MAST CELL/MAST CELL MEDIATORSIN INJURY

摘要：损伤组织，重建血液供应，缺血再灌流， 或者在烧伤后，可能会导致身体自身免疫系统扩大的损伤。桅杆 细胞(MC)在骨骼中这种自体炎症反应的进展中起着重要作用 肌肉和小肠，以及皮肤烧伤后，可能会导致不可逆转的损伤 伤痕累累。通过利用缺乏特定分泌颗粒中性蛋白水解酶的小鼠，小鼠MC蛋白酶 5(mMCP-5)已被发现参与了这些免疫损伤的每一种模型。此外，mMCP-4 它具有不同于mMCP-5的底物特异性，已被发现在烧伤中也具有颗粒板作用。 这一遗传学证据将通过对MC反应和组织的更详细的描述而得到扩展 病理生物学，并通过使用活性部位抑制剂和重组人的药理学方法确认 MMCP-5。MC激活的机制被认为是通过产生补体片段C3a 6 C5a，将通过在一株缺乏 一种受体与另一种受体在药理上被阻断，或使用两种受体都缺乏的菌株。这个 不可逆转的损伤可能需要五种补体的末端细胞毒复合体的作用 蛋白质和MC蛋白酶将通过在产生的新菌株中显示保护来解决，以便 缺乏MC和补体复合体的形成，但对激活部分没有影响 补体途径。在这三个目标中的每一个目标中，涉及特定 在过继转移野生型MC的缺陷菌株中，蛋白质将通过重建损伤而不是 缺乏MC。关联性。自身免疫中MC活化机制的认识 炎症，涉及的mMCPs的特异性，以及mMCPs与细胞毒的相互作用 补体复合体在不可逆性损伤伴瘢痕形成中应提供治疗靶点。

SUMMARY: Trauma to a tissue with impairment and reestablishment of the blood supply, ischemiareperfusion, or after a burn, can lead to an injury that is augmented by the body's own immune system. Mast cells (MC) play an important role in progression of such an autologous inflammatory response in skeletal muscle and small intestine and after a cutaneous burn, possibly contributing to irreversible injury with scarring. Through the use of mice lacking specific secretory granule neutral proteases, mouse MC protease 5 (mMCP-5) has been found to participate in each of these models of immune injury. In addition, mMCP-4 which has a substrate specificity different from mMCP-5 has been found to also participlate in burn injury. This genetic evidence will be extended by more detailed characterization of the MC response and tissue pathobiology and confirmed by pharmacologic approaches using active site inhibitors and recombinant mMCP-5. The mechanism for MC activation, presumed to be via generation of complement fragments, C3a 6 C5a, will be established by showing protection against autologous immune injury in a strain deficient in one receptor and pharmacologically blocked at the other or by using a strain deficient in both receptors. The possibility that irreversible injury requires the action of the terminal cytotoxic complex of five complement proteins and a MC protease will be addressed by showing protection in a new strain generated so as to be deficient in MC and in formation of the complement complex but intact for the activating portion of the complement pathway. In each of these three aims the final proof for involvement of a particular protein will be by reconstituting injury in a deficient strain with adoptive transfer of wild type MC but not deficient MC. RELEVANCE. Understanding the mechanism of MC activation in autologous immune inflammation, the specificity of the mMCPs involved, and the interplay of the mMCPs with the cytotoxic complement complex in irreversible injury with scarring should provide therapeutic targets.