Novel Pharmacologic Approaches to the Management of Sepsis: Targeting the Host Inflammatory Response

Overview

Journal Recent Pat Inflamm Allergy Drug Discov

Publisher Bentham Science Publishers

Specialties Allergy & Immunology
Pharmacology

Date 2009 Jun 13

PMID 19519586

Citations 30

Authors

Derek S Wheeler

Basilia Zingarelli

William J Wheeler

Hector R Wong

Affiliations

Soon will be listed here.

Abstract

Sepsis is currently the 10(th) leading cause of death overall and accounts for significant healthcare expenditures in the developed world. There are now more deaths attributable to sepsis than coronary artery disease, stroke, or cancer, and it is widely believed that the incidence of sepsis and sepsis-related mortality will continue to rise. Based on these sobering statistics, there is great interest in identifying novel treatments for managing critically ill children and adults with sepsis. Unfortunately, to date, there have been very few successful therapeutic agents employed in the clinical setting. Despite these disappointing results, new therapeutic agents continue to be identified, and there is reason for optimism and hope for the future. Herein, we will briefly review several novel therapeutic adjuncts for the management of critically ill patients with sepsis. We will largely focus on those therapies that directly target the host inflammatory response, specifically those that result in activation of the transcription factor, nuclear factor (NF)-kappaB. We will also reference some of the patents recently filed that pertain to the host innate immune response and sepsis.

Citing Articles

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Dexmedetomidine attenuates inflammation and organ injury partially by upregulating Nur77 in sepsis.

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References

Li X, Cui X, Li Y, Fitz Y, Hsu L, Eichacker P . Parthenolide has limited effects on nuclear factor-kappa beta increases and worsens survival in lipopolysaccharide-challenged C57BL/6J mice. Cytokine. 2006; 33(6):299-308. DOI: 10.1016/j.cyto.2006.03.002. View

Klune J, Dhupar R, Cardinal J, Billiar T, Tsung A . HMGB1: endogenous danger signaling. Mol Med. 2008; 14(7-8):476-84. PMC: 2323334. DOI: 10.2119/2008-00034.Klune. View

Zhang X, Mosser D . Macrophage activation by endogenous danger signals. J Pathol. 2007; 214(2):161-78. PMC: 2724989. DOI: 10.1002/path.2284. View

Rossignol D, Lynn M . Antagonism of in vivo and ex vivo response to endotoxin by E5564, a synthetic lipid A analogue. J Endotoxin Res. 2003; 8(6):483-8. DOI: 10.1179/096805102125001127. View

Wang Y, Tang Y, Teng L, Wu Y, Zhao X, Pei G . Association of beta-arrestin and TRAF6 negatively regulates Toll-like receptor-interleukin 1 receptor signaling. Nat Immunol. 2005; 7(2):139-47. DOI: 10.1038/ni1294. View

. Effect of high-dose glucocorticoid therapy on mortality in patients with clinical signs of systemic sepsis. N Engl J Med. 1987; 317(11):659-65. DOI: 10.1056/NEJM198709103171102. View

Aneja R, Odoms K, Denenberg A, Wong H . Theaflavin, a black tea extract, is a novel anti-inflammatory compound. Crit Care Med. 2004; 32(10):2097-103. DOI: 10.1097/01.ccm.0000142661.73633.15. View

Fisher Jr C, Agosti J, Opal S, Lowry S, Balk R, Sadoff J . Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. The Soluble TNF Receptor Sepsis Study Group. N Engl J Med. 1996; 334(26):1697-702. DOI: 10.1056/NEJM199606273342603. View

Dombrovskiy V, Martin A, Sunderram J, Paz H . Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit Care Med. 2007; 35(5):1244-50. DOI: 10.1097/01.CCM.0000261890.41311.E9. View

10.

Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B . Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med. 2002; 345(19):1368-77. DOI: 10.1056/NEJMoa010307. View

11.

Berger M, Chiolero R . Antioxidant supplementation in sepsis and systemic inflammatory response syndrome. Crit Care Med. 2007; 35(9 Suppl):S584-90. DOI: 10.1097/01.CCM.0000279189.81529.C4. View

12.

Vincent J, Sun Q, Dubois M . Clinical trials of immunomodulatory therapies in severe sepsis and septic shock. Clin Infect Dis. 2002; 34(8):1084-93. DOI: 10.1086/339549. View

13.

Reinhart K, Gluck T, Ligtenberg J, Tschaikowsky K, Bruining A, Bakker J . CD14 receptor occupancy in severe sepsis: results of a phase I clinical trial with a recombinant chimeric CD14 monoclonal antibody (IC14). Crit Care Med. 2004; 32(5):1100-8. DOI: 10.1097/01.ccm.0000124870.42312.c4. View

14.

Fan H, Luttrell L, Tempel G, Senn J, Halushka P, Cook J . Beta-arrestins 1 and 2 differentially regulate LPS-induced signaling and pro-inflammatory gene expression. Mol Immunol. 2007; 44(12):3092-9. PMC: 1945129. DOI: 10.1016/j.molimm.2007.02.009. View

15.

Neckers L, Neckers K . Heat-shock protein 90 inhibitors as novel cancer chemotherapeutic agents. Expert Opin Emerg Drugs. 2005; 7(2):277-88. DOI: 10.1517/14728214.7.2.277. View

16.

Modlin R, Brightbill H, Godowski P . The toll of innate immunity on microbial pathogens. N Engl J Med. 1999; 340(23):1834-5. DOI: 10.1056/NEJM199906103402312. View

17.

Zimmerman J . A history of adjunctive glucocorticoid treatment for pediatric sepsis: moving beyond steroid pulp fiction toward evidence-based medicine. Pediatr Crit Care Med. 2007; 8(6):530-9. DOI: 10.1097/01.PCC.0000288710.11834.E6. View

18.

El Mezayen R, El Gazzar M, Seeds M, McCall C, Dreskin S, Nicolls M . Endogenous signals released from necrotic cells augment inflammatory responses to bacterial endotoxin. Immunol Lett. 2007; 111(1):36-44. PMC: 3034364. DOI: 10.1016/j.imlet.2007.04.011. View

19.

Kopp E, Medzhitov R . The Toll-receptor family and control of innate immunity. Curr Opin Immunol. 1999; 11(1):13-8. DOI: 10.1016/s0952-7915(99)80003-x. View

20.

Calvano S, Xiao W, Richards D, Felciano R, Baker H, Cho R . A network-based analysis of systemic inflammation in humans. Nature. 2005; 437(7061):1032-7. DOI: 10.1038/nature03985. View