Mechanisms of Resolution in Experimental Asthma

描述(申请人提供)：哮喘是一种严重的疾病，它会使患者虚弱，有时甚至是致命的。哮喘患者在病情恶化后未能消除呼吸道炎症，这仍然是该疾病最有问题的特征之一。这种持续的炎症被认为是哮喘的频率和严重程度的主要因素，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。然而，Th2介导的炎症消退的正常机制在很大程度上尚不清楚。我们一直在研究细胞表面死亡受体Fas(CD95)在呼吸道炎症消退中的作用。尽管在体外已发现Th2细胞对Fas介导的凋亡具有抵抗力，但我们的初步数据表明，Fas缺乏会导致Th2介导的小鼠呼吸道炎症的消退延迟4-7天。在过继转移模型中，Fas缺陷的T细胞足以诱导这种持续的炎症。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大约两周会消除由过敏原引起的急性炎症，但接受Fas缺陷的T细胞的小鼠会发展出持续的炎症阶段，至少持续4周以上。这一慢性期发生在没有额外抗原挑战的情况下，包括许多人类哮喘的病理特征，包括呼吸道持续的炎性细胞、显著的粘液产生和呼吸道的高反应性。因此，我们的Th2介导的慢性呼吸道炎症的小鼠模型是不寻常的，因为它是由于未能解决急性反应而发展起来的，而不是由于慢性过敏原挑战或基因操作。我们假设，这种持续性炎症是轻、中度哮喘患者在发作间期无症状期间发现的慢性炎症的模型，阐明这种持续性炎症的机制将为哮喘患者肺部炎症的解决提供基础知识。这一建议的总体假设是，哮喘患者持续的炎症特征可能直接或间接地归因于Fas介导的Th2细胞信号在病情缓解过程中的缺陷。这项应用的目的是阐明在我们的小鼠模型中炎症发生和持续的机制。

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.