MCTR1通过抑制中性粒细胞反向跨内皮迁移改善lps诱导的肺损伤

IF 4.7 2区医学 Q2 IMMUNOLOGY

International immunopharmacology Pub Date : 2025-05-07 DOI:10.1016/j.intimp.2025.114777

Yang Cheng , Yuan Xiao , De-Ming Wang , Kun Liu , Xiu Yang , Chuang-Xin Zheng , Zhen-Biao He , Ze-Yu Guo , Yi Yang

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引用次数: 0

摘要

目的：脓毒症期间炎症反应失调常导致急性肺损伤（ALI）。在原发损伤部位激活的中性粒细胞可以通过反向跨内皮迁移（rTEM）重新进入循环，随后浸润其他器官，导致全身性炎症和多器官损伤。专门的促溶解脂质介质（SPM） maresin conjugate in tissue regeneration 1 （MCTR1）已被证明可以减轻败血症中的器官损伤。本研究探讨了中性粒细胞rTEM在ALI中的作用，并探讨MCTR1是否可以通过调节中性粒细胞rTEM来缓解ALI。方法采用脂多糖（LPS）诱导小鼠肺损伤。采用H&；E染色、肺干湿比、炎症介质水平和支气管肺泡灌洗液中的蛋白质含量评估肺损伤。免疫荧光法检测肺组织中性粒细胞浸润，流式细胞术检测肺组织中性粒细胞数量。通过分析中性粒细胞弹性蛋白酶（NE）和连接粘附分子c （JAM-C）的蛋白表达来评估rTEM的活性。利用CXCR4抑制剂AMD3100研究了CXCR4在中性粒细胞rTEM中的作用。此外，分离骨髓源性中性粒细胞以评估MCTR1对CXCR4和GRK2表达的影响。结果smctr1减轻脂多糖所致肺损伤，抑制中性粒细胞rTEM。MCTR1还能降低NE的表达，增加JAM-C的表达。CXCR4抑制剂AMD3100能有效抑制中性粒细胞rTEM，减轻肺损伤。此外，MCTR1抑制CXCR4表达，增强GRK2表达。结论smctr1通过上调GRK2抑制CXCR4表达减轻肺损伤，从而抑制lps诱导的肺损伤中性粒细胞rTEM。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

MCTR1 ameliorates LPS-induced lung injury by inhibiting neutrophil reverse transendothelial migration

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MCTR1 ameliorates LPS-induced lung injury by inhibiting neutrophil reverse transendothelial migration

Objectives

Dysregulated inflammatory responses during sepsis often result in acute lung injury (ALI). Neutrophils activated at the primary site of injury can re-enter the circulation through reverse transendothelial migration (rTEM), subsequently infiltrating other organs and contributing to systemic inflammation and multi-organ damage. The specialized pro-resolving lipid mediator (SPM) maresin conjugate in tissue regeneration 1 (MCTR1) has been shown to mitigate organ injury in sepsis. This study investigated the role of neutrophil rTEM in ALI and examined whether MCTR1 can alleviate ALI by modulating neutrophil rTEM.

Methods

Lung injury was induced in mice by administrating lipopolysaccharide (LPS). Lung damage was assessed using H&E staining, lung wet-to-dry ratio, inflammatory mediator levels, and protein content in the bronchoalveolar lavage fluid. Neutrophil infiltration in lung tissue was evaluated by immunofluorescence, and flow cytometry was used to quantify rTEM neutrophils. Protein expression of neutrophil elastase (NE) and junctional adhesion molecule-C (JAM-C) was analyzed to assess rTEM activity. The role of CXCR4 in neutrophil rTEM was investigated using the CXCR4 inhibitor AMD3100. Additionally, bone marrow-derived neutrophils were isolated to evaluate the effects of MCTR1 on CXCR4 and GRK2 expression.

Results

MCTR1 alleviated lung injury and inhibited neutrophils rTEM in LPS-induced lung injury. MCTR1 also decreased NE expression and increased JAM-C expression. The CXCR4 inhibitor AMD3100 effectively suppressed neutrophil rTEM and alleviated lung injury. Furthermore, MCTR1 inhibited CXCR4 expression and enhanced GRK2 expression.

Conclusions

MCTR1 reduces lung damage by upregulating GRK2 to inhibit CXCR4 expression, thereby suppressing neutrophil rTEM in LPS-induced lung injury.

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来源期刊

International immunopharmacology 医学-免疫学

CiteScore

8.40

自引率

3.60%

发文量

935

审稿时长

53 days

期刊介绍： International Immunopharmacology is the primary vehicle for the publication of original research papers pertinent to the overlapping areas of immunology, pharmacology, cytokine biology, immunotherapy, immunopathology and immunotoxicology. Review articles that encompass these subjects are also welcome. The subject material appropriate for submission includes: • Clinical studies employing immunotherapy of any type including the use of: bacterial and chemical agents; thymic hormones, interferon, lymphokines, etc., in transplantation and diseases such as cancer, immunodeficiency, chronic infection and allergic, inflammatory or autoimmune disorders. • Studies on the mechanisms of action of these agents for specific parameters of immune competence as well as the overall clinical state. • Pre-clinical animal studies and in vitro studies on mechanisms of action with immunopotentiators, immunomodulators, immunoadjuvants and other pharmacological agents active on cells participating in immune or allergic responses. • Pharmacological compounds, microbial products and toxicological agents that affect the lymphoid system, and their mechanisms of action. • Agents that activate genes or modify transcription and translation within the immune response. • Substances activated, generated, or released through immunologic or related pathways that are pharmacologically active. • Production, function and regulation of cytokines and their receptors. • Classical pharmacological studies on the effects of chemokines and bioactive factors released during immunological reactions.