Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
Laboratory of Immunopharmacology, Faculty of Pharmaceutical Sciences, Setsunan University, Osaka, Japan.
Int Immunopharmacol. 2022 Sep;110:109037. doi: 10.1016/j.intimp.2022.109037. Epub 2022 Jul 8.
Subgroups of patients with severe asthma showing marked increases in sputum eosinophils and/or neutrophils are insensitive to corticosteroids. Previous reports have shown that exogenous administration of an anti-inflammatory cytokine, interleukin (IL)-10 negatively regulated both eosinophilic and neutrophilic migration into tissues. The objective of this study was to elucidate whether intratracheal IL-10 administration suppresses asthmatic responses in a steroid-insensitive model of mice. Ovalbumin (OVA)-sensitized BALB/c mice were intratracheally challenged with OVA at 500 µg/animal four times. Dexamethasone (1 mg/kg, intraperitoneal) or IL-10 (25 ng/mouse, intratracheal) was administered during the multiple challenges. The number of leukocytes, expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and IL-10 receptor in the lung, and the development of airway remodeling and hyperresponsiveness were evaluated after the fourth challenge. Consistent with our previous study, dexamethasone hardly suppressed the development of airway remodeling and hyperresponsiveness. Although intratracheal IL-10 administration did not affect the development of airway remodeling, the infiltration of eosinophils and neutrophils, and the development of airway hyperresponsiveness were significantly inhibited. Moreover, IL-10 administration significantly decreased the numbers of ICAM-1 and VCAM-1 pulmonary vascular endothelial cells, which express IL-10 receptor 1, even though neither production of eosinophilic nor neutrophilic cytokines in the lung was inhibited. Therefore, IL-10 can suppress eosinophil and neutrophil infiltration by inhibiting the proliferation of ICAM-1 and VCAM-1 pulmonary vascular endothelial cells, resulting in inhibition of airway hyperresponsiveness in steroid-insensitive asthmatic mice. IL-10 replacement therapy may be clinically useful for the treatment of steroid-insensitive asthma.
在痰中嗜酸性粒细胞和/或中性粒细胞明显增加的重症哮喘患者亚群中，皮质类固醇治疗效果不佳。先前的研究表明，外源性给予抗炎细胞因子白细胞介素（IL）-10 可负调节嗜酸性粒细胞和中性粒细胞向组织中的迁移。本研究的目的是阐明气管内给予 IL-10 是否可抑制类固醇不敏感的哮喘小鼠模型中的哮喘反应。卵清蛋白（OVA）致敏的 BALB/c 小鼠，经气管内给予 OVA（500 µg/只），4 次/只。在多次挑战期间，给予地塞米松（1mg/kg，腹腔内）或 IL-10（25ng/只，气管内）。在第 4 次挑战后，评估肺内白细胞数量、细胞间黏附分子-1（ICAM-1）、血管细胞黏附分子-1（VCAM-1）和 IL-10 受体的表达，以及气道重塑和高反应性的发展。与我们之前的研究一致，地塞米松几乎不能抑制气道重塑和高反应性的发展。尽管气管内给予 IL-10 并不影响气道重塑的发展，但明显抑制了嗜酸性粒细胞和中性粒细胞的浸润以及气道高反应性的发展。此外，IL-10 给药显著减少了表达 IL-10 受体 1 的 ICAM-1 和 VCAM-1 肺血管内皮细胞的数量，尽管肺内嗜酸性粒细胞和中性粒细胞细胞因子的产生未被抑制。因此，IL-10 可通过抑制 ICAM-1 和 VCAM-1 肺血管内皮细胞的增殖来抑制嗜酸性粒细胞和中性粒细胞的浸润，从而抑制类固醇不敏感的哮喘小鼠的气道高反应性。IL-10 替代疗法可能对治疗类固醇不敏感的哮喘具有临床意义。
