Airway Remondeling in Asthma: Modulation By IL-13

哮喘的气道重塑是一个随着时间的推移发生永久性结构变化的过程， 导致固定呼吸道阻塞的一部分，可能导致肺功能下降。我们已经展示了 哮喘患者的近端和远端肺都会发生呼吸道炎症，而且胶原蛋白的表达 增加，而气道弹性蛋白表达减少。Th2炎症导致的机制 随后的宿主对重塑的反应还知之甚少。Th2细胞因子--白介素13 对小鼠模型中的哮喘表型至关重要，也通过对呼吸道成纤维细胞的影响而导致纤维化。一个 IL-13诱导的将炎症与近端和远端肺结构变化联系起来的介质 血小板衍生生长因子(PDGF)是一种强有力的成纤维细胞趋化剂和有丝分裂原。PDGF异构体 受体在肺中表达，由IL-13诱导，皮质类固醇激素诱导表达增加。 动物模型。我们假设白介素13调节人的呼吸道成纤维细胞功能 血小板衍生生长因子和随后的呼吸道成纤维细胞表达增加引起的哮喘 细胞增殖，胶原表达，弹性蛋白表达降低。皮质类固醇类药物，是 治疗哮喘，不要抑制这些过程，并可能增强这些过程。这些过程会导致 肺功能、气道塌陷性和弹性后坐力丧失。皮质类固醇类药物，是 哮喘的治疗，不要抑制这些过程，而且可能会增强这些过程。 轻度和重度哮喘患者和正常对照组将接受支气管镜检查，并进行近端(支气管内)检查。 远端(经支气管镜)肺活检(仅限哮喘患者)和支气管肺泡灌洗。我们将首先 确定IL-13通过哮喘的呼吸道成纤维细胞诱导PDGF的表达，以及这一点 需要激活STAT-6和Egr-1(具体目标1)。在具体目标2中，我们将确定PDGF 通过PIS激酶的激活，调节肺内成纤维细胞胶原和弹性蛋白的表达。在……里面 具体目标3，我们将确定体内中和IL-13将导致改善肺功能和 降低PDGF和气道成纤维细胞的体外活性。我们将把病理性的呼吸道改变和 体外成纤维细胞功能对哮喘患者大、小气道功能的检测 希望在实验室预测谁将遭受最严重的呼吸道生理后果 改建。这项提议将阐明呼吸道的生理和病理后果。 哮喘中的重塑，宿主对导致重塑的Th2炎症的反应以及我们的主要 治疗哮喘，皮质类固醇，调节并可能加强这一过程。该项目将评估 结合项目1和项目4，人类提供了导致哮喘气道重塑的宿主反应 项目1和4的样本，并与所有核心交互。

Airway remodeling in asthma is a process of permanent structural changes occurring over time, resulting in a component of fixed airway obstruction that can lead to reduced lung function. We have shown that airway inflammation occurs in both the proximal and distal lung in asthma and that collagen expression is increased and airway elastin expression is reduced. The mechanisms by which Th2 inflammation leads to the subsequent host response of remodeling are poorly understood. Interleukin (IL)-13, a Th2 cytokine critical to the asthma phenotype in murine models, also causes fibrosis by effects on the airway fibroblast. A mediator induced by IL-13 that links inflammation to the structural changes in the proximal and distal lung is platelet-derived growth factor (PDGF) a potent chemoattractant and mitogen for fibroblasts. PDGF isoforms and receptors are expressed in the lung, induced by IL-13 and expression is inceased by corticosteroids in animal models. We hypothesize that interleukin-13 modulates airway fibroblast function in human asthma via increased expression of platelet-derived growth factor and subsequent airway fibroblast proliferation, collagen expression and decreased elastin expression. Corticosteroids, the mainstay of therapy for asthma, do not suppress and may enhance these processes. These processes result in a reduction in lung function, airway collapsibility and loss of elastic recoil. Corticosteroids, the mainstay of therapy for asthma, do not suppress and may enhance these processes.To test this hypothesis, subjects with mild and severe asthma and normal controls will undergo bronchoscopy with proximal (endobronchial) and distal (transbronchial) lung biopsy (asthmatic subjects only) and bronchoalveolar lavage. We will first determine that IL-13 induces PDGF expression by the airway fibroblast in human asthma, and that this requires activation of STAT-6 and Egr-1 (specific aim 1). In specific aim 2, we will determine that PDGF modulates fibroblast collagen and elastin expression throughout the lung via activation of PIS kinase. In specific aim 3, we will determine that neutralization of IL-13 in vivo will result in improved lung function and decreased PDGF and airway fibroblast activation ex vivo. We will relate the pathologic airway changes and ex vivo fibroblast function to measures of large and small airway function in asthmatic human subjects in vivo in hopes of predicting in the laboratory who will suffer the greatest physiological consequences of airway remodeling. This proposal will shed light on the physiologic and pathologic consequences of airway remodeling in asthma, the host response to Th2 inflammation that lead to remodeling and whether our main therapy for asthma, corticosteroids, modulate and possibly enhance this process. This project will evaluate host responses leading to airway remodeling in asthma in conjunction with projects 1 and 4, provide human samples for projects 1 and 4 and interact with all the Cores.