Gao Shupei, Li Wenjuan, Huang Zhiwen, Deiuliis Jeffrey A, Braunstein Zachary, Liu Xinxin, Li Xinlu, Kosari Mohammadreza, Chen Jun, Min Xinwen, Yang Handong, Gong Quan, Liu Zheng, Wei Yingying, Zhang Ziyang, Dong Lingli, Zhong Jixin
Department of Rheumatology and Immunology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei 430030, China.
Cardiovascular Research Institute, Case Western Reserve University, Cleveland, OH 44106, USA.
Mucosal Immunol. 2024 Dec;17(6):1273-1284. doi: 10.1016/j.mucimm.2024.08.008. Epub 2024 Aug 21.
Acute respiratory distress syndrome (ARDS) is a life-threatening condition characterized by severe inflammation and pulmonary dysfunction. Despite advancements in critical care, effective pharmacological interventions for ARDS remain elusive. While Janus kinase 2 (JAK2) inhibitors have emerged as an innovative treatment for numerous autoinflammatory diseases, their therapeutic potential in ARDS remains unexplored. In this study, we investigated the contribution of JAK2 and its underlying mechanisms in ARDS utilizing myeloid-specific JAK2 knockout murine models alongside a pharmacological JAK2 inhibitor. Notably, myeloid-specific JAK2 knockout led to a notable attenuation of ARDS induced by intratracheal administration of LPS, accompanied by reduced levels of neutrophils and inflammatory cytokines in bronchoalveolar lavage fluid (BALF) and lung tissue. Intriguingly, the ameliorative effects were abolished upon the depletion of monocyte-derived alveolar macrophages (Mo-AMs) rather than tissue-resident alveolar macrophages (TR-AMs). JAK2 deficiency markedly reversed LPS-induced activation of STAT5 in macrophages. Remarkably, pharmacological JAK2 inhibition using baricitinib failed to substantially alleviate neutrophils infiltration, implying that specific inhibition of JAK2 in Mo-AMs is imperative for ARDS amelioration. Collectively, our data suggest that JAK2 may mitigate ARDS progression through the JAK2 pathway in Mo-AMs, underscoring JAK2 in alveolar macrophages, particularly Mo-AMs, as a promising therapeutic target for ARDS treatment.
急性呼吸窘迫综合征（ARDS）是一种危及生命的病症，其特征为严重炎症和肺功能障碍。尽管重症监护有所进展，但针对ARDS的有效药物干预措施仍然难以捉摸。虽然Janus激酶2（JAK2）抑制剂已成为众多自身炎症性疾病的创新治疗方法，但其在ARDS中的治疗潜力仍未得到探索。在本研究中，我们利用髓系特异性JAK2敲除小鼠模型以及一种JAK2药理学抑制剂，研究了JAK2在ARDS中的作用及其潜在机制。值得注意的是，髓系特异性JAK2敲除导致气管内注射脂多糖（LPS）诱导的ARDS明显减轻，同时支气管肺泡灌洗液（BALF）和肺组织中的中性粒细胞和炎性细胞因子水平降低。有趣的是，单核细胞衍生的肺泡巨噬细胞（Mo-AM）而非组织驻留肺泡巨噬细胞（TR-AM）耗竭后，改善作用消失。JAK2缺陷显著逆转了LPS诱导的巨噬细胞中STAT5的激活。值得注意的是，使用巴瑞替尼进行的JAK2药理学抑制未能显著减轻中性粒细胞浸润，这意味着对Mo-AM中的JAK2进行特异性抑制对于改善ARDS至关重要。总体而言，我们的数据表明JAK2可能通过Mo-AM中的JAK2途径减轻ARDS的进展，突出了肺泡巨噬细胞，特别是Mo-AM中的JAK2作为ARDS治疗的一个有希望的治疗靶点。
