Cytokine Phenotypes After the Host's Response During Chronic Lung Inflammation

慢性肺部炎症期间宿主反应后的细胞因子表型

• 批准号: 7993581
• 负责人: Steven Lynn Kunkel
• 金额: $ 37.86万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-01 至 2013-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7993581
• 关键词: Animals; Autoimmune Diseases; Automobile Driving; Cell physiology; Cells; Chronic; Chronic Disease; Chronic lung disease; Clinical; Clinical Management; Collagen; Communicable Diseases; Connective Tissue Diseases; Dendritic Cells; Deterioration; Disease; Disease Progression; Environment; Etiology; Evolution; Experimental Models; Fibroblasts; Fibrosis; Growth; Hamman-Rich syndrome; Health; Immune; Immune Cell Activation; Immune response; Infection; Injury; Interleukin-13; Interleukin-4; Interstitial Lung Diseases; Investigation; Label; Laboratories; Lead; Lesion; Lung; Lung Inflammation; Lung diseases; Maintenance; Modeling; Mus; Outcome; Pathology; Phenotype; Predisposition; Proteins; Research; Respiratory physiology; Risk; Structure of parenchyma of lung; Testing; Tissues; Transforming Growth Factor beta; Viral; Virus Diseases; cytokine; design; gammaherpesvirus; interstitial; pathogen; research study; response

DESCRIPTION (provided by applicant): Chronic interstitial lung disease is observed in a variety of disorders, including infectious diseases, autoimmune disorders of connective tissue, and disorders where the etiology is unknown, such as idiopathic pulmonary fibrosis. While the etiology and mechanism of progression of many of these lung disorders are not known, the exacerbated progression of the disease may be dictated by the host responding to a subsequent pathogen superimposed on the initial etiologic agent. This "second hit" triggers a dynamic interaction in the lung between the inciting agent, immune cells, and structural cells of the lung, culminating in fibroblast activation, proliferation and fibrosis. Understanding the mechanisms responsible for the exacerbation and progression of lung disease chronicity and fibrosis are the broad, long-term objectives of this application. We hypothesize that the host's response to a persistent etiologic agent may predispose lung tissue to an environment of reparative and immunoregulatory cytokines, placing the lungs at risk for a viral infection, which mechanistically contributes to disease chronicity by maintaining a unique cytokine phenotype, altering dendritic cell function, and driving fibroblast activation. We have designed experiments to test this hypothesis and determine if the progression and maintenance of chronic lung inflammation are infuenced by the cytokine phenotype and the host's response to a subsequent viral pathogen superimposed on the initial etiologic agent, constituting a "two hit" mechanism for disease progression. We will focus on mechanisms which lead to a minimally fibrotic lung lesion, induced by type 1 cytokines, versus a fibrotic response, induced by type 2 cytokines, and determine their impact on a subsequent challenging with murine gammaherpesvirus (MHV68). Our specific aims include: 1) To assess the mechanism(s) whereby MHV68 infection alone or superimposed on a polarized cytokine phenotype alters the host response and subsequent lung pathology in experimental models of chronic lung inflammation; 2) To determine the mechanistic contribution of an MHV68-derived gene product on the evolving chronic lung pathology associated with a type 1 or type 2 cytokine tissue phenotype; and 3) To assess the mechanistic contribution of dendritic cell subsets during MHV68 infection to the chronicity and fibrosis of the lung response in animals with developing type 1 or type 2 cytokine phenotypes. PUBLIC HEALTH RELEVANCE: Chronic lung disease is an increasing common clinical disorder caused by many know and unknown (idiopathic) agents. The clinical manifestations of many of these chronic lung diseases are likely the consequences of the host response to an initial agent followed by pulmonary tissue injury, progressive deterioration of lung function, and increase susceptibility to pathogen-induced exacerbations. These factors often make these diseases not well understood with difficult and unrewarding therapies. We have experimentally modeled chronic long disease and will study the underlying mechanisms that we believe support these disorders.

描述（由申请人提供）：在多种疾病中观察到慢性间质性肺疾病，包括传染病，结缔组织的自身免疫性疾病以及病因尚不清楚的疾病，例如定期性肺纤维化。尽管尚不清楚许多这些肺部疾病的病因和进展的病因和机制，但该疾病的加剧进展可能取决于宿主对随后的病原体的反应，叠加在初始病因上。该“第二击”触发了刺激剂，免疫细胞和肺结构细胞之间的肺部动态相互作用，最终在成纤维细胞激活，增殖和纤维化中达到最终形式。了解导致肺部疾病慢性和纤维化的加剧和进展的机制是该应用的广泛，长期目标。 We hypothesize that the host's response to a persistent etiologic agent may predispose lung tissue to an environment of reparative and immunoregulatory cytokines, placing the lungs at risk for a viral infection, which mechanistically contributes to disease chronicity by maintaining a unique cytokine phenotype, altering dendritic cell function, and driving fibroblast activation.我们设计了实验来检验这一假设，并确定慢性肺炎症的进展和维持是否受到细胞因子表型的影响，以及宿主对随后的病毒病原体的反应置于最初的病因学剂上，构成了疾病进展的“两个命中”机制。我们将专注于导致最小纤维化的肺部病变的机制，该病变是由1型细胞因子诱导的，而不是纤维化反应，并通过2型细胞因子诱导，并确定它们对随后对鼠γHERPESVIRUS（MHV68）的挑战的影响。我们的具体目的包括：1）评估单独感染或叠加在极化细胞因子表型上的MHV68感染的机制，在慢性肺炎症实验模型中会改变宿主反应和随后的肺病理； 2）确定MHV68衍生的基因产物对与1型或2型细胞因子组织表型相关的慢性肺病理学的机理贡献； 3）评估MHV68感染过程中树突状细胞亚群的机理贡献对患有1型或2型细胞因子表型的动物中肺反应的慢性和纤维化。公共卫生相关性：慢性肺部疾病是许多知识和未知（特发性）剂引起的常见临床疾病。许多这些慢性肺疾病的临床表现可能是宿主对初始药物的反应的后果，其次是肺组织损伤，肺功能的进行性降低以及增加对病原体诱导的病原体加重的敏感性。这些因素通常会使这些疾病通过困难和不受欢迎的疗法不太了解。我们已经实验室建模了慢性疾病，并将研究我们认为支持这些疾病的潜在机制。