Kiss1 receptor knockout exacerbates airway hyperresponsiveness and remodeling in a mouse model of allergic asthma.

IF 5.8 2区 医学 Q1 Medicine Respiratory Research Pub Date : 2024-10-28 DOI:10.1186/s12931-024-03017-4
Nilesh Sudhakar Ambhore, Premanand Balraj, Ashish Kumar, Mohammad Irshad Reza, Yogaraj S Ramakrishnan, Jacob Tesch, Sahil Lohana, Venkatachalem Sathish
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Abstract

Background: In asthma, sex-steroids signaling is recognized as a critical regulator of disease pathophysiology. However, the paradoxical role of sex-steroids, especially estrogen, suggests that an upstream mechanism or even independent of estrogen plays an important role in regulating asthma pathophysiology. In this context, in our previous studies, we explored kisspeptin (Kp) and its receptor Kiss1R's signaling in regulating human airway smooth muscle cell remodeling in vitro and airway hyperresponsiveness (AHR) in vivo in a mouse (wild-type, WT) model of asthma. In this study, we evaluated the effect of endogenous Kp in regulating AHR and remodeling using Kiss1R knockout (Kiss1R-/-) mice.

Methods: C57BL/6J WT (Kiss1R+/+) and Kiss1R-/- mice, both male and female, were intranasally challenged with mixed-allergen (MA) and/or phosphate-buffered saline (PBS). We used flexiVent analysis to assess airway resistance (Rrs), elastance (Ers), and compliance (Crs). Following this, broncho-alveolar lavage (BAL) was performed for differential leukocyte count (DLC) and cytokine analysis. Histology staining was performed using hematoxylin and eosin (H&E) for morphological analysis and Masson's Trichrome (MT) for collagen deposition. Additionally, lung sections were processed for immunofluorescence (IF) of Ki-67, α-smooth muscle actin (α-SMA), and tenascin-c.

Results: Interestingly, the loss of Kiss1R exacerbated lung function and airway contractility in mice challenged with MA, with more profound effects in Kiss1R-/- female mice. MA-challenged Kiss1R-/- mice showed a significant increase in immune cell infiltration and proinflammatory cytokine levels. Importantly, the loss of Kiss1R aggravated Th2/Th17 biased cytokines in MA-challenged mice. Furthermore, histology of lung sections from Kiss1R-/- mice showed increased collagen deposition on airway walls and mucin production in airway cells compared to Kiss1R+/+ mice. In addition, immunofluorescence analysis showed loss of Kiss1R significantly aggravated airway remodeling and subsequently AHR.

Conclusions: These findings demonstrate the importance of inherent Kiss1R signaling in regulating airway inflammation, AHR, and remodeling in the pathophysiology of asthma.

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在过敏性哮喘小鼠模型中,Kiss1 受体敲除会加剧气道高反应性和重塑。
背景:在哮喘中,性类固醇信号被认为是疾病病理生理学的关键调节因子。然而,性激素(尤其是雌激素)的矛盾作用表明,上游机制甚至独立于雌激素的机制在调节哮喘病理生理学方面发挥着重要作用。在此背景下,我们在之前的研究中探讨了吻肽(Kp)及其受体 Kiss1R 在体外调节人气道平滑肌细胞重塑和体内调节小鼠(野生型,WT)哮喘模型中气道高反应性(AHR)的信号传导。在本研究中,我们利用 Kiss1R 基因敲除(Kiss1R-/-)小鼠评估了内源性 Kp 在调节 AHR 和重塑中的作用:雌雄C57BL/6J WT(Kiss1R+/+)和Kiss1R-/-小鼠经鼻内注射混合过敏原(MA)和/或磷酸盐缓冲盐水(PBS)。我们使用 flexiVent 分析方法评估气道阻力 (Rrs)、弹性 (Ers) 和顺应性 (Crs)。然后进行支气管肺泡灌洗(BAL),以进行白细胞计数差异(DLC)和细胞因子分析。组织学染色采用苏木精和伊红(H&E)进行形态学分析,采用马森三色染色法(MT)进行胶原沉积分析。此外,还对肺部切片进行了免疫荧光(IF),以检测Ki-67、α-平滑肌肌动蛋白(α-SMA)和tenascin-c:结果:有趣的是,Kiss1R缺失会加剧MA挑战小鼠的肺功能和气道收缩力,对Kiss1R-/-雌性小鼠的影响更深。受到 MA 挑战的 Kiss1R-/- 小鼠的免疫细胞浸润和促炎细胞因子水平显著增加。重要的是,Kiss1R 的缺失加剧了 MA 攻击小鼠体内 Th2/Th17 偏向细胞因子的水平。此外,与 Kiss1R+/+ 小鼠相比,Kiss1R-/- 小鼠肺切片的组织学显示气道壁上的胶原沉积和气道细胞中的粘蛋白生成增加。此外,免疫荧光分析表明,Kiss1R 的缺失会显著加重气道重塑,进而导致 AHR:这些研究结果表明,在哮喘的病理生理学过程中,固有的 Kiss1R 信号在调节气道炎症、AHR 和重塑方面起着重要作用。
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来源期刊
Respiratory Research
Respiratory Research RESPIRATORY SYSTEM-
CiteScore
9.70
自引率
1.70%
发文量
314
审稿时长
4-8 weeks
期刊介绍: Respiratory Research publishes high-quality clinical and basic research, review and commentary articles on all aspects of respiratory medicine and related diseases. As the leading fully open access journal in the field, Respiratory Research provides an essential resource for pulmonologists, allergists, immunologists and other physicians, researchers, healthcare workers and medical students with worldwide dissemination of articles resulting in high visibility and generating international discussion. Topics of specific interest include asthma, chronic obstructive pulmonary disease, cystic fibrosis, genetics, infectious diseases, interstitial lung diseases, lung development, lung tumors, occupational and environmental factors, pulmonary circulation, pulmonary pharmacology and therapeutics, respiratory immunology, respiratory physiology, and sleep-related respiratory problems.
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