Age-related skewing of angiotensin II signaling potentiates B. pertussis-induced pulmonary hypertension

与年龄相关的血管紧张素 II 信号传导增强百日咳博德特氏菌诱导的肺动脉高压

• 批准号: 10087891
• 负责人: Karen Scanlon
• 金额: $ 19.31万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-24 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10087891
• 关键词: ACE2; AGTR2 gene; Address; Adult; Age; Angiotensin II; Angiotensin II Receptor; Angiotensinogen; Angiotensins; Bordetella pertussis; Cardiopulmonary; Catheterization; Cause of Death; Cessation of life; Child; Coupled; Data; Development; Disease; Echocardiography; Etiology; Exposure to; Failure; Fatal Outcome; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genes; Health; Heart; Heart Arrest; Heart failure; Hypertension; Immune response; In Vitro; Infant; Infection; Infectious Agent; Knowledge; Link; Lung; Mediating; Modeling; Mus; Myocardial dysfunction; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Peptides; Peptidyl-Dipeptidase A; Pertussis; Pertussis Toxin; Production; Public Health; Pulmonary Hypertension; Pulmonary artery structure; Refractory; Regulation; Renin-Angiotensin System; Research; Right ventricular structure; Risk; Severities; Severity of illness; Signal Transduction; System; Testing; Therapeutic Agents; Therapeutic Intervention; Transcript; Vasodilation; age related; effective therapy; experimental study; improved; in vivo; infant infection; mortality risk; mouse model; novel strategies; novel therapeutics; postnatal; receptor; targeted treatment; therapeutically effective; transcriptome; treatment strategy; vasoconstriction

PROJECT SUMMARY Pertussis, caused by Bordetella pertussis, is a reemerging disease of major public health concern. Pertussis severity is age-related, with B. pertussis causing severe manifestations that are unique to young infants and not observed at an older age. These infants are at increased risk of cardiopulmonary failure and death from B. pertussis-induced pulmonary hypertension (PH). Age-related differences in disease severity indicate that host responses to B. pertussis differ with age. The causal mechanism for PH in severe pertussis is unknown and there are currently no effective therapeutic interventions for the treatment of pertussis-associated PH or death. The study proposed here aims to address this critical gap in knowledge, providing mechanistic information and validating the use of potentially novel therapeutics for pertussis. PH-associated cardiac dysfunction is initiated by remodeling of pulmonary arteries, but how does B. pertussis cause this remodeling? And, why is this function age-related? In unpublished and preliminary studies, B. pertussis was found to induce activation of the renin-angiotensin system (RAS) in the lungs of infant mice but not adult mice and pertussis toxin (PT) expression was required for B. pertussis-induced PH in infant mice. The RAS is one of the most important and best-studies systems in the pathogenesis of hypertension but has not been linked to infection-induced PH. The proposed experiments will test the hypothesis that high RAS activity in the infant lung and PT-mediated inhibition of a protective component of this system cause pathogenic RAS signaling and initiates pathologies that drive the onset of PH. Critical points of regulation in the RAS include the formation and degradation of angiotensin II (ANGII) by angiotensin-converting enzyme (ACE) and ACE2 respectively and ANGII signaling via AT1 and AT2 receptors to mediate opposing actions that may be pathogenic (AT1, vasoconstriction and proliferation) or protective (AT2, vasodilation and anti-proliferative) in our system. Preliminary data also shows that 1) basal pulmonary ANGII levels are higher in infants than adults, 2) B. pertussis downregulates expression of the angiotensin precursor gene Agt in adult lungs but increases expression in infant lungs, 3) B. pertussis downregulates ACE in adult lungs but not infant lungs and 4) basal expression of AT2 is significantly greater in infant lungs than adult lungs. These data indicate that, in infants, high AT2 levels are required to limit the effect of excessive ANGII signaling through AT1. However, AT2, but not AT1, is susceptible to PT-mediated inhibition, hence PT produced during infection would have a greater impact on ANGII signaling in infants than it would in adults. In aim 1, the age-related effect of B. pertussis on ANGII peptide accumulation and ACE and ACE2 activity will be examined. Age-related expression of AT2 will also be determined and the effect of infection of AT2 activity will be tested. In aim 2, the contribution of the RAS and PT-mediated inhibition of AT2 on B. pertussis-induced PH and death will be resolved. If our hypothesis is correct, RAS-targeting therapeutics may save the lives of young infants with severe pertussis.

项目摘要 百日咳百日咳引起的百日咳是一种重新出现的主要公共卫生关注的疾病。百日咳 严重程度与年龄有关，百日咳芽孢杆菌引起的严重表现是年轻婴儿独有的， 在年龄较大的时候未观察到。这些婴儿的心肺衰竭和死亡的风险增加。 百日咳诱导的肺动脉高压（pH）。与年龄有关的疾病严重程度差异表明宿主 对百日咳芽孢杆菌的反应随着年龄的增长而有所不同。严重百日咳pH的因果机制尚不清楚，并且 目前尚无有效的治疗干预措施来治疗与百日咳相关的pH或死亡。 这里提出的研究旨在解决知识中的这一关键差距，提供机械信息和 验证使用潜在的新型治疗学用于百日咳。 pH相关的心脏功能障碍是通过肺动脉的重塑而引发的，但是B. 百日咳导致这种重塑？而且，为什么此功能与年龄相关？在未发表和初步研究中 发现百日咳诱导婴儿小鼠肺中肾素 - 血管紧张素系统（RAS）的激活 但是，不需要成年小鼠和百日咳毒素（PT）表达芽孢杆菌诱导的婴儿小鼠pH值。 RAS是高血压发病机理中最重要，最佳研究的系统之一，但具有 与感染诱导的pH无关。提出的实验将检验高RAS的假设 婴儿肺和PT介导的该系统保护成分的抑制作用 致病性RAS信号传导并启动驱动pH发作的病理。监管的关键点 RAS包括血管紧张素转换酶（ACE）的血管紧张素II（ANGII）的形成和降解 分别通过AT1和AT2受体分别和ANGII信号传导，以介导可能的相对动作 是致病性（AT1，血管收缩和增殖）或保护性（AT2，血管舒张和抗增殖） 我们的系统。初步数据还表明，1）婴儿的基础肺血管a含量高于成年人， 2）百日咳B.百日咳下调成年肺中血管紧张素前体基因AGT的表达，但增加 在婴儿肺中的表达，3）B。百日咳在成年肺中下调ACE，但没有婴儿肺和4）基础 婴儿肺的AT2表达明显高于成年肺。这些数据表明，在婴儿中， 需要高的AT2水平来限制通过AT1过度ANGII信号传导的影响。但是，AT2，但不是 AT1，容易受到PT介导的抑制作用，因此在感染过程中产生的PT会产生更大的影响 在婴儿中的Angii信号传导上比成年人的信号。在AIM 1中，百日咳B. b. angii的年龄相关影响 将检查肽的积累以及ACE和ACE2活性。与年龄相关的AT2表达也将是 确定和AT2活性感染的影响将测试。在AIM 2中，Ras和Ras的贡献 PT介导的AT2对百日咳芽孢杆菌诱导的pH和死亡的抑制作用将得到解决。如果我们的假设是 正确，靶向RAS的治疗方法可以挽救严重百日咳的年轻婴儿的生命。

项目成果

Pertussis Toxin Promotes Pulmonary Hypertension in an Infant Mouse Model of Bordetella pertussis Infection.

百日咳毒素在百日咳博德特氏菌感染的婴儿小鼠模型中促进肺动脉高压。

• DOI: 10.1093/infdis/jiab325
• 发表时间: 2022
• 期刊: The Journal of infectious diseases
• 作者: Scanlon,KarenM;Chen,Ling;Carbonetti,NicholasH
• 通讯作者: Carbonetti,NicholasH