Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil.
Am J Physiol Lung Cell Mol Physiol. 2011 Nov;301(5):L636-44. doi: 10.1152/ajplung.00158.2011. Epub 2011 Aug 26.
Asthma is a chronic lung disease characterized by local inflammation that can result in structural alterations termed airway remodeling. One component of airway remodeling involves fibroblast accumulation and activation, resulting in deposition of collagen I around small bronchi. Prostaglandin E(2) (PGE(2)) is the main eicosanoid lipid mediator produced by lung fibroblasts, and it exerts diverse anti-fibrotic actions. Dysregulation of the PGE(2) synthesis/response axis has been identified in human pulmonary fibrotic diseases and implicated in the pathogenesis of animal models of lung parenchymal fibrosis. Here we investigated the relationship between the fibroblast PGE(2) axis and airway fibrosis in an animal model of chronic allergic asthma. Airway fibrosis increased progressively as the number of airway challenges with antigen increased from 3 to 7 to 12. Compared with cells from control lungs, fibroblasts grown from the lungs of asthmatic animals, regardless of challenge number, exhibited no defect in the ability of PGE(2) or its analogs to inhibit cellular proliferation and collagen I expression. This correlated with intact expression of the EP(2) receptor, which is pivotal for PGE(2) responsiveness. However, cytokine-induced upregulation of PGE(2) biosynthesis as well as expression of cyclooxygenase-2 (COX-2) and microsomal PGE synthase-1 declined with increasing numbers of antigen challenges. In addition, treatment with the COX-2-selective inhibitor nimesulide potentiated the degree of airway fibrosis following repeated allergen challenge. Because endogenous COX-2-derived PGE(2) acts as a brake on airway fibrosis, the inability of fibroblasts to upregulate PGE(2) generation in the inflammatory milieu presented by repeated allergen exposure could contribute to the airway remodeling and fibrosis observed in chronic asthma.
哮喘是一种慢性肺部疾病，其特征为局部炎症，可导致气道重塑等结构改变。气道重塑的一个组成部分涉及成纤维细胞的积累和激活，导致胶原 I 在小支气管周围沉积。前列腺素 E2 (PGE2) 是肺成纤维细胞产生的主要类二十烷脂质介质，具有多种抗纤维化作用。在人类肺部纤维化疾病中已经确定了 PGE2 合成/反应轴的失调，并暗示其与肺部实质纤维化动物模型的发病机制有关。在这里，我们研究了慢性变应性哮喘动物模型中成纤维细胞 PGE2 轴与气道纤维化之间的关系。随着抗原气道挑战次数从 3 次增加到 7 次再增加到 12 次，气道纤维化逐渐增加。与来自对照肺的细胞相比，无论挑战次数如何，来自哮喘动物肺的成纤维细胞生长均未显示出 PGE2 或其类似物抑制细胞增殖和胶原 I 表达的能力缺陷。这与 EP2 受体的完整表达相关，该受体对于 PGE2 反应至关重要。然而，细胞因子诱导的 PGE2 生物合成以及环氧化酶-2 (COX-2) 和微粒体 PGE 合酶-1 的表达随着抗原挑战次数的增加而下降。此外，重复抗原挑战后，COX-2 选择性抑制剂尼美舒利的治疗增强了气道纤维化的程度。由于内源性 COX-2 衍生的 PGE2 作为气道纤维化的制动因素，成纤维细胞在重复过敏原暴露引起的炎症环境中不能上调 PGE2 的产生，这可能导致慢性哮喘中观察到的气道重塑和纤维化。
