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

描述(申请人提供)：慢性间质性肺疾病可见于多种疾病，包括感染性疾病、结缔组织自身免疫性疾病以及病因不明的疾病，如特发性肺纤维化。虽然许多肺部疾病的病因和进展机制尚不清楚，但疾病的恶化可能是由宿主对叠加在最初病原体上的后续病原体做出反应所决定的。这种“二次撞击”在肺中触发了激动剂、免疫细胞和肺结构细胞之间的动态相互作用，最终导致成纤维细胞的激活、增殖和纤维化。了解导致肺部疾病慢性和纤维化恶化和进展的机制是这项应用的广泛、长期的目标。我们假设，宿主对持续病原体的反应可能使肺组织倾向于修复和免疫调节细胞因子的环境，使肺处于病毒感染的风险中，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而机械地促进疾病的慢性化。我们设计了实验来检验这一假说，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随后病毒病原体的反应的影响，这些病毒病原体叠加在最初的病原体上，构成了疾病进展的“两次打击”机制。我们将集中在由1型细胞因子诱导的轻度纤维化肺损害与由2型细胞因子诱导的纤维化反应的机制上，并确定它们对随后的小鼠伽马疱疹病毒(MHV68)挑战的影响。我们的具体目标包括：1)在慢性肺部炎症的实验模型中，评估MHV68感染单独或叠加在极化的细胞因子表型上改变宿主反应和随后的肺病理的机制(S)；2)确定MHV68衍生基因产物在与1型或2型细胞因子组织表型相关的慢性肺病理演变中的机制贡献；以及3)评估MHV68感染过程中树突状细胞亚群对发生1型或2型细胞因子表型的动物肺反应的慢性化和纤维化的机制贡献。公共卫生相关性：慢性肺病是一种越来越常见的临床疾病，由许多已知和未知的(特发性)病原体引起。许多这些慢性肺部疾病的临床表现可能是宿主对初始药物的反应，随后是肺组织损伤，肺功能进行性恶化，并增加了对病原体诱导的恶化的易感性。这些因素往往使这些疾病难以得到很好的理解，治疗起来既困难又没有回报。我们已经对慢性慢性疾病进行了实验性建模，并将研究我们认为支持这些疾病的潜在机制。

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.