细胞表面受体进入细胞,但并不立即以活性形式释放。其次巨噬细胞可以产生具有金属蛋白酶性质的弹性蛋白酶(Ca~(++)-依赖)该酶不能储存,由活化的巨噬细胞释放。这种特异的巨噬细胞金属蛋白酶是否能够单独引起肺气肿,仍然未明。3.中性粒细胞人的多形核白细胞含有两种具     

Proteinase-activated receptor-2: physiological and pathophysiological roles

Protease-activated receptor 2 (PAR2) is the second member of a new subfamily of G-protein coupled receptors: the protease-activated receptors (PARs). At present, four different PARs have been cloned and all of them share the same basic mechanism of activation. A serine protease cleaves the extended, extracellular N-terminus of the receptor at a specific site within the protein chain to expose an N-terminal tethered ligand domain, which binds to and activates the cleaved receptor. In this manner, trypsin and mast cell beta-tryptase activate PAR2. PARs are single use receptors because proteolytic activation is irreversible and the cleaved receptors are degraded in lysosomes. Thus, PARs play important roles in emergency situations, such as trauma and inflammation. Emerging evidence indicates that PAR2 is involved in the cardiovascular, pulmonary and gastrointestinal systems, where it controls inflammation and nociception. Work with selective agonists and knockout animals suggests a contribution of PAR2 to certain inflammatory diseases. Therefore, selective antagonists or agonists of these receptors may be useful therapeutic agents for the treatment of human diseases.     

Proteinases as hormone-like signal messengers

Proteinases like thrombin and trypsin, long known for their ability to activate the coagulation cascade or to act as hormone-processing enzymes, are now recognised as hormone-like regulators of cell function. These serine proteinases activate cell signalling by triggering a novel four-member family of G-protein-coupled receptors, termed Proteinase-Activated Receptors (PARs). This review article summarises historically the discovery of PARs as well as their unique mechanism of activation and outlines a number of different pathophysiological settings in which PARs can act to regulate cell and tissue function. PARs can be seen to play a role in pathophysiological processes ranging from inflammation and pain to cardiovascular disease and cancer. Apart from activating PARs to cause their physiological effects in tissues, proteinases can also mediate cell signalling via a number of other mechanisms, including the activation of growth factor receptors, like the one for insulin. Therefore, this article also describes the non-PAR mechanisms whereby proteinases can have hormone-like actions in cells and tissues.     

How the protease thrombin talks to cells.

How does a protease act like a hormone to regulate cellular functions? The coagulation protease thrombin (EC 3.4.21.5) activates platelets and regulates the behavior of other cells by means of G protein-coupled protease-activated receptors (PARs). PAR1 is activated when thrombin binds to and cleaves its amino-terminal exodomain to unmask a new receptor amino terminus. This new amino terminus then serves as a tethered peptide ligand, binding intramolecularly to the body of the receptor to effect transmembrane signaling. The irreversibility of PAR1's proteolytic activation mechanism stands in contrast to the reversible ligand binding that activates classical G protein-coupled receptors and compels special mechanisms for desensitization and resensitization. In endothelial cells and fibroblasts, activated PAR1 rapidly internalizes and then sorts to lysosomes rather than recycling to the plasma membrane as do classical G protein-coupled receptors. This trafficking behavior is critical for termination of thrombin signaling. An intracellular pool of thrombin receptors refreshes the cell surface with na?ve receptors, thereby maintaining thrombin responsiveness. Thus cells have evolved a trafficking solution to the signaling problem presented by PARs. Four PARs have now been identified. PAR1, PAR3, and PAR4 can all be activated by thrombin. PAR2 is activated by trypsin and by trypsin-like proteases but not by thrombin. Recent studies with knockout mice, receptor-activating peptides, and blocking antibodies are beginning to define the role of these receptors in vivo.     

Protease-activated receptors as targets for antiplatelet therapy

Arterial thrombosis, manifesting as acute myocardial infarction or ischaemic stroke, is the single most common cause of morbidity and mortality in industrialised societies. Platelets are a pre-requisite for the formation of arterial thrombi and, as a consequence, novel antiplatelet agents are sought to meet the significant clinical need for a potent, safe, and orally available therapy for the management of cardiovascular disease. Platelet thrombin receptors, termed protease-activated receptors (PARs), represent one promising candidate for the development of such therapy. This review outlines the role of platelet PARs in haemostasis and thrombosis and discusses the preclinical and clinical evidence supporting the potential of PAR antagonists as novel antiplatelet therapy.     

蛋白酶激活受体在免疫炎症性疾病中的研究进展

蛋白酶激活受体(protease activated receptors, PARs)是G蛋白偶联受体的一个亚家族,最早发现其与血栓形成、组织止血、癌症相关,随着研究的深入,发现PARs在感染、免疫炎症性疾病、纤维化疾病中发挥重要作用。目前已发现PARs有4种亚型,分别为PAR1~4,研究较多的为PAR1和PAR2,现就PAR1、PAR2在免疫炎症性疾病中的作用作一概述。     

The roles of proteinase-activated receptors in the vascular physiology and pathophysiology

Proteinase-activated receptors (PARs) belong to a family of G protein-coupled receptors, thus mediating the cellular effects of proteinases. In the vascular system, thrombin and other proteinases in the coagulation-fibrinolysis system are considered to be the physiologically relevant agonists, whereas PARs are among the most important mechanisms mediating the interaction between the coagulation-fibrinolysis system and the vascular wall. Under physiological conditions, PARs are mainly expressed in endothelial cells, and participate in the regulation of vascular tone, mostly by inducing endothelium-dependent relaxation. PARs in endothelial cells are also suggested to contribute to a proinflammatory phenotypic conversion and an increase in the permeability of vascular lesions. In smooth muscle cells, PARs mediate contraction, migration, proliferation, hypertrophy, and production of the extracellular matrix, thereby contributing to the development of vascular lesions and the pathophysiology of such vascular diseases as atherosclerosis. However, the expression of PARs in the smooth muscle of normal arteries is limited. The upregulation of PARs in the smooth muscle is thus considered to be a key step for PARs to participate in the pathogenesis of vascular lesions. Elucidating the molecular mechanism regulating the PARs expression is therefore important to develop new strategies for the prevention and treatment of vascular diseases.     

Protease-activated receptors in cardiovascular diseases

Thrombosis associated with the pathophysiological activation of platelets and vascular cells has brought thrombin and its receptors to the forefront of cardiovascular medicine. Thrombin signaling through the protease-activated receptors (PARs) has been shown to influence a wide range of physiological responses including platelet activation, intimal hyperplasia, inflammation, and maintenance of vascular tone and barrier function. The thrombin receptors PAR1 and PAR4 can be effectively targeted in animals in which acute or prolonged exposure to thrombin leads to thrombosis and/or restenosis. In the present study, we describe the molecular and pharmacological basis of small-molecule inhibitors that target PAR1. In addition, we discuss a new class of cell-penetrating inhibitors, termed pepducins, that provide insight into previously unidentified roles of PAR1 and PAR4 in protease signaling.     

Protease-activated receptor-2 (PAR2) in the airways.

Protease-activated receptors (PARs) act as sensors for active extracellular serine proteases. Since serine proteases like mast cell tryptase are associated with inflammatory processes, PARs may represent novel pharmacological targets in airway diseases like asthma and chronic obstructive pulmonary disease. However, our present understanding of the physiological roles of PARs is in its infancy. In this review we highlight evidence for the involvement of PARs in airway disease and propose that these novel receptors may play mainly protective roles. Copyright Academic Press.     

Roles of Platelets and Proteinase-Activated Receptors in Gastric Ulcer Healing

Proteinase-activated receptors (PARs) are expressed on the surface of many cells, but those on the platelet have been among the most thoroughly characterized. PARs act as key receptors mediating the proaggregatory and prosecretory effects of thrombin. In addition to contributing to hemostasis, platelets are increasingly being viewed as important contributors to healing and to tumor growth. This is attributable to the many pro- and anti-angiogenic factors that are stored within platelets, which can be released at the sites of injury and new vessel growth. In this paper, we review the importance of the platelet in gastric ulcer healing, the contribution of platelet-contained angiogenic factors to the healing of gastric ulcers, and the role of PARs in regulating the release of angiogenic factors from platelets. Taken together, our results suggest that PARs, including those expressed on platelets, are a rational therapeutic target for modulating healing processes and tumor growth.     

Protease-activated receptors: how proteases signal to cells to cause inflammation and pain

Certain serine proteases that originate from the circulation (coagulation factors), inflammatory cells (mast cell tryptase, neutrophil granzyme A, and proteinase 3), and epithelial and neuronal tissues (trypsins) can specifically regulate cells by cleaving protease-activated receptors (PARs), a family of four G-protein-coupled receptors. Proteases cleave PARs on multiple cell types to reveal tethered ligand domains that bind to and activate the cleaved receptors. The proteases that activate PARs are often generated and secreted during injury and inflammation, and PARs orchestrate tissue responses to these insults, including hemostasis, inflammation, nociception, and repair mechanisms. Agonists of PARs, notably PAR2, induce inflammation in many tissues that is characterized by hyperemia, extravasation of plasma proteins, granulocyte infiltration, and alterations in epithelial permeability. These effects are mediated in part by the release of neuropeptides substance P and calcitonin gene-related peptide from sensory nerve fibers in peripheral tissues. Proteases that activate PAR2 also induce the release of neuropeptides from the central projections of these nerves in the dorsal horn of the spinal cord, where they participate in pain transmission. Accumulating evidence from PAR-deficient mice indicates that these mechanisms may contribute to experimental models of disease and raise the possibility that protease inhibitors and PAR antagonists may be useful therapies for a variety of inflammatory and painful conditions.