Club Cell Secretory Protein Deficiency Leads to Altered Lung Function
Club Cell Secretory Protein Deficiency Leads to Altered Lung Function
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DOI：
10.1164/rccm.201807-1345oc
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发表时间：
2019-02-01
影响因子：
24.7
通讯作者：
Ledford, Julie G.
中科院分区：
文献类型：
--
作者：
Zhai, Jing;Insel, Michael;Ledford, Julie G.
研究背景：CC16是分泌型珠蛋白家族的一员，是正常呼吸道分泌物中含量最丰富的蛋白质之一，被认为是阻塞性肺疾病的血清生物标志物。目的：确定低CC16是否为这些疾病的气道病理标志物或参与进行性呼吸道损害的病理生理学机制。方法：利用图森儿童呼吸研究出生队列中的人类数据，我们研究了从儿童到32岁的循环CC16水平与肺功能和对支气管乙酰胆碱激发的反应的关系。在野生型和CC16(-/-)小鼠中，我们开始全面检查肺生理学、炎症和幼稚气道中的重塑。测量和主要结果：我们观察到，血清CC16水平最低三分位数的图森儿童呼吸研究参与者从11岁开始在年轻的成年生活中对甲氧胆碱激发有显著的肺功能缺陷和增强的呼吸道高反应性。同样，与野生型小鼠相比，CC16(-/-)小鼠的肺功能显著受损，对乙酰甲胆碱的呼吸道高反应性增强，这与炎症和粘蛋白产生无关。与野生型小鼠相比，CC16(-/-)小鼠的I型前胶原蛋白、III型前胶原蛋白和α-平滑肌肌动蛋白的基因表达显著增加，胶原沉积明显，平滑肌厚度显著增加。结论：我们的发现支持临床观察，提供了证据，证明肺中缺乏CC16会导致肺功能显著改变和结构改变，与增强的重塑一致。
Rationale: CC16 (club cell secretory protein-16), a member of the secretoglobin family, is one of the most abundant proteins in normal airway secretions and has been described as a serum biomarker for obstructive lung diseases.Objectives: To determine whether low CC16 is a marker for airway pathology or is implicated in the pathophysiology of progressive airway damage in these conditions.Methods: Using human data from the birth cohort of the Tucson Children's Respiratory Study, we examined the relation of circulating CC16 levels with pulmonary function and responses to bronchial methacholine challenge from childhood up to age 32 years. In wild-type and CC16(-/-) mice, we set out to comprehensively examine pulmonary physiology, inflammation, and remodeling in the naive airway.Measurements and Main Results: We observed that Tucson Children's Respiratory Study participants in the lowest tertile of serum CC16 had significant deficits in their lung function and enhanced airway hyperresponsiveness tomethacholine challenge from 11 years throughout young adult life. Similarly, CC16(-/-) mice had significant deficits in lung function and enhanced airway hyperresponsiveness to methacholine as compared with wild-typemice, which were independent of inflammation and mucin production. As compared with wild-type mice, CC16(-/-) mice had significantly elevated gene expression of procollagen type I, procollagen type III, and alpha-smooth muscle actin, areas of pronounced collagen deposition and significantly enhanced smooth muscle thickness.Conclusions: Our findings support clinical observations by providing evidence that lack of CC16 in the lung results in dramatically altered pulmonary function and structural alterations consistent with enhanced remodeling.