Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea.
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea; Institute of Allergy, Yonsei University College of Medicine, Seoul, Republic of Korea.
Life Sci. 2023 Dec 1;334:122163. doi: 10.1016/j.lfs.2023.122163. Epub 2023 Oct 25.
Despite recent investigations on the role of chitinase in asthma, its role in obesity-induced asthma has not been evaluated. Therefore, we investigated the roles of chitin, chitinase-1, and a chitinase-1 inhibitor (compound X, CPX) in a murine model.
We assigned C57BL/6 mice to the ovalbumin (OVA) model or obesity model group. In the OVA model, mice received intraperitoneal OVA twice within a 2-week interval and intranasal OVA for 3 consecutive days. Additionally, chitin was intranasally administered for 3 consecutive days, and CPX was intraperitoneally injected three times over 5 days. In the obesity model, a high-fat diet (HFD) was maintained for 13 weeks, and CPX was intraperitoneally injected eight times over 4 weeks.
In the OVA model, chitin aggravated OVA-induced airway hyper-responsiveness (AHR), increased bronchoalveolar lavage fluid (BALF) cell proliferation, increased fibrosis, and increased the levels of various inflammatory cytokines (including chitinase-1, TGF-β, TNF-α, IL-1 β, IL-6, IL-4, and IL-13). CPX treatment significantly ameliorated these effects. In the obesity model, HFD significantly increased AHR, BALF cell proliferation, fibrosis, and the levels of various inflammatory cytokines. Particularly, compared to the control group, the mRNA expression of chitinase, chitinase-like molecules, and other molecules associated with inflammation and the immune system was significantly upregulated in the HFD and HFD/OVA groups. Immunofluorescence analysis also showed increased chitinase-1 expression in these groups. CPX significantly ameliorated all these effects in this model.
This study showed that CPX can be an effective therapeutic agent in asthma, especially, obesity-induced and -aggravated asthma to protect against the progression to airway remodeling and fibrosis.
尽管最近有研究探讨了壳聚糖酶在哮喘中的作用，但它在肥胖诱导性哮喘中的作用尚未得到评估。因此，我们在小鼠模型中研究了壳聚糖、壳聚糖酶-1 及其抑制剂（化合物 X，CPX）的作用。
我们将 C57BL/6 小鼠分为卵清蛋白（OVA）模型组或肥胖模型组。在 OVA 模型中，小鼠在 2 周内接受两次腹腔注射 OVA，并连续 3 天接受鼻腔内 OVA 处理。此外，连续 3 天给予壳聚糖鼻腔内给药，5 天内腹腔内注射 CPX 3 次。在肥胖模型中，高脂肪饮食（HFD）喂养 13 周，4 周内腹腔内注射 CPX8 次。
在 OVA 模型中，壳聚糖加重了 OVA 诱导的气道高反应性（AHR），增加了支气管肺泡灌洗液（BALF）细胞增殖，加重了纤维化，并增加了各种炎症细胞因子（包括壳聚糖酶-1、TGF-β、TNF-α、IL-1β、IL-6、IL-4 和 IL-13）的水平。CPX 治疗显著改善了这些作用。在肥胖模型中，HFD 显著增加了 AHR、BALF 细胞增殖、纤维化和各种炎症细胞因子的水平。与对照组相比，HFD 和 HFD/OVA 组中壳聚糖酶、壳聚糖样分子和其他与炎症和免疫系统相关的分子的 mRNA 表达显著上调。免疫荧光分析也显示这些组中壳聚糖酶-1 的表达增加。CPX 显著改善了该模型中的所有这些作用。
本研究表明，CPX 可作为一种有效的治疗药物，用于治疗哮喘，特别是肥胖诱导和加重的哮喘，以防止气道重塑和纤维化的进展。
