用C646对P300进行药理学抑制，通过调节M1型肺泡巨噬细胞中的CXCL1来改善脂多糖诱导的急性肺损伤。

Pharmacological inhibition of P300 with C646 ameliorates LPS-induced acute lung injury by modulating CXCL1 in M1 alveolar macrophages.

作者信息

Deng Yao, Wen Guanxi, Yin Yongtao, Chen Dandan, Li Difei, Chen Rongchang

机构信息

Department of Pulmonary and Critical Care Medicine, Shenzhen Institute of Respiratory Diseases, The First Affiliated Hospital (Shenzhen People's Hospital) and School of Medicine, Southern University of Science and Technology, Shenzhen 518055, China; National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, State Key Laboratory of Respiratory Disease, First Affiliated Hospital of Guangzhou Medical University, Guang Zhou 510150, China.

出版信息

Int Immunopharmacol. 2025 Jan 10;144:113674. doi: 10.1016/j.intimp.2024.113674. Epub 2024 Nov 25.

DOI:10.1016/j.intimp.2024.113674

PMID:39591828

Abstract

OBJECTIVES

Acute lung injury (ALI) is an excessive inflammatory condition with the involvement of M1 alveolar macrophage (AM) polarization. Given the high mortality rate of ALI, elucidating its underlying mechanisms is crucial for identifying therapeutic targets. Inhibition of P300, a lysine acetyltransferase, has illustrated the potential to alleviate inflammatory diseases through the regulation of immune cell activation. However, little is known whether P300 inhibition could ameliorate ALI through regulating the polarization of M1 AMs.

METHODS

We established an LPS-induced ALI model and evaluated the effects of the P300 inhibitor C646 on pulmonary pathology, inflammation and M1 AM polarization via H&E staining, ELISA and flow cytometry. Additionally, the specific inflammatory mediators regulated by P300 in M1 AMs affecting ALI were analyzed by RNA sequencing and validated by intratracheal instillation experiment.

RESULTS

Intratracheal instillation of LPS resulted in neutrophil accumulation within the pulmonary alveoli and interstitial areas, along with increased levels of total inflammatory cells and IL-1β in the lung. However, administration of C646 ameliorated these pulmonary pathology and inflammation, accompanied by a diminished proportion and quantity of M1 AMs in BALF. Furthermore, by taking the intersection of P300-targeted genes in macrophages from the Cistrome, genes upregulated after M1 polarization of AMs, and genes downregulated following C646 treatment in M1 AMs, we identified 'Cxcl1' among the intersecting genes. Also, intratracheal instillation of CXCL1 aggravated pulmonary pathology and inflammation in C646 treated-ALI models.

CONCLUSION

Our study suggested that pharmacological inhibition of P300 with C646 ameliorated LPS-induced ALI by modulating CXCL1 in M1 AMs.

摘要

目的

急性肺损伤（ALI）是一种过度炎症状态，伴有M1型肺泡巨噬细胞（AM）极化。鉴于ALI的高死亡率，阐明其潜在机制对于确定治疗靶点至关重要。赖氨酸乙酰转移酶P300的抑制已显示出通过调节免疫细胞激活来减轻炎症性疾病的潜力。然而，P300抑制是否能通过调节M1型AMs的极化来改善ALI尚不清楚。

方法

我们建立了脂多糖（LPS）诱导的ALI模型，并通过苏木精-伊红（H&E）染色、酶联免疫吸附测定（ELISA）和流式细胞术评估P300抑制剂C646对肺部病理、炎症和M1型AM极化的影响。此外，通过RNA测序分析P300在影响ALI的M1型AMs中调节的特定炎症介质，并通过气管内滴注实验进行验证。

结果

气管内滴注LPS导致肺泡和间质区域中性粒细胞积聚，同时肺内总炎症细胞和白细胞介素-1β水平升高。然而，给予C646改善了这些肺部病理和炎症，同时支气管肺泡灌洗液（BALF）中M1型AMs的比例和数量减少。此外，通过取Cistrome中巨噬细胞的P300靶向基因、AMs M1极化后上调的基因以及C646处理的M1型AMs中下调的基因的交集，我们在交集基因中鉴定出“Cxcl1”。此外，气管内滴注CXC趋化因子配体1（CXCL1）加重了C646处理的ALI模型中的肺部病理和炎症。