Plasma concentrations of LDL and HDL rapidly and markedly decline in acutely ill, septic humans with known bacterial infections. This acute phase response is felt to be mediated by inflammatory cytokines such as TNF-alpha and IL6 which are known from animal studies to strongly perturb lipid metabolism. Surprisingly, there have been no previous studies of the effect of endotoxin on human lipid and apolipoprotein metabolism. Our plan is to use an established and safe model of human endotoxemia with intravenous endotoxin and stable isotopic tracers in normal volunteers studied in the controlled setting of the Rockefeller GCRC to understand the mechanism(s) for the declines in LDL and HDL lipoproteins. The role of cytokine mediators produced in response to endotoxin will also be evaluated. Once the magnitude, time course, variability and mediators of the lipoprotein changes are characterized, then the second phase of the study in normal volunteers will be designed using an intravenous phospholipid-rich emulsion infused with and without endotoxin. This lipid emulsion, developed by the Rogosin Institute, is expected to bind endotoxin, raise lipid levels, and reverse the metabolic alterations induced by endotoxin. It may ultimately be used to enhance the host lipoprotein defense against endotoxin and reduce the immense mortality and morbidity associated with septic shock.

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
General Clinical Research Centers Program (M01)
Project #
3M01RR000102-35S1
Application #
6264665
Study Section
Project Start
1997-12-01
Project End
1999-11-30
Budget Start
1998-10-01
Budget End
1999-09-30
Support Year
35
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Rockefeller University
Department
Type
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Bagdade, John D; Jilma, Bernd; Hudgins, Lisa C et al. (2018) LpA-II:B:C:D:E: a new immunochemically-defined acute phase lipoprotein in humans. Lipids Health Dis 17:127
Butelman, Eduardo Roque; Bacciardi, Silvia; Maremmani, Angelo Giovanni Icro et al. (2017) Can a rapid measure of self-exposure to drugs of abuse provide dimensional information on depression comorbidity? Am J Addict 26:632-639
Ansar, Muhammad; Raza, Syed Irfan; Lee, Kwanghyuk et al. (2015) A homozygous missense variant in type I keratin KRT25 causes autosomal recessive woolly hair. J Med Genet 52:676-80
Rosenbaum, Michael; Leibel, Rudolph L (2014) 20 years of leptin: role of leptin in energy homeostasis in humans. J Endocrinol 223:T83-96
Ohmatsu, Hanako; Humme, Daniel; Gulati, Nicholas et al. (2014) IL32 is progressively expressed in mycosis fungoides independent of helper T-cell 2 and helper T-cell 9 polarization. Cancer Immunol Res 2:890-900
Alemán, José O; Eusebi, Leonardo H; Ricciardiello, Luigi et al. (2014) Mechanisms of obesity-induced gastrointestinal neoplasia. Gastroenterology 146:357-373
Barbuto, Scott; Idoyaga, Juliana; Vila-Perelló, Miquel et al. (2013) Induction of innate and adaptive immunity by delivery of poly dA:dT to dendritic cells. Nat Chem Biol 9:250-6
Guo, Xiuyang; Dhodapkar, Kavita M (2012) Central and overlapping role of Cathepsin B and inflammasome adaptor ASC in antigen presenting function of human dendritic cells. Hum Immunol 73:871-8
Dustin, Lynn B; Charles, Edgar D (2012) Primary, post-primary and non-specific immunoglobulin M responses in HCV infection. Antivir Ther 17:1449-52
Pendyala, Swaroop; Walker, Jeanne M; Holt, Peter R (2012) A high-fat diet is associated with endotoxemia that originates from the gut. Gastroenterology 142:1100-1101.e2

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