Mechanisms of Resolution in Experimental Asthma

描述（由申请人提供）：哮喘是一种严重的疾病，可能会对患者造成衰弱，有时甚至致命的影响。哮喘患者在加重后未能解决气道炎症仍然是该疾病最有问题的特征之一。这种持续性炎症被认为是哮喘的频率和严重程度以及哮喘的许多特征如气道重塑、平滑肌肥大和气道高反应性的主要贡献者。然而，Th 2介导的炎症消退的正常机制在很大程度上是未知的。我们一直在研究Fas（CD 95），一种细胞表面死亡受体，在气道炎症消退中的作用。尽管已经发现Th 2细胞在体外对Fas介导的细胞凋亡具有抗性，但我们的初步数据表明，Fas缺乏导致Th 2介导的小鼠气道炎症消退延迟4-7天。Fas缺陷型T细胞足以在过继转移模型中诱导这种炎症的持续性。重要的是，虽然接受野生型T细胞的小鼠在最后一次挑战后约2周解决了急性过敏原诱导的炎症，但接受Fas缺陷型T细胞的小鼠发展了持续至少4周的持续炎症期。该慢性期在没有额外抗原攻击的情况下发生，并且包括人类哮喘的许多病理特征，包括气道中持续的炎性细胞、剧烈的粘液产生和气道高反应性。因此，我们的慢性Th 2介导的气道炎症的小鼠模型是不寻常的，因为它的发展是由于未能解决急性反应，而不是由于慢性过敏原挑战或遗传操作。我们认为，这种持续性炎症是在轻中度哮喘患者急性发作之间的无炎症期发现的慢性炎症的模型，阐明这种持续性炎症的机制将提供有关哮喘患者肺部炎症消退的基础知识。该建议的总体假设是，哮喘患者的长期炎症特征可能直接或间接归因于在缓解急性发作期间Fas介导的Th 2细胞信号的缺陷。本申请的目的是阐明我们的小鼠模型中炎症的发展和持续性所涉及的机制。

DESCRIPTION (provided by applicant): Asthma is a serious disease that can have debilitating and sometimes fatal effects on its sufferers. The failure of asthmatics to resolve inflammation in their airways after exacerbations remains one of the most problematic features of the disease. This persistent inflammation is believed to be a major contributor to the frequency and severity of asthma as well as many characteristics of asthma such as airway remodeling, smooth muscle hypertrophy, and airway hyperreactivity. However, the normal mechanisms by which Th2-mediated inflammation resolves are largely unknown. We have been investigating the role of Fas (CD95), a cell surface death receptor, in the resolution of airway inflammation. Even though Th2 cells have been found to be resistant to Fas-mediated apoptosis in vitro, our preliminary data demonstrate that Fas-deficiency leads to a 4-7 day delay in resolution of Th2-mediated murine airway inflammation. Fas-deficient T cells are sufficient to induce this persistence of inflammation in an adoptive transfer model. Importantly, while mice that receive wild type T cells resolve acute allergen-induced inflammation around 2 weeks after the last challenge, mice that receive Fas-deficient T cells develop a persistent inflammatory phase that lasts at least 4 weeks longer. This chronic phase occurs in the absence of additional antigen challenges, and includes many pathological features of human asthma including continued inflammatory cells in the airways, dramatic mucus production, and airway hyperreactivity. Thus, our murine model of chronic Th2-mediated airway inflammation is unusual since it develops due to a failure to resolve an acute response, not due to chronic allergen challenges or genetic manipulation. We posit that this persistent inflammation is a model for the chronic inflammation found in mild to moderate asthmatics during symptom-free periods between exacerbations and that elucidating the mechanisms involved of this persistent inflammation will provide fundamental knowledge about resolution of lung inflammation in asthmatic patients. The overall hypothesis of this proposal is that the prolonged inflammation characteristic of asthmatic patients may be due directly or indirectly to defects in Fas-mediated signals to Th2 cells during the resolution of exacerbations. The goal of this application is to elucidate the mechanisms involved in the development and persistence of inflammation in our murine model.