Models of P. carinii infections SP-A and SP-D null mice

卡氏疟原虫感染 SP-A 和 SP-D 无效小鼠模型

• 批准号: 7469387
• 负责人: MICHAEL FRANCIS BEERS
• 金额: $ 36.46万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7469387
• 关键词: Acute respiratory failure; Adrenal Cortex Hormones; Affect; Aftercare; Alveolar Macrophages; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antigens; Binding; Biological Models; Bronchoalveolar Lavage; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Collagen; Collectins; Complex; Condition; Cytokine Activation; Data; Defect; Diagnosis; Distal; Effector Cell; Elements; Epidemiologic Studies; Epithelial Cells; Epithelium; Equilibrium; Event; Excision; Exhibits; Family; Feedback; Functional disorder; Funding; Gases; Genetic Polymorphism; HIV; Highly Active Antiretroviral Therapy; Host Defense; Hypoxemia; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Response; Injury; Interleukin-13; Interleukin-4; Kinetics; Knock-out; Knockout Mice; Lectin; Life; Light; Link; Literature; Lung; Lung Inflammation; Lung diseases; Lymphocyte; Lymphocyte Activation; Lymphocyte Subset; Macrophage Activation; Mediating; Mediator of activation protein; Metabolism; Modeling; Mononuclear; Morbidity - disease rate; Mus; Nitric Oxide; Numbers; Opportunistic Infections; Organism; Pathogenesis; Pathway interactions; Patients; Peroxonitrite; Pneumocystis; Pneumocystis Infections; Pneumocystis carinii; Pneumocystis carinii Pneumonia; Pneumonia; Population; Principal Investigator; Production; Proliferating; Property; Protein C; Protein Overexpression; Proteins; Publishing; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Protein B; Pulmonary Surfactant-Associated Protein D; Pulmonary Surfactants; Reagent; Reporting; Research Personnel; Residual state; Resolution; Respiratory Failure; Respiratory physiology; Role; Signal Pathway; Signal Transduction; Syndrome; System; T-Lymphocyte; Transgenic Organisms; Treatment Protocols; Virus Diseases; Work; alveolar epithelium; antiretroviral therapy; base; clinically significant; cytokine; design; in vivo; in vivo Model; inhibitor/antagonist; lung injury; macrophage; member; microorganism; mortality; mouse model; neutrophil; novel; pathogen; programs; prophylactic; reconstitution; respiratory; response; response to injury; surfactant

DESCRIPTION (provided by applicant): Despite advances in diagnosis, highly active antiretroviral therapy, and prophylactic regimens, Pneumocystis carinii pneumonia (PCP) remains a significant cause of morbidity and mortality in HIV infected patients, as well as an important life-threatening opportunistic infection in other immunocompromised patients. Pneumocystis entry into the distal lung triggers involvement of both adaptive (cellular and humoral) and innate immune systems with specific inflammatory cascades characterized by initiation of CD4/CD8 lymphocyte responses, production of proinflammatory cytokines, recruitment of mononuclear cells, macrophage activation, and elaboration of nitric oxide and its intermediates. Two proteins isolated from lung lavage, surfactant protein (SP) -A and SP-D, members of the collectin (collagen-like lectin) family are elements of the local non-antibody mediated innate immune response. In the previous funding period, this project characterized the effects of and mechanisms by which PCP affected collectin expression in an immunocompromised mouse model of PCP. In both SP-A and SP-D null mice, PCP was associated with increased organism burden and lung injury. Building upon the previous results, the overall theme of the current proposal is to use additional novel murine models of collectin expression and in vitro systems to define the interplay between these local innate host defense molecules, Pneumocystis, innate and adaptive effector cells, and the distal pulmonary epithelia. Specifically we propose to: 1) Define the role of lung collectins (SP-A, SP-D) in clearance of Pneumocystis infection and modulation of inflammation-associated pulmonary injury using constitutively overexpressing and inducible mouse models; 2) Define cell populations and mechanisms contributing to inflammation associated surfactant dysfunction and lung injury in PCP under conditions of immune reconstitution in these murine models of collectin expression; 3) Characterize the direct effects of collectins on key effector cell responses in PCP; 4) Mechanistically define the relationship between the collectins and nitric oxide metabolism in modulating lung damage in PCP. Results from these studies are significant to enhancing our understanding of PCP pathogenesis in light of epidemiological studies linking collectin genetic polymorphisms with lung disease and recent reports of patients developing acute respiratory failure following immune reconstitution therapy after treatment for PCP.

描述（由申请方提供）：尽管在诊断、高效抗逆转录病毒治疗和预防方案方面取得了进展，但卡氏肺孢子虫肺炎（PCP）仍然是HIV感染患者发病和死亡的重要原因，也是其他免疫功能低下患者重要的危及生命的机会性感染。肺孢子虫进入远端肺触发适应性（细胞和体液）和先天性免疫系统参与特异性炎症级联反应，其特征在于启动CD 4/CD 8淋巴细胞反应，产生促炎细胞因子，募集单核细胞，巨噬细胞活化，以及一氧化氮及其中间体的产生。从肺灌洗液中分离的两种蛋白质，表面活性蛋白（SP）-A和SP-D，胶原凝集素（胶原样凝集素）家族的成员，是局部非抗体介导的先天免疫应答的要素。在上一个供资期间，该项目描述了五氯苯酚影响免疫功能低下小鼠五氯苯酚模型中胶原聚集蛋白表达的影响和机制。在SP-A和SP-D基因敲除小鼠中，PCP均与机体负荷增加和肺损伤相关。基于以前的结果，目前的建议的总体主题是使用额外的新的小鼠模型的聚集蛋白表达和体外系统来定义这些本地先天宿主防御分子，肺孢子虫，先天和适应性效应细胞，和远端肺上皮细胞之间的相互作用。具体而言，我们建议：1）定义肺聚集素的作用（SP-A，SP-D）在清除肺孢子虫感染和调节炎症相关的肺损伤中的作用; 2）在这些聚集蛋白表达的鼠模型中，在免疫重建条件下，确定有助于PCP中炎症相关的表面活性剂功能障碍和肺损伤的细胞群和机制; 3）表征胶原凝集素对PCP中关键效应细胞应答的直接作用; 4）机械地定义胶原凝集素和一氧化氮代谢在调节PCP中肺损伤中的关系。从这些研究的结果是显着的，以提高我们的理解PCP的发病机制，在流行病学研究与肺疾病和最近的报告，患者发生急性呼吸衰竭后，免疫重建治疗PCP治疗后的聚集蛋白基因多态性。