Role of Eotaxins and CCR3 in IL-13 Induced Asthma

尽管正在进行密集的哮喘研究，但这种疾病目前在西方世界流行，而且发病率正在上升。临床和实验研究表明，CD4+Th2细胞和嗜酸性粒细胞的存在与疾病严重程度有很强的相关性，表明这些细胞在哮喘的病理生理学中起着不可或缺的作用。Th2细胞被认为通过分泌一系列细胞因子(IL-4， -5、-6、-9、-10、-13、-25)。IL-13的阻断能够消除实验性哮喘的几个关键方面，这导致了一种观点，即这是疾病发病机制中的关键细胞因子。广泛的研究还表明，趋化因子在协调哮喘反应的多个方面发挥着核心作用。特别是，CCR3及其配体(嗜酸性粒细胞趋化因子)已成为哮喘反应期间嗜酸性粒细胞的中央调节因子。在我们最近的研究中，我们已经证明，在实验性哮喘的诱导过程中，嗜酸性粒细胞、趋化因子和IL-13之间存在密切的联系。特别是，嗜酸性粒细胞趋化因子与IL-5一起诱导肺嗜酸性粒细胞增多，进而放大IL-13的产生。此外，在实验性哮喘中产生的CCR3的非激活配体(例如，由γ-干扰素[Mig]诱导的单核细胞因子)抑制了IL-13相关的肺反应。中心假说 这项拨款的应用是IL-13和趋化因子在嗜酸性粒细胞相关性肺部炎症的发病机制中起关键作用。特别是，Th2细胞来源的IL-13促进嗜酸性粒细胞的产生，这随后为嗜酸性粒细胞放大IL-13的产生(来自嗜酸性粒细胞本身和Th2细胞)和IL-13相关的肺病理提供了关键信号。此外，过敏原诱导的Mig矛盾地抑制与过敏原和IL-13相关的过敏性呼吸道炎症。我们提出了一系列旨在测试我们的中心假说并揭示趋化因子、嗜酸性粒细胞和IL-13相互作用在实验性哮喘发病机制中的分子机制和后果的目标。在目标I中，我们提出了旨在研究CCR3和嗜酸性粒细胞趋化因子在IL-13诱导的实验性哮喘中的作用的研究。我们假设嗜酸性粒细胞趋化因子-1、嗜酸性粒细胞趋化因子-2和CCR3在IL-13诱导的实验性哮喘的几个方面起关键作用。我们还将测试IL-13在促进变应原诱导的肺内趋化因子表达方面的特定作用。

Despite intense ongoing asthma research, there is currently an epidemic of this disease in the western world and the incidence is on the rise. Clinical and experimental investigations have demonstrated a strong correlation between the presence of CD4+ Th2 cells, eosinophils and disease severity suggesting an integral role for these cells in the pathophysiology of asthma. Th2 cells are thought to induce asthma through the secretion of an array of cytokines (IL-4, -5, -6, -9, -10, -13, -25). The ability of IL-13 blockade to abrogate several critical aspects of experimental asthma has led to the view that this is a critical cytokine in disease pathogenesis. Extensive studies have also demonstrated a central role for chemokines in orchestrating multiple aspects of the asthmatic response. In particular, CCR3 and its ligands (eotaxins) have emerged as central regulators of eosinophils during asthmatic responses. In our recent studies we have demonstrated that there is an intimate connection between eosinophils, chemokines, and IL-13 during the induction of experimental asthma. In particular, the eotaxins in conjunction with IL-5, induce lung eosinophilia, which in turn amplify IL-13 production. Furthermore, non-activating ligands for CCR3, which are produced in experimental asthma (e.g. monokine induced by gamma-interferon [Mig]), inhibit IL-13 associated lung responses. The central hypothesis of this grant application is that IL-13 and chemokines critically cooperate in the pathogenesis of eosinophil-associated lung inflammation. In particular, Th2 cell derived IL-13 promotes eotaxin production, which subsequently provides a critical signal for eosinophils to amplify IL-13 production (from eosinophils themselves and from Th2 cells) and IL-13-associated lung pathology. Furthermore, allergen-induced Mig paradoxically curtails aspects of allergen- and IL-13-associated allergic airway inflammation. We propose a series of aims designed to test our central hypothesis and uncover the molecular mechanisms and consequences of chemokine, eosinophil, and IL-13 interactions in the pathogenesis of experimental asthma. In Aim I we propose studies designed to examine the role of CCR3 and eotaxins in IL-13-induced experimental asthma. We hypothesize that eotaxin-1, eotaxin-2, and CCR3 are critically involved in several aspects of IL-13-induced experimental asthma. We will also test the specific role of IL-13 in promoting allergen-induced chemokine expression in the lung.