Mechanisms of Vascular Toxicity from Inhaled Toxicants

吸入毒物的血管毒性机制

• 批准号: 10228021
• 负责人: Matthew J Campen
• 金额: $ 32.46万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10228021
• 关键词: Acute; Address; Adverse effects; Air Pollutants; Air Pollution; Amniotic Fluid; Angiogenesis Inhibitors; Arteries; Atherosclerosis; Atrophic; Beds; Biological Markers; Blood Circulation; Blood Pressure; Blood Vessels; Brain; CD36 gene; CD47 gene; Cardiac; Cardiac Output; Cardiomyopathies; Cardiovascular Physiology; Cardiovascular system; Chronic; Complex; Coronary; Endothelium; Epidemiology; Event; Exposure to; Face; Feedback; Fetal Development; Fetus; Funding; Generations; Growth; Health; Heart Hypertrophy; Histopathology; Hypertension; Hypertrophy; Impairment; Inflammatory; Inhalation; Inhibition of Matrix Metalloproteinases Pathway; Kidney; Knowledge; LOX gene; Life; Lung; Maternal Physiology; Mediator of activation protein; Metabolic; Modeling; Mothers; Organ; Ozone; Particulate Matter; Pathologic; Pathology; Pathway interactions; Peptide Fragments; Peptide Hydrolases; Peptides; Pharmacology; Physiology; Placenta; Placental Insufficiency; Postpartum Period; Pre-Clinical Model; Pre-Eclampsia; Pregnancy; Protein Fragment; Proteins; Proteomics; Rattus; Reporting; Resistance; Role; Serum; Signal Pathway; Signal Transduction; Structure; Testing; Toxic effect; Toxicology; Uterus; adverse birth outcomes; angiogenesis; constriction; design; epidemiology study; hemodynamics; multidisciplinary; neurovascular; ozone exposure; peripartum cardiomyopathy; pollutant; pregnancy disorder; pregnancy hypertension; proteinase In; response; scavenger receptor; toxicant; vasculogenesis

Air pollution exposure has a well-appreciated negative impact on vascular health. Over the past decade, several epidemiological reports have highlighted associations between particulate matter (PM) and ozone (O3) exposures and pregnancy-related events, including preeclampsia, peripartum cardiomyopathy, and adverse birth outcomes. In the past funding cycle, we have greatly expanded our understanding of the crucial pathways that are essential to systemic vascular responses to inhaled toxicants. Both particulate matter (PM) and gaseous pollutants have the capacity to induce proteolytic activity in the lung, leading to the shedding of protein fragments that are bioactive and promote endothelial inflammatory, antiangiogenic, and vasoconstrictive responses. We propose to use this knowledge to study the cardiovascular impacts of inhaled pollutants on maternal physiology during and after pregnancy, periods of vulnerability due to dynamic metabolic demands, cardiovascular remodeling, and angiogenesis. Our discoveries of vasoactive, endogenous protein fragments arising from exposure to inhaled pollutants raises questions for how such mechanisms may impact the highly dynamic cardiovascular system during and after pregnancy. We hypothesize that specific peptide motifs, shed from the lung in response to air pollutant exposure, can drive uterine arterial constriction and reduce placental angiogenesis during pregnancy, promoting the pathological feedback mechanisms that further predispose dams to cardiomyopathic remodeling postpartum. We propose to first characterize the impact that pulmonary peptidase-derived circulating factors arising from inhaled pollutants exert on uterine artery and placental endothelial function. We anticipate that peptide fragments shed from the lung after exposure to ozone O3 or ambient PM can negatively impact uterine artery tone during pregnancy and also impair placental vasculogenesis, leading to pathological placental insufficiency. Further, we will assess the role of pulmonary proteinases in creating the serum bioactive components by pharmacological inhibition of matrix metalloproteinase activity. Second, we will assess how early gestational exposure to pollutants (O3, PM) can perturb hemodynamic and cardiac structural changes in normal and perturbed models of pregnancy. We posit that pollutant-induced generation of constrictive factors, along with the placental antiangiogenic response, will increase uterine artery resistance and maternal systemic arterial blood pressure. Third, we will examine the pollutant-induced perturbation of normal cardiac hypertrophy pathways during pregnancy and involution pathways postpartum. We hypothesize that pollutant exposure during pregnancy will promote maladaptive hypertrophy through suppression of stat3 signaling and also impair cardiac atrophy postpartum, which will lead to irreversible, functional deficits. Lastly, we will investigate proteomic changes in the amniotic fluid relative to O3 concentration and temporal exposure dynamics. The amniotic fluid has a complex origin and may reflect pathological changes to the placenta or fetus, but it may also influence fetal development. These studies are designed to address a specific and important period of vulnerability that has been largely unstudied from the perspective of adverse environemental impacts on the mother.

空气污染暴露对血管健康产生了充分的负面影响。在过去的十年中， 几份流行病学报告突出了颗粒物（PM）和臭氧（O3）之间的关联 暴露和与妊娠有关的事件，包括先兆子痫，心肌病和不良事件 出生结果。在过去的资金周期中，我们大大扩展了对关键的理解 对吸入毒物的全身血管反应至关重要的途径。两个颗粒物（PM） 气态污染物具有诱导肺部蛋白水解活性的能力，导致脱落 生物活性并促进内皮炎症，抗血管生成和 血管收缩的反应。我们建议利用这些知识研究吸入的心血管影响 怀孕期间和之后的孕产妇生理学污染物，由于动态而引起的脆弱时期 代谢需求，心血管重塑和血管生成。我们的血管活性，内源性的发现 暴露于吸入污染物引起的蛋白质碎片提出了有关这种机制如何可能如何的问题 在怀孕期间和后影响高度动态的心血管系统。我们假设该具体 从肺部响应空气污染物暴露的肽图案可以驱动子宫动脉收缩 并减少怀孕期间的胎盘血管生成，促进病理反馈机制 进一步的大坝倾向于心肌疗法的重塑产后。我们建议首先描述 影响肺肽酶衍生的循环因子，该因子引起的污染物在子宫上施加 动脉和胎盘内皮功能。我们预计肽片段在 暴露于臭氧O3或环境PM会对怀孕期间子宫动脉张力产生负面影响 损害胎盘血管生成，导致病理胎盘功能不全。此外，我们将评估角色 通过药理学抑制基质创建血清生物活性成分的肺蛋白酶的 金属蛋白酶活性。其次，我们将评估妊娠暴露于污染物（O3，PM）的早期暴露 正常和扰动妊娠模型中的扰动血液动力学和心脏结构变化。我们认为 污染物引起的收缩因子产生以及胎盘抗血管生成反应将 增加子宫动脉抗性和母体全身动脉血压。第三，我们将检查 怀孕期间污染物引起的正常心肥大途径的扰动 产后途径。我们假设怀孕期间的污染物暴露会促进适应不良 通过抑制STAT3信号传导和肥大，也损害了心脏萎缩产后，这将导致 不可逆的功能缺陷。最后，我们将研究相对于羊水的蛋白质组学变化 O3浓度和时间暴露动力学。羊水具有复杂的起源，可能反映 胎盘或胎儿的病理变化，但也可能影响胎儿发育。这些研究是 旨在解决特定而重要的脆弱时期 对母亲的不利环境影响的观点。