Immunomodulation of Sophorolipids in Sepsis

槐糖脂在脓毒症中的免疫调节作用

• 批准号: 7536365
• 负责人: Maja Nowakowski
• 金额: $ 10万
• 依托单位: BIOMEDICA MANAGEMENT CORPORATION
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7536365
• 关键词: Acylation; Adverse effects; Affect; Animal Experiments; Anti-Bacterial Agents; Anti-Inflammatory Agents; Anti-inflammatory; Antibiotic Therapy; Antibiotics; Antimicrobial Effect; Biological; Biomedical Engineering; Bioterrorism; Blood Coagulation Disorders; Cell Adhesion Molecules; Cell surface; Characteristics; Chemical Structure; Chemicals; Class; Clinical; Clinical Management; Condition; Data; Data Analyses; Designer Drugs; Development; Dose; Drug Formulations; Drug Kinetics; Endotoxins; Exhibits; Exposure to; Feasibility Studies; Galactosamine; Glycolipids; Gram-Negative Bacteria; Hemorrhage; Hospitals; Human; Immune response; Immunologist; In Vitro; Individual; Infection; Inflammatory; Inflammatory Response; Intensive Care; Interleukin-1; Interleukin-6; Intra-abdominal; Intravenous; Knowledge; Laboratories; Lead; Ligation; Link; Lipase; Lipid A; Lipopolysaccharides; Local Anti-Infective Agents; Membrane; Methods; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; Operative Surgical Procedures; Patients; Phase; Phase II Clinical Trials; Production; Property; Protective Agents; Protein Isoforms; Public Health; Puncture procedure; Range; Rate; Reaction; Regulation; Research Design; Rodent; Selectins; Sepsis; Sepsis Syndrome; Septic Shock; Signaling Molecule; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Specialist; Therapeutic; Therapeutic Agents; Time; Toxic effect; Transforming Growth Factor beta; Trauma; Viral; Yeasts; amidation; analog; antimicrobial; carboxyl group; cytokine; dosage; hydroxyl group; immunoregulation; in vivo; interest; intraperitoneal; intravenous injection; microbial; mortality; novel strategies; novel therapeutics; protective effect; receptor; research study; response; septic

DESCRIPTION (provided by applicant): Microbial sophrolipids are a new a class of membrane-derived glycolipids that have wide ranging potential in clinical practice. We have demonstrated that sophorolipids possess remarkable anti-inflammatory effects in various inflammatory conditions including sepsis. Preliminary data from our laboratory show that natural sophrolipids can be isolated in quantities sufficient for animal experiments. In vivo experiments showed that both intraperitoneal and intravenous injection of natural and select sophrolipid components during cecal ligation and puncture and endotoxin (galactosamine-LPS model) induced rodent sepsis models have a protective effect against the morbidity of systemic sepsis and that these protective effects persisit when sophorolipids are administred duraing and after the sepsis insult. In vitro experiments indicate that sophrolipids have immunomodulatory characteristics after exposure to lipopolysaccharide, specifically by decreasing production of pro-inflammatory cytokines. Furthermore, sophorolipids affect other important anti- inflammatory immune responses including regulation of cell surface adhesion molecule expression, and the ability to exert antimicrobial effects. We have identified eight primary derivatives of sophrolipids in the natural mixture, and developed methods to prepare each in sufficient quantities and purity for animal experiments. Preliminary data demonstrate that these isoforms selectively modulate cytokine expression in vitro. We propose to study each sophrolipid derivative and identify its potential use in the clinical management of sepsis. The Specific Aims of this SBIR Phase I are to determine whether synthetically prepared sophrolipids or their individual isoofrm components are biologically active, establish an effective dose, and assess the effect of delayed dosing on survival in intra-abdominal sepsis The company has established a unique team of bio-organic chemists, trauma specialists, and molecular immunologists to synthesize the sophrolipid components, conceive experiments, and analyze data in an academic department of surgery. Ultimately this partnership will lay the groundwork for the development of a unique class of designer drugs for the treatment of intra-abdominal sepsis. We postulate that sophorolipids are novel therapeutic candidates for the treatment of sepsis and act primarily through decreasing inflammatory cytokines and elicit other synergistic anti-inflammatory mechanisms. Knowledge obtained from the proposed studies will bring this promising therapy closer to human application. PUBLIC HEALTH RELEVANCE: Septic shock is a common and frequent cause of mortality in hospitals. There are approximately 750,000 new sepsis cases each year, with at least 210,000 fatalities. Bacterial bioterrorism agents constitute an additional treat capable of causing infections that lead to systemic inflammatory response syndrome (SIRS) and septic shock often resulting in multiple organ dysfunction syndrome. Current treatments for septic shock caused by gram-negative bacteria include antibiotic therapy and intensive-care support. However, many antibiotics may be potentially harmful when given in the setting of gram-negative sepsis. Attempts to use immunomodulation to control sepsis have met with mixed results. Although there is one approved therapy for sepsis , (XigrisTM) it is contraindicated in patients with recent or active bleeding/coagulopathy making it unsuitable for use in many septic, traumatic or surgical patients. There is a great interest in identifying novel strategies to treat not only infections, but also the underlying inflammatory responses; agents that can modulate inflammatory responses, in addition to having direct antimicrobial activity. We have demonstrated that sophorolipids were able to decrease sepsis related mortality in experimental sepsis and that recent sophorolipids possess anti-bacterial anti-viral and anti-inflammatory properties. Indeed the development of glycolipid structural analogues can have a very important therapeutic impact in the treatment of septic patients.

描述（由申请人提供）：微生物糖脂是一类新的膜源性糖脂，在临床实践中具有广泛的潜力。我们已经证明，槐脂具有显著的抗炎作用，在各种炎症条件下，包括败血症。我们实验室的初步数据表明，天然磷脂可以分离出足够数量的动物实验。体内实验表明，在盲肠结扎和穿刺以及内毒素（半乳糖胺-脂多糖模型）诱导的啮齿动物脓毒症模型中，腹腔和静脉注射天然和选择的皂角脂成分对全身性脓毒症的发病具有保护作用，并且在脓毒症损伤期间和之后给予皂角脂时，这种保护作用持续存在。体外实验表明，磷脂暴露于脂多糖后具有免疫调节特性，特别是通过减少促炎细胞因子的产生。此外，槐脂还影响其他重要的抗炎免疫反应，包括调节细胞表面粘附分子的表达，以及发挥抗菌作用的能力。我们在天然混合物中鉴定了八种主要的磷脂衍生物，并开发了制备足够数量和纯度的方法用于动物实验。初步数据表明，这些异构体在体外选择性地调节细胞因子的表达。我们建议研究每一种皂荚脂衍生物，并确定其在败血症临床治疗中的潜在用途。该SBIR一期的具体目的是确定合成制备的树脂或其单独的异质成分是否具有生物活性，确定有效剂量，并评估延迟给药对腹内败血症患者生存的影响。该公司建立了一个由生物有机化学家、创伤专家和分子免疫学家组成的独特团队来合成树脂成分，构思实验，在外科的学术部门分析数据。最终，这种伙伴关系将为开发一种独特的设计药物来治疗腹内败血症奠定基础。我们假设槐脂是治疗败血症的新候选药物，主要通过降低炎症细胞因子和引发其他协同抗炎机制起作用。从拟议的研究中获得的知识将使这种有前途的疗法更接近于人类应用。公共卫生相关性：感染性休克是医院常见和常见的死亡原因。每年大约有75万例新的败血症病例，其中至少21万例死亡。细菌生物恐怖制剂是一种额外的治疗手段，能够引起感染，导致全身炎症反应综合征（SIRS）和感染性休克，通常导致多器官功能障碍综合征。目前对革兰氏阴性菌引起的感染性休克的治疗包括抗生素治疗和重症监护支持。然而，在革兰氏阴性败血症的情况下，许多抗生素可能有潜在的危害。尝试使用免疫调节来控制败血症的结果好坏参半。虽然有一种被批准的治疗败血症的药物（XigrisTM），但它禁忌用于近期或活动性出血/凝血功能障碍的患者，因此不适合用于许多败血症，创伤或手术患者。有很大的兴趣确定新的策略，不仅治疗感染，而且潜在的炎症反应；除了具有直接抗菌活性外，还能调节炎症反应的药物。我们已经证明槐脂能够降低实验性败血症的败血症相关死亡率，并且最近的槐脂具有抗菌、抗病毒和抗炎特性。事实上，糖脂结构类似物的发展对脓毒症患者的治疗有非常重要的影响。