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

慢性间质性肺病可见于各种疾病，包括传染病、 结缔组织的自身免疫性疾病，以及病因不明的疾病，如特发性 肺纤维化。虽然这些肺部疾病的病因和进展机制并不是 已知，疾病的恶化可能是由宿主对随后的 病原体叠加在最初的病原体上。这一“二次命中”触发了 肺在激动剂、免疫细胞和肺的结构细胞之间，最终形成成纤维细胞 活化、增殖和纤维化。了解导致病情恶化的机制和 肺部疾病的慢性进展和纤维化是这一应用的广泛的、长期的目标。我们 假设宿主对持久性病原体的反应可能使肺组织易患上 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，这 通过维持一种独特的细胞因子表型，改变 树突状细胞的功能，并驱动成纤维细胞的激活。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反应， 构成疾病发展的“两击”机制。我们将重点介绍导致 1型细胞因子诱导的轻度纤维化肺损害与2型诱导的纤维化反应 细胞因子，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)评估MHV68单独感染或叠加感染的机制(S 极化细胞因子表型改变宿主反应和随后的肺病理 慢性肺部炎症模型；2)确定MHV68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慢性肺病理演变的产品； 3)探讨MHV68感染过程中树突状细胞亚群在慢性化中的作用。 以及发展中的1型或2型细胞因子表型的动物的肺反应的纤维化。

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.