Transforming growth Factor-β1 suppresses airway hyperresponsiveness on allergic airway disease
Transforming growth Factor-β1 suppresses airway hyperresponsiveness on allergic airway disease
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DOI：
10.1164/rccm.200702-334oc
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发表时间：
2007-11-15
影响因子：
24.7
通讯作者：
Irvin, Charles G.
中科院分区：
文献类型：
--
作者：
Alcorn, John F.;Rinaldi, Lisa M.;Irvin, Charles G.
理由：。哮喘的特征是气道阻力增加、肺部重塑和肺部炎症。细胞因子转化生长因子 (TGF)-β 已被证明在哮喘发病机制和过敏性气道疾病小鼠模型中具有核心作用。 目的：为了确定 TGF-β 对气道高反应性 (AHR) 的贡献，我们检查了体内小鼠哮喘模型中 TGF-β 产生的时间过程、来源和亚型特异性。为了阐明 TGF-β 在 AHR、炎症和肺纤维化中的功能，我们检查了用中和抗体阻断 TGF-β 信号传导的效果。方法：用卵清蛋白 (OVA) 致敏并激发小鼠以建立过敏性气道疾病。通过鼻内施用单克隆抗体来中和 TGF-β 活性。测量和主要结果：与初始对照相比，OVA 攻击的肺部中 TGF-β1 蛋白水平升高，并且气道上皮细胞被证明是 TGF-β1 的可能来源。此外，在 OVA 暴露的 IL-5-null 中，TGF-β1 水平升高 小鼠，无法将嗜酸性粒细胞募集到气道中。尽管抗 TGF-β 1 抗体增强了 OVA 诱导的 AHR 并抑制了肺纤维化，但用特异性抗体中和 TGF-β 1 对气道炎症和嗜酸性粒细胞增多没有显着影响。 结论：这些数据表明 TGF-β 1 是 OVA 攻击后产生的主要 TGF-β 亚型，可能的细胞来源是气道上皮。阻断 TGF-β1 信号传导对 AHR、纤维化和炎症有不同的影响。虽然 TGF-β 中和可能有利于消除气道重塑，但它可能会增加 AHR，从而损害肺功能。
Rationale:. Asthma is characterized by increases in airway resistance, pulmonary remodeling, and lung inflammation. The cytokine transforming growth factor (TGF)-beta has been shown to have a central role in asthma pathogenesis and in mouse models of allergic airway disease.Objectives: To determine the contribution of TGF-beta to airway hyperresponsiveness (AHR), we examined the time course, source, and isoform specificity of TGF-beta production in an in vivo mouse asthma model. To then elucidate the function of TGF-beta in AHR, inflammation, and pulmonary fibrosis, we examined the effects of blocking TGF-beta signaling with neutralizing antibody.Methods: Mice were sensitized and challenged with ovalbumin (OVA) to establish allergic airway disease. TGF-beta activity was neutralized by intranasal administration of monoclonal antibody.Measurements and Main Results: TGF-beta 1 protein levels were increased in OVA-challenged lungs versus naive controls, and airway epithelial cells were shown to be a likely source of TGF-beta 1. In addition, TGF-beta 1 levels were elevated in OVA-exposed IL-5-null mice, which fail to recruit eosinophils into the airways. Neutralization of TGF-beta 1 with specific antibody had no significant effect on airway inflammation and eosinophilia, although anti-TGF-beta 1 antibody enhanced OVA-induced AHR and suppressed pulmonary fibrosis.Conclusions: These data show that TGF-beta 1 is the main TGF-beta isoform produced after OVA challenge, with a likely cellular source being the airway epithelium. The effects of blocking TGF-beta 1 signaling had differential effects on AHR, fibrosis, and inflammation. While TGF-beta neutralization may be beneficial to abrogating airway remodeling, it may be detrimental to lung function by increasing AHR.