MAST CELL/MAST CELL MEDIATORSIN INJURY

肥大细胞/肥大细胞介质损伤

• 批准号: 7428732
• 负责人: KARL FRANK AUSTEN
• 金额: $ 45.89万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-16 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7428732
• 关键词: Accounting; Active Sites; Address; Adoptive Transfer; Anaphylatoxin; Anaphylatoxins; Appearance; Autologous; Back; Bone Marrow; Burn injury; Carboxypeptidase A; Cell Degranulation; Cell Lineage; Cells; Chromosomes, Human, Pair 14; Chymase; Cicatrix; Class; Complement; Complement 3a; Complement 5a; Complement Membrane Attack Complex; Complex; Connective Tissue; Cutaneous; Development; Disruption; Elastases; Endopeptidases; Epithelial; Evaluation; Exhibits; Gene Cluster; Generations; Genetic; Germ Cells; Heart; Hematopoietic; Histologic; Human; Immune; Immune system; Immunoglobulin M; Impairment; Inflammation; Inflammatory; Inflammatory Response; Injury; Ischemia; Knockout Mice; Lead; Limb structure; Location; Modeling; Mus; Mutation; Not Defined; Pancreatic Elastase; Pathway interactions; Peptide Hydrolases; Phenotype; Physiological reperfusion; Play; Process; Production; Protease Inhibitor; Proteins; Proto-Oncogene Protein c-kit; Recombinants; Reperfusion Therapy; Role; Secretory Vesicles; Signal Transduction; Site; Skeletal Muscle; Skeletal muscle injury; Skin; Small Intestines; Source; Specificity; Stem Cell Factor; Substrate Specificity; System; Testing; Time; Tissues; Trauma; Tryptase; Vascular blood supply; base; complement pathway; cytotoxic; elastase inhibitor; inhibitor/antagonist; limb injury; mMCP-5; mast cell; mast cell protease 4; melanocyte; mutant; prevent; receptor; reconstitution; research study; response; therapeutic target

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.

总结：组织创伤伴血供受损和重建、缺血再灌注， 或烧伤后，可能导致身体自身免疫系统增强的损伤。桅杆 细胞（MC）在骨骼中这种自体炎症反应的进展中发挥重要作用 肌肉和小肠以及皮肤烧伤后，可能导致不可逆损伤， 疤痕通过使用缺乏特异性分泌颗粒中性蛋白酶的小鼠， 5（mMCP-5）参与这些免疫损伤模型中的每一种。此外，mMCP-4 其具有不同于mMCP-5的底物特异性，已发现其也参与烧伤损伤。 这一遗传学证据将通过对MC反应和组织的更详细的表征来扩展。 病理生物学和药理学方法证实，使用活性位点抑制剂和重组 mMCP-5。MC激活的机制，推测是通过产生补体片段，C3 a 6 C5 a，将通过在缺乏以下的菌株中显示针对自体免疫损伤的保护来建立： 一种受体和另一种受体阻断的受体，或通过使用两种受体都缺陷的菌株。的 不可逆损伤需要五种补体的末端细胞毒性复合物的作用的可能性 蛋白质和MC蛋白酶将通过在新菌株中显示保护来解决， 缺乏MC和补体复合物的形成，但完整的激活部分， 补体途径在这三个目标中的每一个目标中， 蛋白质将通过在具有野生型MC的过继转移的缺陷型菌株中重建损伤而获得，但不 缺乏MC。本案无关了解自身免疫中MC激活的机制 炎症，所涉及的mMCP的特异性，以及mMCP与细胞毒性因子的相互作用， 补体复合物在不可逆损伤与疤痕应该提供治疗目标。