Gram-negative sepsis in man often results in fatal hypotensive shock and disseminated intravascular coagulation. It is likely that the pathogenic mechanisms for these changes are initiated by mediators resulting from interactions of bacterial lipopolysaccharide (LPS) with one or more components of the host inflammatory system. It is our contention that one of the most important events is that of LPS binding to and stimulating the mononuclear phagocytes/macrophages (MO) of the host. The experiments proposed here will explore selected aspects of this interaction with in vitro and in vivo models. The proposed studies consist of three aspects; namely (i) Investigation of the biochemical mechanisms of LPS binding to and stimulation of the MO; (ii) Study of the MO product, Tumor Necrosis Factor (TNF), as a mediator of LPS-induced injury; and (iii) Determination of the role of a Ca2+ dependent, membrane bound phospholipase A2 of the MO in regulating arachiodonic acid release and therefore determining the availability of substrate for prostaglandin and leukotriene biosynthesis. Each area to be studied represents new investigations into the mechanism of action of LPS-induced injury. To accomplish this work we will utilize biochemical and immunologic approaches with the long range goal of evaluating findings from in vitro studies with in vivo models of LPS-induced hypotension and DIC. In addition to these specific goals, the data obtained from the proposed studies will be widely applicable to other human diseases that result from the stimulation of the host inflammatory system.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM028485-08
Application #
3275763
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1981-03-01
Project End
1991-06-30
Budget Start
1988-07-01
Budget End
1989-06-30
Support Year
8
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
City
San Diego
State
CA
Country
United States
Zip Code
92037
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