Etiology of microvascular changes in Gram-positive sepsis: mechanisms and therape

革兰氏阳性脓毒症微血管变化的病因学：机制和治疗

• 批准号: 8239374
• 负责人: Perenlei Enkhbaatar
• 金额: $ 28.85万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2017-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239374
• 关键词: Accounting; Achievement; Acquired Immunodeficiency Syndrome; Affect; Agonist; Angiopoietin-2; Animal Experimentation; Antibiotics; Argipressin; Attenuated; Blood Pressure; Blood Vessels; Cardiovascular system; Cause of Death; Cell Culture Techniques; Clinical; Clinical Research; Communities; Development; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Etiology; Evaluation; Extravasation; Fluid Balance; Functional disorder; Goals; Growth Factor; Health; Heart; Histology; Hospitals; Human; Hypotension; In Vitro; Infection; Intensive Care Units; Knowledge; Lead; Liquid substance; Lung; Lymph; MAP Kinase Gene; Measurement; Mediating; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Nitrates; Nitric Oxide; Pathway interactions; Patients; Permeability; Peroxonitrite; Plasma; Pneumonia; Production; Proteins; Reactive Nitrogen Species; Receptor Activation; Research; Resistance; Sepsis; Septic Shock; Severities; Sheep; Skeletal Muscle; Source; Staphylococcus aureus; Stream; Structure of parenchyma of lung; Therapeutic; V2 Receptors; Vascular Endothelial Growth Factors; Vascular Permeabilities; Weight; argipressin receptor; catalyst; clinically relevant; human tissue; indexing; mRNA Expression; methicillin resistant Staphylococcus aureus; mortality; novel; pressure; prevent; protein expression; receptor; septic; soft tissue; tissue/cell culture; translational study

DESCRIPTION (provided by applicant): Methicillin-resistant Staphylococcus aureus (MRSA) infection has become a serious health problem both in the community and in hospitals. ~20,000 people die annually in the U.S. because of MRSA, the rate is greater than those die from AIDS. The goal of the present proposal is to characterize novel mechanistic aspects of microvascular hyper-permeability during MRSA pneumonia/sepsis and offer novel and efficient therapeutic options that will reduce morbidity and mortality. Our general hypothesis is that stimulation of arginine vasopressin V1a receptors (V1aR) will mitigate MRSA sepsis-induced vascular hyper-permeability and reverse the hypotension, whereas the stimulation of the arginine vasopressin V2 receptors (V2R) will augment the vascular hyper- permeability and will not affect the hypotension. We propose to elucidate the downstream mechanisms, focusing on the interaction between V1aR, V2R, reactive nitrogen species (RNS), and potent angiogenic growth factors such as angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF). Aim 1: In an ovine MRSA sepsis model, establish mechanisms of severe vascular hyper-permeability, focusing on opposing effects of V1aR and V2R on release of potent permeability factor Ang-2 and microvascular hyper- permeability. Hypotheses: 1) V1aR activation reduces vascular hyper-permeability by inhibiting Ang-2 release; 2) V2R stimulation increases vascular hyper-permeability by promoting Ang-2 release; 3) a selective V1aR agonist is superior to a mixed V1aR/V2R agonist arginine vasopressin (AVP) for preventing cardiovascular collapse. Aim 2: In an ovine MRSA sepsis model, determine that novel and selective V1aR agonist will mitigate severe vascular leakage by preventing RNS formation through inhibiting excessive nitric oxide production. The down- stream mechanisms of how RNS cause vascular leakage will be also determined. Hypotheses: 1) The vascular hyper-permeability caused by RNS is mediated by Ang-2 release and VEGF expression; 3) RNS cause hypo- reactivity of V1aR: 3) V1aR agonist reduces RNS formation by inhibiting excessive nitric oxide production. Aim 3: In human cell culture studies, determine the molecular mechanisms of MRSA-induced severe vascular hyper-permeability with especial reference to downstream mechanisms of how V2R activation causes, and of how V1aR agonist inhibits, vascular hyper-permeability in MRSA sepsis. Hypotheses: 1) V2R stimulation pro- motes Ang-2 release in a MAPK-dependent pathway; 2) The V1aR agonist suppresses V2R and thus prevents Ang-2 release; 3) V1aR agonist modulates interaction of Ang-2 with Tie-2 receptors, most probably by sup- pressing the Tie-2 activation; 4) VEGF promotes Ang-2 release by its direct action or via V2R stimulation; 5) V2R activation in MRSA sepsis is mediated by RNS; 6) V1aR is oxidized/nitrated by RNS. To achieve the aims, the study will utilize a novel ovine model of MRSA sepsis and sophisticated cell culture techniques. We are particularly optimistic about the possibility that the proposed research will lead to translational clinical studies for agonists of the selective V1aR and peroxynitrite modulators. PUBLIC HEALTH RELEVANCE: Sepsis and septic shock are the most common cause of death in intensive care units, accounting for mortality rates of up to 70%. Methicillin-resistant Staphylococcus aureus is a frequent source of sepsis associated with high mortality because it is resistant to most of the conventional antibiotics. This study investigates the pathophysiology of sepsis/septic shock induced by methicillinresistant Staphylococcus aureus and offers novel treatment options.

描述（由申请人提供）：耐甲氧西林金黄色葡萄球菌（MRSA）感染已成为社区和医院的严重健康问题。在美国，每年约有20，000人死于MRSA，这一比率高于死于艾滋病的人数。本提案的目标是表征MRSA肺炎/脓毒症期间微血管高通透性的新机制方面，并提供将降低发病率和死亡率的新的和有效的治疗选择。我们的一般假设是，精氨酸加压素V1 a受体（V1 aR）的刺激将减轻MRSA脓毒症诱导的血管高渗透性并逆转低血压，而精氨酸加压素V2受体（V2 R）的刺激将增加血管高渗透性而不会影响低血压。我们建议阐明下游机制，重点是V1 aR，V2 R，活性氮类（RNS）和有效的血管生成因子，如血管生成素-2（Ang-2）和血管内皮生长因子（VEGF）之间的相互作用。目标1：在绵羊MRSA脓毒症模型中，建立严重血管通透性过高的机制，重点是V1 aR和V2 R对强效通透性因子Ang-2释放和微血管通透性过高的相反作用。假设条件：1）V1 aR激活通过抑制Ang-2释放降低血管通透性过高; 2）V2 R刺激通过促进Ang-2释放增加血管通透性过高; 3）选择性V1 aR激动剂上级混合V1 aR/V2 R激动剂精氨酸加压素（AVP）用于预防心血管崩溃。目标二：在绵羊MRSA脓毒症模型中，确定新型和选择性V1 aR激动剂通过抑制过量一氧化氮产生来防止RNS形成，从而减轻严重的血管渗漏。RNS如何引起血管渗漏的下游机制也将被确定。假设条件：1）RNS引起的血管通透性增高是由Ang-2释放和VEGF表达介导的; 3）RNS引起V1 aR的低反应性; 3）V1 aR激动剂通过抑制过量的一氧化氮产生来减少RNS的形成。目标三：在人体细胞培养研究中，确定MRSA诱导的严重血管高通透性的分子机制，特别是参考V2 R激活如何导致以及V1 aR激动剂如何抑制MRSA脓毒症中血管高通透性的下游机制。假设条件：1）V2 R刺激促进MAPK依赖性途径中的Ang-2释放; 2）V1 aR激动剂抑制V2 R并因此阻止Ang-2释放; 3）V1 aR激动剂调节Ang-2与Tie-2受体的相互作用，最可能通过抑制Tie-2活化; 4）VEGF通过其直接作用或通过V2 R刺激促进Ang-2释放; 5）MRSA脓毒症中V2 R活化由RNS介导; 6）V1 aR被RNS氧化/硝化。为了实现这些目标，该研究将利用新型的MRSA败血症绵羊模型和复杂的细胞培养技术。我们特别乐观的可能性，拟议的研究将导致翻译的选择性V1 aR和过氧亚硝酸盐调节剂的激动剂的临床研究。 公共卫生关系：脓毒症和脓毒性休克是重症监护病房最常见的死亡原因，占死亡率高达70%。耐甲氧西林金黄色葡萄球菌是败血症的常见来源，与高死亡率相关，因为它对大多数常规抗生素具有耐药性。本研究探讨了耐甲氧西林金黄色葡萄球菌诱导的脓毒症/脓毒性休克的病理生理学，并提供了新的治疗选择。