Role of intestinal inflammation in oxidized lipid induced pulmonary hypertension

肠道炎症在氧化脂质诱导的肺动脉高压中的作用

• 批准号: 10381356
• 负责人: Mansoureh Eghbali
• 金额: $ 61.11万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-02-10 至 2026-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10381356
• 关键词: Apoptosis; Bioinformatics; Blood Vessels; C57BL/6 Mouse; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; CXCL10 gene; Cells; Cessation of life; Chronic lung disease; Conditioned Culture Media; Data; Development; Diet; Dietary Supplementation; Disease; Endothelial Cells; Epithelial; Epithelial Cells; Experimental Designs; Fatty Acids; Feedback; Functional disorder; Gene Chips; Genes; Human; Hydroxyeicosatetraenoic Acids; Hypertension; Immune; Immune system; Immunohistochemistry; Inflammation; Inflammatory; Interferon Type II; Interferons; Intestines; Lamina Propria; Ligands; Lipoxygenase; Lung; Lung Transplantation; Mediating; Medical; Microarray Analysis; Molecular; Mononuclear; Mus; Oxides; Pathogenesis; Pathologic; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Phase; Phenotype; Phospholipase; Play; Production; Proteins; Publications; Publishing; Pulmonary Hypertension; Rattus; Recombinants; Reporting; Rodent; Role; Small Intestines; Stimulus; Supporting Cell; Symptoms; T-Lymphocyte; TNF gene; TNFSF10 gene; Time; Up-Regulation; Wild Type Mouse; base; cytokine; dietary; experimental study; gut inflammation; improved; intestinal epithelium; knock-down; new therapeutic target; novel; oxidized lipid; peripheral blood; prevent; pulmonary arterial hypertension; pulmonary arterial pressure; right ventricular failure; transcriptome sequencing

SUMMARY Pulmonary arterial hypertension (PAH) is a chronic lung disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular (RV) heart failure and death. Over the last five years, our group and others have demonstrated the critical role of oxidized fatty acids in the pathogenesis of PAH. Levels of oxidized fatty acids of the lipoxygenase (LOX) pathway; hydroxyeicosatetraenoic acids (HETEs) are upregulated in the lungs of patients with PAH as well as in rats with pulmonary hypertension (PH). We were the first to establish that dietary supplementation of a single oxidized fatty acid (15HETE) of the LOX pathway is sufficient to cause PH in wild type mice in the absence of any other PH stimulus. In our very recent publication in Hypertension, we reported T cell-dependent endothelial cell apoptosis as one of the mechanisms underlying 15HETE induced PH. However, the exact molecular mechanisms leading to PAEC apoptosis and onset of PH are not known. To unravel the molecular mechanisms, we performed RNA-Seq on the lungs and intestine of mice on 15HETE diet and integrated our RNA-Seq data with online microarrays of human PAH lungs and identified IFI44 (IFN inducible protein 44) as the only novel common gene that was significantly upregulated. IFI44 is an interferon inducible protein and our preliminary data shows that IFNα4 is specifically increased in the small intestine of mice on 15HETE diet. Our preliminary time course experiments revealed increased expression of IFI44 in the small intestine, which precedes its upregulation in the lung, suggesting that 15HETE may act on the small intestine initially. In addition, our pilot data shows that IFI44 is expressed in the immune cells in the lungs of human PAH patients and in T cells in mouse lungs on 15HETE diet. Our bioinformatic analysis also revealed that expression of IFI44 in immune cells in the lungs correlates with CXCL10 (a proinflammatory cytokine) and TRAIL (Tumor Necrosis Factor Related Apoptosis Inducing Ligand). TRAIL and CXCL10 are both known to induce endothelial cell apoptosis. Our preliminary data also shows i) Knockdown of IFI44 in the lungs of mice on 15HETE diet prevented development of PH, and ii) blocking the pathologic action of Cxcl10 rescues PH development. Taken together, our overall hypotheses are i) dietary 15HETE acts on intestinal epithelial cells to produce IFN4, which induces IFI44 in specific immune cells of the Lamina Propria. IFI44 positive immune cells migrate to the lungs and in coordination with CXCL10/TRAIL trigger PAEC death, causing PH; and ii) IFI44 and CXCL10 can serve as novel therapeutic targets in the lungs to prevent or even rescue development of PH in mice on 15HETE diet. Aim 1 will determine the mechanisms by which 15HETE activates the intestinal epithelium resulting in the development of PH; Aim 2 will examine how activation of IFI44 in immune cells in the small intestine induces endothelial cell apoptosis in the lungs through CXC10 and/or TRAIL dependent mechanisms causing pulmonary hypertension; and Aim 3 will examine whether IFI44 and CXCL10 can serve as novel therapeutic targets in the lungs to prevent or rescue development of PH in mice on 15HETE diet.

概括 肺动脉高压（PAH）是一种慢性肺肺肺，其特征是计划的增加 肺动脉促进导致右心（RV）心力衰竭和死亡。 组和其他人已经证明了氧化脂肪酸在PAH病原体中的关键作用。 脂氧酶（LOX）途径的氧化脂肪酸； 在患有肺部突出的大鼠的患者和大鼠的肺部（pH）中上调 首先确定饮食中的单个氧化脂肪酸（15HETE）是LOX途径IS 在我们最近的出版物中，足以引起phin野生型小鼠。 在高血压中，我们报道了T细胞entherthother的细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞细胞copposis是一部分的体系机构之一 15HETE诱导的pH。但是，导致PAEC凋亡和OND发作的精确分子机制 不知道要揭开分子机制，我们在肺上进行了RNA-seq 15-饮食的小鼠将我们的RNA-seq数据与人类PAH肺的在线微阵列相结合 Identified IFI4444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444444! IFI44是一种干扰素诱导蛋白，我们的预后数据表明，IFNα4在您中明确增加了 小鼠在15Hete饮食上的小肠显示。 小肠中的ofi44在肺部上调，建议15hete可以作用 最初的小肠。此外，我们的飞行员数据表明​​，IFI44在您的免疫细胞中表达 人类患者的肺和T细胞中的T细胞中小鼠肺的肺部15HETE饮食。 在肺中的免疫细胞中的IFI44的表达与CXCL10相关（促炎性 细胞因子）和步道（肿瘤坏死因子相关的appletostosis诱导配体）。 已知会诱导内皮细胞细胞凋亡。 15-饮食上的小鼠阻止了pH的发展，ii）阻止CXCL10救援的病理作用 pH的发展。 产生IFN4，这会在层层的特定免疫细胞中诱导IFI44 细胞迁移到肺部，并与CXCL10/TRAIL触发PAEC死亡，导致pH和II）IFI44 和CXCL10可以在肺部促进治疗靶标，以防止甚至营救pH的发展 在15HETE饮食上的小鼠中，AIM 1将确定15HETE激活肠道的机制 导致pH的上皮； AIM 2将检查如何在免疫细胞中的激活 小肠可诱导肺CXC10和/或依赖性肺部肺部细胞细胞细胞细胞凋亡 引起肺动脉高压的机制 肺部的新型治疗靶标，以防止或挽救15HETE饮食的开发。