Sphingolipids play a pivotal role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, little is known about the precise roles of sphingosine-1-phosphate (S1P), a bioactive sphingolipid metabolite, and its receptor modulation in COPD. In this study, we demonstrated that the S1P receptor modulator ONO-4641 induced the expansion of lung CD11b⁺Gr-1⁺ cells and lymphocytopenia in naive mice. ONO-4641-expanded CD11b⁺Gr-1⁺ cells showed higher arginase-1 activity, decreased T cell proliferation, and lower IFN-γ production in CD3⁺ T cells, similar to the features of myeloid-derived suppressor cells. ONO-4641 treatment decreased airspace enlargement in elastase-induced and cigarette smoke-induced emphysema models and attenuated emphysema exacerbation induced by post-elastase pneumococcal infection, which was also associated with an increased number of lung CD11b⁺Gr-1⁺ cells. Adoptive transfer of ONO-4641-expanded CD11b⁺Gr-1⁺ cells protected against elastase-induced emphysema. Lymphocytopenia observed in these models likely contributed to beneficial ONO-4641 effects. Thus, ONO-4641 attenuated murine pulmonary emphysema by expanding lung CD11b⁺Gr-1⁺ cell populations and inducing lymphocytopenia. The S1P receptor might be a promising target for strategies aimed at ameliorating pulmonary emphysema progression.

中文翻译：

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Sphingosine 1-phosphate receptor modulator ONO-4641 刺激 CD11b+Gr-1+ 细胞扩增并抑制肺部淋巴细胞浸润以改善小鼠肺气肿。

鞘脂在慢性阻塞性肺疾病 (COPD) 的发病机制中起着关键作用。然而，关于鞘氨醇-1-磷酸 (S1P)（一种具有生物活性的鞘脂代谢物）及其在 COPD 中的受体调节作用的确切作用知之甚少。在这项研究中，我们证明了 S1P 受体调节剂 ONO-4641 在幼稚小鼠中诱导了肺 CD11b ⁺ Gr-1 ⁺细胞的扩张和淋巴细胞减少症。ONO-4641 扩增的 CD11b ⁺ Gr-1 ⁺细胞显示出更高的精氨酸酶-1 活性、降低的 T 细胞增殖和更低的 CD3 ^{+中的 IFN-γ 产生}T细胞，类似于髓源性抑制细胞的特征。ONO-4641 治疗减少了弹性蛋白酶诱导和香烟烟雾诱导的肺气肿模型中的空域扩大，并减轻了弹性蛋白酶后肺炎球菌感染诱导的肺气肿恶化，这也与肺 CD11b ⁺ Gr-1 ⁺细胞数量增加有关。ONO-4641 扩增的 CD11b ⁺ Gr-1 ⁺细胞的过继转移可防止弹性蛋白酶诱导的肺气肿。在这些模型中观察到的淋巴细胞减少可能促成了有益的 ONO-4641 效应。^{因此，ONO-4641 通过扩张肺 CD11b +} Gr-1 ⁺减轻小鼠肺气肿细胞群和诱导淋巴细胞减少。S1P 受体可能是旨在改善肺气肿进展的策略的有前途的目标。