Attenuation of Multiorgan Dysfunction after Shock in the Aged

老年人休克后多器官功能障碍的减弱

• 批准号: 10719678
• 负责人: ERIK KISTLER
• 金额: $ 33.18万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10719678
• 关键词: Acute; Address; Affect; Aftercare; Age; Aging; Amylases; Animals; Attenuated; Blood Coagulation Disorders; Brain Injuries; Carbohydrates; Cardiac Surgery procedures; Cardiovascular Surgical Procedures; Cause of Death; Cells; Characteristics; Chronic; Circulation; Clinical; Digestion; Enteral; Enzyme Inhibitor Drugs; Enzymes; Epithelium; Event; Exposure to; Extracellular Matrix Degradation; Extracellular Matrix Proteins; FDA approved; Female; Food; Functional disorder; Gastrointestinal Surgical Procedures; Gastrointestinal tract structure; Gender; Hemorrhage; Human; Impairment; Incidence; Individual; Infiltration; Inflammation; Injury; Insulin Resistance; Intervention; Intestinal permeability; Intestines; Life; Lipase; Lipids; Matrix Metalloproteinases; Measurement; Measures; Mediating; Membrane; Morbidity - disease rate; Mucins; Nucleotides; Older Population; Operative Surgical Procedures; Organ; Outcome; Pancreas; Pathogenesis; Pathologic; Patients; Peptide Hydrolases; Perfusion; Peripheral; Phase II Clinical Trials; Phase III Clinical Trials; Plasma Proteins; Probability; Process; Productivity; Proteins; Rattus; Research; Resistance; Respiratory distress; Risk; Sepsis; Serine Protease; Shock; Site; Small Intestines; Source; Symptoms; Testing; Time; Tissues; Trauma; Vasoconstrictor Agents; Work; aged; attenuation; blood pressure reduction; enzyme activity; high risk; improved; inhibitor; injured; intestinal barrier; male; meter; mortality; novel strategies; older patient; organ growth; phase 2 study; phase III trial; receptor; senescence; septic patients; stressor; systemic barrier; trauma exposure

Abstract Multiple organ dysfunction is the most common cause of death in injured patients who do not die from brain injury or uncontrolled hemorrhage. Older patients are at highest risk for morbidity with reduced probability to return to productive life after trauma and shock. Current therapy is symptomatic without addressing the underlying mechanisms for the increased morbidity seen in aged individuals. In the past, we advanced the revolutionary idea that multiorgan dysfunction after trauma/shock is due to leak of the powerful digestive enzymes across the intestinal mucosal barrier systemically. Specifically, enteral blockade of digestive proteases in multiple forms of acute shock and sepsis significantly reduces diverse cell dysfunctions, morbidity and mortality; this intervention is currently being tested in FDA-approved Phase III clinical trial after completion of multiple successful Phase II studies in cardiac and gastrointestinal surgery patients. In this application we hypothesize and provide preliminary results that demonstrate chronic escape of digestive enzymes in old animals from the bowel into systemically, with subsequent infiltration into peripheral organs. Digestive enzymes cleave extracellular matrix proteins and membrane receptors, causing cell and organ dysfunctions in the old. When exposed to trauma/shock, the old are subjected to acute leak of digestive enzymes (just like the young) but in addition, must contend with a chronically accumulated digestive enzyme load in their tissues, leading to significantly increased multiorgan dysfunction after shock. Our Overall Objective is to use pretreatment of old rats with inhibitors of digestive enzymes prior to acute trauma/shock to reduce their high level of multiple organ dysfunction and mortality. Our Specific Aims are to (1) determine the accumulation and activities of digestive enzymes in tissues outside the gastrointestinal tract of old versus young rats of both genders. Preliminary results indicate that aged animals have significantly increased levels of digestive enzymes in peripheral tissues and consequently reduced organ function. (2) measure the protease activity and organ dysfunction in the old after treatment with digestive enzyme inhibitors. Our rationale is that one-week blockade of digestive enzymes with competitive inhibitors at low level (µM) reduces their activity in tissues outside the intestine and improves cell and organ function without significantly affecting digestive enzyme activity and digestion inside the small intestine (at mM concentrations). (3) determine multiorgan dysfunction and mortality after trauma/shock in pretreated old animals with attenuated digestive enzyme activity in their tissues outside the intestine. Our studies will bring to light a new mechanism for development of organ and cell dysfunction in the old that is translatable to humans. We will determine the first time the accumulation and temporal activity of digestive enzymes (including, but not limited to serine protease, lipase, amylase) in tissues outside the intestine, develop new approaches to attenuate their activity and reduce multiorgan dysfunction upon exposure to trauma/shock.

摘要 多器官功能障碍是未死于脑的受伤患者最常见的死亡原因 受伤或失控出血。年龄较大的患者发病风险最高，发生 在经历了创伤和震惊之后，回归到有生产力的生活。目前的治疗是有症状的，而不是解决 老年人发病率增加的潜在机制。在过去，我们将 创伤/休克后多器官功能障碍的革命性观点是由于强大的消化系统渗漏 酶系统地穿过肠粘膜屏障。具体地说，肠内阻断消化酶 在多种形式的急性休克和脓毒症中显著减少各种细胞功能障碍、发病率和 死亡率；这种干预措施目前正在FDA批准的第三阶段临床试验中进行测试 心脏和胃肠道手术患者的多项成功的II期研究。在此应用程序中，我们 假设并提供初步结果，证明老年人消化酶的慢性逃逸 动物从肠道进入全身，随后又渗透到外周器官。消化酶 切断细胞外基质蛋白和膜受体，导致老年人细胞和器官功能障碍。 当受到创伤/休克时，老年人会出现消化酶的急性渗漏(就像年轻人一样)。 但除此之外，还必须与组织中长期积累的消化酶负荷作斗争，导致 休克后多器官功能障碍显著增加。我们的总体目标是使用旧的前处理 大鼠急性创伤/休克前应用消化酶抑制剂降低其多器官高水平 功能障碍和死亡率。我们的具体目标是 (1)测定猪胃肠道外组织中消化酶的积累量和活性 无论男女，年长的老鼠与年轻的老鼠。初步结果表明，老年动物的数量显著增加 外周组织中消化酶的水平降低，从而降低器官功能。 (2)测定老年人消化酶治疗后的蛋白水解酶活性及器官功能障碍。 抑制剂。我们的理由是用低水平的竞争性抑制物阻断消化酶一周 (µM)减少它们在肠道外组织中的活性，并改善细胞和器官功能 显著影响消化酶活性和小肠内消化(在毫米波浓度下)。 (3)测定老年动物创伤/休克后多器官功能障碍和死亡率。 肠道外组织中的消化酶活性。 我们的研究将揭示老年人器官和细胞功能障碍发生的新机制 是可以翻译给人类的。我们将首次测定消化系统的积累量和时间活动 肠道外组织中的酶(包括但不限于丝氨酸蛋白酶、脂肪酶、淀粉酶) 新的方法，以减少他们的活动和减少暴露在创伤/休克时的多器官功能障碍。