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

描述（由申请方提供）：慢性间质性肺病见于多种疾病，包括感染性疾病、结缔组织自身免疫性疾病和病因不明的疾病，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初始病原体上的后续病原体的反应决定的。这种“第二次打击”在肺中引发剂、免疫细胞和肺的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本申请的广泛、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易受修复性和免疫调节性细胞因子的环境影响，使肺处于病毒感染的风险中，这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活化而在机制上促成疾病慢性化。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初始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“两次打击”机制。我们将重点关注导致1型细胞因子诱导的最低程度纤维化肺病变的机制，以及2型细胞因子诱导的纤维化反应，并确定其对随后用鼠γ疱疹病毒（MHV 68）进行挑战的影响。我们的具体目标包括：1）评估MHV 68感染单独或叠加在极化细胞因子表型上改变慢性肺部炎症实验模型中的宿主应答和随后的肺部病理的机制; 2）确定MHV 68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演变中的慢性肺部病理的机制贡献;和3）评估树突状细胞亚群在MHV 68感染期间对具有发展中的1型或2型细胞因子表型的动物的肺应答的慢性化和纤维化的机制贡献。公共卫生相关性：慢性肺病是一种由许多已知和未知（特发性）因子引起的日益常见的临床疾病。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的结果，随后是肺组织损伤、肺功能进行性恶化和对病原体诱导的加重的易感性增加。这些因素往往使这些疾病没有得到很好的理解与困难和徒劳的治疗。我们已经对慢性长期疾病进行了实验建模，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.