Immunomodulation of Sophorolipids in Sepsis
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AbstractDESCRIPTION (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 var ious 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 injecti on 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 pers isit 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-inflammato ry 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 derivati ves 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 biological ly 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 sophr olipid 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 post ulate 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 b ring 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 cause d 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 mixe d 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 i n 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 prope
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