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

慢性间质性肺病在多种疾病中观察到，包括感染性疾病， 结缔组织的自身免疫性疾病，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， 已知，疾病的恶化进展可由宿主对随后的免疫应答决定。 病原体叠加在最初的病原体上。这一“第二击”触发了 肺之间的激发剂，免疫细胞和肺的结构细胞，最终在成纤维细胞 活化、增殖和纤维化。了解导致病情加重的机制， 肺部疾病慢性化和纤维化的进展是该应用的广泛、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易于发生 修复和免疫调节细胞因子的环境，使肺部处于病毒感染的风险中， 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。我们设计了实验来验证这一假设 并确定慢性肺部炎症的进展和维持是否受到细胞因子的影响 表型和宿主对叠加在初始病原体上的后续病毒病原体的应答， 构成疾病进展的“两次打击”机制。我们将重点关注导致 由1型细胞因子诱导的最小纤维化肺病变与由2型细胞因子诱导的纤维化反应 细胞因子，并确定它们对随后用鼠γ疱疹病毒（MHV 68）攻击的影响。 我们的具体目的包括：1）评估MHV 68感染单独或叠加的机制 极化细胞因子表型改变宿主反应和随后的肺病理学 慢性肺部炎症模型; 2）确定MHV 68衍生基因的机制贡献 关于与1型或2型细胞因子组织表型相关的演变中的慢性肺病理学的产品; 3）探讨MHV 68感染时树突状细胞亚群在慢性化中的作用机制 和肺纤维化反应。

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.