S1P-fluid therapy to reduce hemorrhagic shock & intoxication-induced injury

S1P 液体疗法可减少失血性休克

• 批准号: 9310336
• 负责人: JEROME W BRESLIN
• 金额: $ 28.78万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-15 至 2020-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9310336
• 关键词: Acute; Adult; Agonist; Alcohol-Induced Disorders; Alcoholic Intoxication; Alcohols; Apoptotic; Architecture; Biochemical; Biological Preservation; Blood Pressure; Cell Survival; Clinical; Complement; Complex; Confocal Microscopy; Conscious; Data; Development; Dose; Edema; Effectiveness; Endothelial Cells; Ethanol Metabolism; Extravasation; Fluid Therapy; Foundations; Functional disorder; Goals; Health Care Costs; Hemorrhage; Hemorrhagic Shock; Hypotension; Individual; Inflammation; Inflammatory; Injury; Innovative Therapy; Intercellular Junctions; Intervention; Intoxication; Investigation; Knowledge; Laboratory Finding; Lasers; Life; Lipids; Liquid substance; Mediating; Mesentery; Microvascular Permeability; Mission; Modeling; Outcome; Pathway interactions; Patients; Pharmacology; Physiological; Protocols documentation; Public Health; Rattus; Research; Resuscitation; Rodent Model; Role; Severities; Shock; Signal Transduction; Small Interfering RNA; Sphingosine-1-Phosphate Receptor; System; Testing; Therapeutic; Time; Trauma; Trauma patient; Traumatic injury; United States National Institutes of Health; Work; alcohol exposure; binge drinking; design; disability; effective therapy; improved; in vivo; in vivo Model; innovation; intravenous administration; intravital microscopy; knock-down; mimetics; monolayer; postcapillary venule; pre-clinical; prevent; receptor; repaired; sphingosine 1-phosphate; success; translational impact; trend

There is a fundamental gap in understanding pertaining to why standard fluid resuscitation protocols work so poorly in alcohol-intoxicated trauma victims with hemorrhagic shock, representing a significant portion of all trauma cases. Continued existence of this gap represents an important problem, because until it is filled, the development of effective therapies to prevent systemic inflammation and prolonged hypotension in trauma patients will continue to be unsuccessful. The long-term goal of this study is to develop effective therapies to reduce elevated microvascular permeability and edema. The overall objective in this application is to determine the effectiveness of the bioactive lipid sphingosine-1-phosphate (S1P) for ameliorating alcohol-induced elevated microvascular permeability. The central hypothesis is that S1P reduces alcohol/injury-induced microvascular hyperpermeability by activating S1P receptor-1 (S1P1R), causing initial junctional repair, and longer term pro-survival signals, thereby promoting a healthy endothelial barrier. The rationale for the proposed research is that it will provide important details obtained from a relevant model of combined alcohol intoxication and hemorrhagic injury that will be needed for development of effective fluid resuscitation strategies. Guided by strong preliminary data, the central hypothesis will be tested with three specific aims: Aim 1 is to determine the optimal dose and window of opportunity for S1P therapy after combined alcohol intoxication and hemorrhagic shock. Aim 2 is to test selective S1P1R agonist therapies to ameliorate alcohol/shock-induced microvascular hyperpermeability and hypotension. Aim 3 is to determine the extent to which S1P-induced, RhoA-mediated junctional enhancement and cell survival signals contribute to ameliorate endothelial barrier dysfunction. These aims will utilize an established conscious rat model of combined alcohol intoxication and hemorrhagic shock and resuscitation. The experimental endpoints will be the extent to which S1P or S1P1R agonists ameliorate hypotension, microvascular leakage in the gut, and gut barrier injury. The in vivo studies will be complemented by an investigation of the ability of S1P or S1P1R agonists to improve barrier integrity of cultured microvascular endothelial cell monolayers exposed to alcohol. Pharmacologic antagonists or specific siRNA knockdown will be used to assess the role of the S1P1R. A combination of intravital microscopy, laser confocal microscopy, and biochemical analyses will be used to study microvascular endothelial junctional architecture and survival signals in individual endothelial cells of postcapillary venules. The contribution of the proposed research will be significant because it will provide proof of concept from a rodent model that alcohol-induced amplifications of elevated microvascular permeability contribute to the lack of success with current clinical interventions used to resuscitate alcohol-intoxicated hemorrhagic shock patients. The proposed research is innovative because it represents a substantive departure from the status quo by investigating a therapeutic approach to ameliorate alcohol intoxication-induced microvascular hyperpermeability as the key approach to stabilize blood pressure.

关于为什么标准的液体复苏方案如此有效，在理解上存在根本性的差距