Severe airway epithelial injury, aberrant repair and bronchiolitis obliterans develops after diacetyl instillation in rats.
Severe airway epithelial injury, aberrant repair and bronchiolitis obliterans develops after diacetyl instillation in rats.
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DOI：
10.1371/journal.pone.0017644
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发表时间：
2011-03-25
期刊：
影响因子：
3.7
通讯作者：
Morgan DL
中科院分区：
文献类型：
--
作者：
Palmer SM;Flake GP;Kelly FL;Zhang HL;Nugent JL;Kirby PJ;Foley JF;Gwinn WM;Morgan DL
闭塞性细支气管炎（BO）是一种纤维化肺部疾病，可发生在各种临床环境中，包括毒素暴露、自身免疫和肺或骨髓移植。尽管其临床重要性日益增加，但由于缺乏足够的小动物BO模型，人们对其潜在的疾病机制知之甚少。最近的流行病学研究表明，暴露于双乙酰（DA），一种人造黄油调味料的挥发性成分，是导致健康工厂工人BO的原因。我们的总体假设是DA诱导严重的上皮损伤和异常修复，从而导致BO的发生。因此，本研究的目的是：1)确定通过气管内灌注（ITI）给药DA是否会导致大鼠BO的发生；2)表征DA ITI后上皮再生和基质修复的特性。雄性Sprague-Dawley大鼠经ITI单剂量DA （125 mg/kg）或无菌水（对照）处理。灌注DA导致气道特异性损伤，随后是快速上皮再生，以及BO特征的广泛腔内气道纤维化。随着BO的发展，气道阻力和肺液中性粒细胞增多，与人类疾病相似。尽管DA处理后上皮细胞快速再生，但正常表型标志物Clara细胞分泌蛋白和乙酰化微管蛋白的表达减少。相比之下，基质成分Tenascin C的表达显著增加，尤其在BO病变中明显。我们已经确定DA的ITI导致BO，创建了一种新的化学诱导动物模型，复制了人类疾病的组织学，生物学和生理特征。此外，我们证明了上皮修复失调和基质Tenacin C过度沉积在BO中发生，为潜在的疾病机制和治疗靶点提供了新的见解。
Bronchiolitis obliterans (BO) is a fibrotic lung disease that occurs in a variety of clinical settings, including toxin exposures, autoimmunity and lung or bone marrow transplant. Despite its increasing clinical importance, little is known regarding the underlying disease mechanisms due to a lack of adequate small animal BO models. Recent epidemiological studies have implicated exposure to diacetyl (DA), a volatile component of artificial butter flavoring, as a cause of BO in otherwise healthy factory workers. Our overall hypothesis is that DA induces severe epithelial injury and aberrant repair that leads to the development of BO. Therefore, the objectives of this study were 1) to determine if DA, delivered by intratracheal instillation (ITI), would lead to the development of BO in rats and 2) to characterize epithelial regeneration and matrix repair after ITI of DA. Male Sprague-Dawley rats were treated with a single dose of DA (125 mg/kg) or sterile water (vehicle control) by ITI. Instilled DA resulted in airway specific injury, followed by rapid epithelial regeneration, and extensive intraluminal airway fibrosis characteristic of BO. Increased airway resistance and lung fluid neutrophilia occurred with the development of BO, similar to human disease. Despite rapid epithelial regeneration after DA treatment, expression of the normal phenotypic markers, Clara cell secretory protein and acetylated tubulin, were diminished. In contrast, expression of the matrix component Tenascin C was significantly increased, particularly evident within the BO lesions. We have established that ITI of DA results in BO, creating a novel chemical-induced animal model that replicates histological, biological and physiological features of the human disease. Furthermore, we demonstrate that dysregulated epithelial repair and excessive matrix Tenacin C deposition occur in BO, providing new insights into potential disease mechanisms and therapeutic targets.
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