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Repetitive Ozone Exposures and Evaluation of Pulmonary Inflammation and Remodeling in Diabetic Mouse Strains
Environmental Health Perspectives ( IF 10.1 ) Pub Date : 2020-11-30 , DOI: 10.1289/ehp7255
James G Wagner 1 , Christina E Barkauskas 2 , Aaron Vose 2 , Ryan P Lewandowski 1 , Jack R Harkema 1 , Robert M Tighe 2
Affiliation  

Abstract

Background:

Epidemiological studies support the hypothesis that diabetes alters pulmonary responses to air pollutants like ozone (O3). The mechanism(s) underlying these associations and potential links among diabetes, O3, and lung inflammation and remodeling are currently unknown.

Objectives:

The goal was to determine whether pulmonary responses to repetitive ozone exposures are exacerbated in murine strains that are hyperglycemic and insulin resistant.

Methods:

Normoglycemic and insulin-sensitive C57BL/6J mice; hyperglycemic, but mildly insulin-resistant, KK mice; and hyperglycemic and markedly insulin-resistant KKAy mice were used for ozone exposure studies. All animals were exposed to filtered air (FA) or repetitive ozone (0.5 ppmO3, 4 h/d, for 13 consecutive weekdays). Tissue analysis was performed 24 h following the final exposure. This analysis included bronchoalveolar lavage (BAL) for cell and fluid analysis, and tissue for pathology, immunohistology, mRNA, and hydroxyproline.

Results:

Following repetitive O3 exposure, higher bronchoalveolar lavage fluid inflammatory cells were observed in all mice (KKAy>KK>C57BL/6), with a notable influx of neutrophils and eosinophils in KK and KKAy mice. Although the lungs of O3-exposed C57BL/6J and KK mice had minimal centriacinar histological changes without fibrosis, the lungs of O3-exposed KKAy mice contained marked epithelial hyperplasia in proximal alveolar ducts and adjacent alveoli with associated centriacinar fibrosis. Fibrosis in O3-exposed KKAy lungs was confirmed with immunohistochemistry, tissue hydroxyproline content, and tissue mRNA expression of fibrosis-associated genes (Ccl11, Il13, and Mmp12). Immunofluorescence staining and confocal microscopy revealed alterations in the structure and composition of the airway and alveolar epithelium in regions of fibrosis.

Discussion:

Our results demonstrate that in diabetic animal strains repetitive ambient ozone exposure led to early and exaggerated pulmonary inflammation and remodeling. Changes in distal and interstitial airspaces and the activation of Th2 inflammatory and profibrotic pathways in experimental animals provide a preliminary, mechanistic framework to support the emerging epidemiological associations among air pollution, diabetes, and lung disease. https://doi.org/10.1289/EHP7255



中文翻译:


糖尿病小鼠品系的重复臭氧暴露以及肺部炎症和重塑的评估


 抽象的

 背景:


流行病学研究支持这样的假设:糖尿病会改变肺部对臭氧等空气污染物的反应。3 )。这些关联背后的机制以及糖尿病之间的潜在联系,3 ,肺部炎症和重塑目前尚不清楚。

 目标:


目的是确定高血糖和胰岛素抵抗的小鼠品系对重复臭氧暴露的肺部反应是否会加剧。

 方法:


血糖正常且胰岛素敏感的 C57BL/6J 小鼠;高血糖但轻度胰岛素抵抗的 KK 小鼠;高血糖和明显胰岛素抵抗的 KKAy 小鼠被用于臭氧暴露研究。所有动物均暴露于过滤空气(FA)或重复臭氧( 0.5百万分之一3 ,4 小时/天,连续 13 个工作日)。最终暴露后 24 小时进行组织分析。该分析包括用于细胞和液体分析的支气管肺泡灌洗液 (BAL),以及用于病理学、免疫组织学、mRNA 和羟脯氨酸分析的组织。

 结果:


以下重复3暴露后,在所有小鼠中观察到较高的支气管肺泡灌洗液炎症细胞(凯凯> KK > C 57 BL / 6 ),KK 和 KKAy 小鼠中中性粒细胞和嗜酸性粒细胞显着涌入。虽然肺3 -暴露的C57BL/6J和KK小鼠有最小的中心腺组织学变化,没有纤维化,肺3 -暴露的KKAy小鼠在近端肺泡管和邻近肺泡中含有明显的上皮增生,并伴有相关的中心纤维化。纤维化于3通过免疫组织化学、组织羟脯氨酸含量和纤维化相关基因( Ccl11Il13Mmp12 )的组织 mRNA 表达来证实暴露的 KKAy 肺。免疫荧光染色和共聚焦显微镜揭示了纤维化区域气道和肺泡上皮的结构和组成的变化。

 讨论:


我们的结果表明,在糖尿病动物品系中,重复暴露于环境臭氧会导致早期和严重的肺部炎症和重塑。实验动物中远端和间质气腔的变化以及 Th2 炎症和促纤维化途径的激活提供了一个初步的机制框架来支持空气污染、糖尿病和肺部疾病之间新兴的流行病学关联。 https://doi.org/10.1289/EHP7255

更新日期:2020-12-01
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