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: 7743005
• 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/7743005
• 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; 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; public health relevance; 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）：慢性间质性肺病可见于多种疾病，包括传染病、结缔组织自身免疫性疾病以及病因不明的疾病，例如特发性肺纤维化。虽然许多这些肺部疾病的病因和进展机制尚不清楚，但疾病的恶化进展可能是由宿主对叠加在最初病因上的后续病原体的反应决定的。这种“第二次打击”触发了肺部的刺激剂、免疫细胞和肺部结构细胞之间的动态相互作用，最终导致成纤维细胞活化、增殖和纤维化。了解导致肺部疾病慢性化和纤维化恶化和进展的机制是该应用的广泛、长期目标。我们假设宿主对持久性病原体的反应可能使肺组织容易处于修复和免疫调节细胞因子的环境中，使肺部面临病毒感染的风险，病毒感染通过维持独特的细胞因子表型、改变树突状细胞功能和驱动成纤维细胞激活，从机制上导致疾病慢性化。我们设计了实验来检验这一假设，并确定慢性肺部炎症的进展和维持是否受到细胞因子表型和宿主对叠加在最初病原体上的后续病毒病原体的反应的影响，从而构成疾病进展的“二次打击”机制。我们将重点关注导致 1 型细胞因子诱导的轻微肺纤维化病变与 2 型细胞因子诱导的纤维化反应的机制，并确定它们对随后鼠伽马疱疹病毒 (MHV68) 攻击的影响。我们的具体目标包括：1) 评估慢性肺部炎症实验模型中，单独的 MHV68 感染或叠加在极化细胞因子表型上的 MHV68 感染改变宿主反应和随后的肺部病理学的机制； 2) 确定 MHV68 衍生基因产物对与 1 型或 2 型细胞因子组织表型相关的慢性肺部病理演变的机制贡献； 3) 评估 MHV68 感染期间树突状细胞亚群对形成 1 型或 2 型细胞因子表型的动物肺部反应的慢性和纤维化的机制贡献。公共卫生相关性：慢性肺病是一种日益常见的临床疾病，由许多已知和未知的（特发性）病原体引起。许多这些慢性肺病的临床表现可能是宿主对初始药物反应的结果，随后出现肺组织损伤、肺功能进行性恶化以及对病原体引起的病情加重的易感性增加。这些因素常常使得这些疾病无法被充分理解，并且治疗方法困难且无回报。我们已经通过实验模拟了慢性长期疾病，并将研究我们认为支持这些疾病的潜在机制。