Exogenous leptin enhances markers of airway fibrosis in a mouse model of chronic allergic airways disease.
Exogenous leptin enhances markers of airway fibrosis in a mouse model of chronic allergic airways disease.
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DOI：
10.1186/s12931-022-02048-z
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发表时间：
2022-05-24
影响因子：
5.8
通讯作者：
中科院分区：
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患有肥胖症的哮喘患者表现出疾病严重程度增加，部分原因是气道重塑，这也在哮喘和肥胖症的小鼠模型中观察到。在肥胖症中增加的重塑介质是瘦素。我们假设在过敏性气道疾病的小鼠模型中，接受外源性瘦素的小鼠会表现出气道炎症和纤维化的增加。用鼻内屋尘螨（HDM）过敏原或盐水攻击5周龄雄性和雌性C57 BL/6 J小鼠，每周5天，持续6周（每组每种性别n = 6-9）。在每次HDM暴露后，小鼠接受皮下重组人瘦素或盐水。在最终HDM攻击后48小时，评价肺力学并处死小鼠。进行支气管肺泡灌洗并测定细胞分类计数。肺组织用Masson三色、高碘酸-希夫和苏木精和伊红染色。培养小鼠肺成纤维细胞，分离全肺mRNA。瘦素不影响小鼠体重，但HDM+瘦素增加基线血糖。在混合性别组中，瘦素增加小鼠肺成纤维细胞侵袭性和增加肺Col 1a 1 mRNA表达。总肺阻力和组织阻尼增加HDM+瘦素治疗，但不瘦素或HDM单独。HDM+瘦素处理的雌性小鼠对乙酰甲胆碱的气道反应性增强，而瘦素单独处理的雄性小鼠总呼吸系统阻力降低。在HDM诱导的过敏性气道疾病中，给予小鼠外源性瘦素增强了肺阻力并增加了纤维化标志物，雄性和雌性之间的影响不同。在线版本包含补充材料，可通过10.1186/s12931-022-02048-z获得。
Asthma patients with comorbid obesity exhibit increased disease severity, in part, due to airway remodeling, which is also observed in mouse models of asthma and obesity. A mediator of remodeling that is increased in obesity is leptin. We hypothesized that in a mouse model of allergic airways disease, mice receiving exogenous leptin would display increased airway inflammation and fibrosis. Five-week-old male and female C57BL/6J mice were challenged with intranasal house dust mite (HDM) allergen or saline 5 days per week for 6 weeks (n = 6–9 per sex, per group). Following each HDM exposure, mice received subcutaneous recombinant human leptin or saline. At 48 h after the final HDM challenge, lung mechanics were evaluated and the mice were sacrificed. Bronchoalveolar lavage was performed and differential cell counts were determined. Lung tissue was stained with Masson’s trichrome, periodic acid-Schiff, and hematoxylin and eosin stains. Mouse lung fibroblasts were cultured, and whole lung mRNA was isolated. Leptin did not affect mouse body weight, but HDM+leptin increased baseline blood glucose. In mixed-sex groups, leptin increased mouse lung fibroblast invasiveness and increased lung Col1a1 mRNA expression. Total lung resistance and tissue damping were increased with HDM+leptin treatment, but not leptin or HDM alone. Female mice exhibited enhanced airway responsiveness to methacholine with HDM+leptin treatment, while leptin alone decreased total respiratory system resistance in male mice. In HDM-induced allergic airways disease, administration of exogenous leptin to mice enhanced lung resistance and increased markers of fibrosis, with differing effects between males and females. The online version contains supplementary material available at 10.1186/s12931-022-02048-z.
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