Targeting SELPLG/P-selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the SELPLG promoter.
Targeting SELPLG/P-selectin glycoprotein ligand 1 in preclinical ARDS: Genetic and epigenetic regulation of the SELPLG promoter.
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DOI：
10.1002/pul2.12206
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发表时间：
2023-01
影响因子：
2.6
通讯作者：
Bime, Christian
中科院分区：
文献类型：
--
作者：
Sun, Xiaoguang;Sammani, Saad;Hufford, Matthew;Sun, Belinda L.;Kempf, Carrie L.;Camp, Sara M.;Garcia, Joe G. N.;Bime, Christian
我们先前在选择素-P-配体基因（SELPLG）中发现了一个错义单核苷酸多态性rs 2228315（G>A，Met 62 Ile），编码P-选择素糖蛋白配体1（PSGL-1），与急性呼吸窘迫综合征（ARDS）易感性增加相关。这些早期研究表明，暴露于脂多糖（LPS）和呼吸机诱导的肺损伤（VILI）的小鼠中，SELPLG肺组织表达增加，表明炎症和表观遗传因素调节SELPLG启动子活性和转录。在本报告中，我们使用了一种新型重组串联PSGL 1免疫球蛋白融合分子（TSGL-IG），一种PSGL 1/P-选择素相互作用的竞争性抑制剂，以证明TSGL-IG介导的SELPLG肺组织表达的显著降低以及对LPS和VILI诱导的肺损伤的高度显著保护。体外研究检查了关键ARDS刺激（LPS，18%循环拉伸以模拟VILI）对SELPLG启动子活性的影响，并显示LPS介导的SELPLG启动子活性增加，并鉴定了与SELPLG表达增加相关的推定启动子区域。SELPLG启动子活性受到关键的缺氧诱导转录因子HIF-1α和HIF-2α以及NRF 2的强烈调节。最后，证实了ARDS刺激对SELPLG启动子的转录调控以及DNA甲基化对内皮细胞SELPLG表达的影响。这些发现表明临床相关炎症因子对SELPLG转录的调节，TSGL-IG介导的LPS和VILI的显著衰减与作为ARDS治疗靶点的PSGL 1/P-选择素高度一致。
We previously identified a missense single nucleotide polymorphism rs2228315 (G>A, Met62Ile) in the selectin‐P‐ligand gene (SELPLG), encoding P‐selectin glycoprotein ligand 1 (PSGL‐1), to be associated with increased susceptibility to acute respiratory distress syndrome (ARDS). These earlier studies demonstrated that SELPLG lung tissue expression was increased in mice exposed to lipopolysaccharide (LPS)‐ and ventilator‐induced lung injury (VILI) suggesting that inflammatory and epigenetic factors regulate SELPLG promoter activity and transcription. In this report, we used a novel recombinant tandem PSGL1 immunoglobulin fusion molecule (TSGL‐Ig), a competitive inhibitor of PSGL1/P‐selectin interactions, to demonstrate significant TSGL‐Ig‐mediated decreases in SELPLG lung tissue expression as well as highly significant protection from LPS‐ and VILI‐induced lung injury. In vitro studies examined the effects of key ARDS stimuli (LPS, 18% cyclic stretch to simulate VILI) on SELPLG promoter activity and showed LPS‐mediated increases in SELPLG promoter activity and identified putative promoter regions associated with increased SELPLG expression. SELPLG promoter activity was strongly regulated by the key hypoxia‐inducible transcription factors, HIF‐1α, and HIF‐2α as well as NRF2. Finally, the transcriptional regulation of SELPLG promoter by ARDS stimuli and the effect of DNA methylation on SELPLG expression in endothelial cell was confirmed. These findings indicate SELPLG transcriptional regulation by clinically‐relevant inflammatory factors with the significant TSGL‐Ig‐mediated attenuation of LPS and VILI highly consistent with PSGL1/P‐selectin as therapeutic targets in ARDS.
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影响因子：
2.7
作者：
Karki NR;Kutlar A
通讯作者：
Kutlar A
DOI：
10.1183/13993003.02536-2020
发表时间：
2021-05
期刊：
The European respiratory journal
影响因子：
--
作者：
Quijada H;Bermudez T;Kempf CL;Valera DG;Garcia AN;Camp SM;Song JH;Franco E;Burt JK;Sun B;Mascarenhas JB;Burns K;Gaber A;Oita RC;Reyes Hernon V;Barber C;Moreno-Vinasco L;Sun X;Cress AE;Martin D;Liu Z;Desai AA;Natarajan V;Jacobson JR;Dudek SM;Bime C;Sammani S;Garcia JGN
通讯作者：
Garcia JGN
影响因子：
9.6
作者：
Marshall, RP;Webb, S;Laurent, GJ
通讯作者：
Laurent, GJ
影响因子：
15.9
作者：
Kisseleva, Tatiana;Song, Li;Schindler, Christian
通讯作者：
Schindler, Christian
影响因子：
11.5
作者：
Blair, Hannah A.
通讯作者：
Blair, Hannah A.