Immunomodulation of Sophorolipids in Sepsis

槐糖脂在脓毒症中的免疫调节作用

基本信息

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
项目类别：
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

项目摘要

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衍生糖脂，在临床实践中具有广泛的潜力。我们已经证明槐糖脂在包括脓毒症在内的各种炎症性疾病中具有显着的抗炎作用。我们实验室的初步数据表明，可以分离出足以进行动物实验的天然槐糖脂。体内实验表明，在盲肠结扎和穿刺过程中腹膜内和静脉注射天然和选择的槐糖脂成分以及内毒素（半乳糖胺-LPS模型）诱导的啮齿动物脓毒症模型对系统性脓毒症的发病率具有保护作用，并且这些保护作用在以下情况下持续存在：在败血症期间和之后给予槐糖脂。体外实验表明，槐糖脂在接触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，槐糖脂影响其他重要的抗炎免疫反应，包括细胞表面粘附分子表达的调节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槐脂的初级衍生物，并开发了方法来制备足够数量和纯度的每种衍生物以用于动物实验。初步数据表明，这些异构体在体外选择性调节细胞因子的表达。我们建议研究每种槐脂衍生物并确定其在脓毒症临床治疗中的潜在用途。该 SBIR 第一阶段的具体目标是确定合成制备的槐糖脂或其单独的异构体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脓毒症患者生存的影响。该公司已建立了一个独特的团队生物有机化学家、创伤专家和分子免疫学家在外科学术部门合成槐脂成分、构思实验并分析数据。最终，这种伙伴关系将为开发一类独特的治疗腹内脓毒症的设计药物奠定基础。我们假设槐糖脂是治疗脓毒症的新型候选药物，主要通过减少炎症细胞因子并引发其他协同抗炎机制发挥作用。从拟议研究中获得的知识将使这种有前景的疗法更接近人类应用。公共卫生相关性：感染性休克是医院常见且常见的死亡原因。每年大约有 75 万新发脓毒症病例，至少有 21 万人死亡。细菌生物恐怖剂是一种额外的治疗方法，能够引起感染，导致全身炎症反应综合征 (SIRS) 和脓毒性休克，通常导致多器官功能障碍综合征。目前治疗革兰氏阴性菌引起的感染性休克的方法包括抗生素治疗和重症监护支持。然而，许多抗生素在革兰氏阴性败血症的情况下使用可能具有潜在的危害。使用免疫调节来控制脓毒症的尝试取得了不同的结果。尽管有一种已获批准的脓毒症疗法 (XigrisTM)，但它对于近期或活动性出血/凝血障碍的患者是禁忌的，因此不适合用于许多脓毒症、创伤或手术患者。人们对寻找不仅治疗感染而且治疗潜在炎症反应的新策略非常感兴趣。除了具有直接抗菌活性之外，还可以调节炎症反应的药物。我们已经证明，槐糖脂能够降低实验性败血症中败血症相关的死亡率，并且最近的槐糖脂具有抗菌、抗病毒和抗炎特性。事实上，糖脂结构类似物的开发可以对脓毒症患者的治疗产生非常重要的治疗影响。