We shall study how toxic lipopolysaccharide (LPS) activates macrophages and B cells. For this study, we shall use the petaacyl diphosphoryl lipid A derived from the nontoxic lipopolysaccharide of Rhodobacter sphaeroides (Rs-DPLA) as the competitive inhibitor of the action of a highly purified and toxic deep rough chemotype LPS of Escherichia coli D31m4 (Re-LPS). We shall study the effect of Rs-DPLA (and its analogs) on: (a) binding of toxic LPS to macrophages (using [14C]-labeled Ra-LPS from E. coli); (b) the appearance of early LPS-inducible genes and protein tyrosine phosphorylation; (c) activation of NF-kappaB and Oct-2 in 7OZ/3 pre-B cells. From these studies, we hope to elucidate the mechanism of activation of the immune cells by toxic LPS which triggers the shock syndrome. We shall attempt to develop a novel multiple drug therapy for the prevention of Gram-negative septic shock which is a life-threatening medical problem associated with high mortality. The major component in this therapy will be Rs-DPLA. It is a potent antagonist of toxic LPS (i.e., against the Re-LPS) and induces corticosteroids in vivo. Thus, we shall prevent the induction of the two important mediators of septic shock, TNF-alpha and IL-1beta, with Rs-DPLA, and at a later stage of sepsis neutralize or control the level of another well-known mediator of shock, IFN-gamma, by the use of either anti-IFN-gamma antibody or cyclosporin A. Antibiotics and other drugs will also be tested in combination with those listed above. The murine galactosamine-sensitized and the cecal ligation and puncture shock models will be used for this study. We shall also study how Rs-DPLA/Re-LPS induces corticosteroids in vivo, which probably involves the hypothalamic-pituitary-adrenal axis. Rs-DPLA might become one of the important component in the development of an effective multiple-drug therapy for the prevention of mitigation of septic shock.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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University of Wisconsin Madison
Schools of Earth Sciences/Natur
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Qureshi, Asaf A; Zuvanich, Eleanor G; Khan, Dilshad A et al. (2018) Proteasome inhibitors modulate anticancer and anti-proliferative properties via NF-kB signaling, and ubiquitin-proteasome pathways in cancer cell lines of different organs. Lipids Health Dis 17:62
Qureshi, Asaf A; Khan, Dilshad A; Mushtaq, Shahida et al. (2018) ?-Tocotrienol feeding modulates gene expression of EIF2, mTOR, protein ubiquitination through multiple-signaling pathways in chronic hepatitis C patients. Lipids Health Dis 17:167
Silswal, Neerupma; Reis, Julia; Qureshi, Asaf A et al. (2017) Of Mice and Men: Proteasome's Role in LPS-Induced Inflammation and Tolerance. Shock 47:445-454
Qureshi, Asaf A; Khan, Dilshad A; Mahjabeen, Wajiha et al. (2013) Nutritional Supplement-5 with a Combination of Proteasome Inhibitors (Resveratrol, Quercetin, ?-Tocotrienol) Modulate Age-Associated Biomarkers and Cardiovascular Lipid Parameters in Human Subjects. J Clin Exp Cardiolog 4:
Qureshi, Asaf A; Khan, Dilshad A; Mahjabeen, Wajiha et al. (2012) Suppression of Nitric Oxide Production and Cardiovascular Risk Factors in Healthy Seniors and Hypercholesterolemic Subjects by a Combination of Polyphenols and Vitamins. J Clin Exp Cardiolog S5:8
Beasley, Ashley S; Cotter, Robert J; Vogel, Stefanie N et al. (2012) A variety of novel lipid A structures obtained from Francisella tularensis live vaccine strain. Innate Immun 18:268-78
Liu, Xun; Silverstein, Peter S; Singh, Vijeta et al. (2012) Methamphetamine increases LPS-mediated expression of IL-8, TNF-? and IL-1? in human macrophages through common signaling pathways. PLoS One 7:e33822
Qureshi, Nilofer; Morrison, David C; Reis, Julia (2012) Proteasome protease mediated regulation of cytokine induction and inflammation. Biochim Biophys Acta 1823:2087-93
Qureshi, Asaf A; Guan, Xiu Qin; Reis, Julia C et al. (2012) Inhibition of nitric oxide and inflammatory cytokines in LPS-stimulated murine macrophages by resveratrol, a potent proteasome inhibitor. Lipids Health Dis 11:76
Rockwell, Cheryl E; Monaco, John J; Qureshi, Nilofer (2012) A critical role for the inducible proteasomal subunits LMP7 and MECL1 in cytokine production by activated murine splenocytes. Pharmacology 89:117-26

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