Neuropeptide Modulators of High Mobility Group Box 1 Secretion as Potential Therapeutic Agents for Severe Sepsis

Abstract

This Commentary describes a study suggesting that the endogenous neuropeptides vasoactive intestinal peptide (VIP) and urocortin can improve survival in an animal model of lethal sepsis, possibly through their ability to decrease circulating levels of the cytokine-like protein high mobility group box 1 (HMGB1). This Commentary describes a study suggesting that the endogenous neuropeptides vasoactive intestinal peptide (VIP) and urocortin can improve survival in an animal model of lethal sepsis, possibly through their ability to decrease circulating levels of the cytokine-like protein high mobility group box 1 (HMGB1). Sepsis is a potentially life-threatening condition caused by infection and characterized by a poorly controlled systemic inflammatory response.1Levy MM Fink MP Marshall JC Abraham E Angus D Cook D Cohen J Opal SM Vincent JL Ramsay G SCCM/ESICM/ACCP/ATS/SIS 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.Crit Care Med. 2003; 31: 1250-1256Crossref PubMed Scopus (4679) Google Scholar Severe sepsis is sepsis with the evidence of acute organ system dysfunction, and septic shock is sepsis associated with systemic arterial hypotension.1Levy MM Fink MP Marshall JC Abraham E Angus D Cook D Cohen J Opal SM Vincent JL Ramsay G SCCM/ESICM/ACCP/ATS/SIS 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference.Crit Care Med. 2003; 31: 1250-1256Crossref PubMed Scopus (4679) Google Scholar Severe sepsis remains a huge public health problem. In the United States alone, epidemiological data suggest that there are more than 600,000 cases annually2Martin GS Mannino DM Eaton S Moss M The epidemiology of sepsis in the United States from 1979 through 2000.N Engl J Med. 2003; 348: 1546-1554Crossref PubMed Scopus (4831) Google Scholar, 3Angus DC Linde-Zwirble WT Lidicker J Clermont G Carcillo J Pinsky MR Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.Crit Care Med. 2001; 29: 1303-1310Crossref PubMed Scopus (6673) Google Scholar and more than 200,000 people die every year from severe sepsis and its complications.3Angus DC Linde-Zwirble WT Lidicker J Clermont G Carcillo J Pinsky MR Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care.Crit Care Med. 2001; 29: 1303-1310Crossref PubMed Scopus (6673) Google Scholar In this issue of The American Journal of Pathology, Chorny and Delgado4Chorny A Delgado M Neuropeptides rescue mice from lethal sepsis by downregulating the secretion of the late-acting inflammatory mediator high mobility group box 1.Am J Pathol. 2008; 172: 1287-1292Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar report on the results of a series of studies that suggest that treatment with endogenous neuropeptides, either vasoactive intestinal peptide or urocortin, can improve survival in a clinically relevant animal model of lethal sepsis. Treatment of septic mice with vasoactive intestinal peptide or urocortin decreased circulating levels of high mobility group box 1, a small protein that has been implicated as being an important mediator of sepsis. Originally identified in the early 1960s,5Johns EW Studies on histones. 7. Preparative methods for histone fractions from calf thymus.Biochem J. 1964; 92: 55-59Crossref PubMed Scopus (737) Google Scholar high mobility group (HMG) proteins have been isolated and characterized from a wide variety of eukaryotic species, ranging from yeast to humans.6Aleporou-Marinou V Marinou H Patargias T A mini review of the high mobility group proteins of insects.Biochem Genet. 2003; 41: 291-304Crossref PubMed Scopus (6) Google Scholar HMG proteins all have an unusual amino acid composition characterized by a high content of charged amino acids and a high content of proline.7Goodwin GH Sanders C Johns EW A new group of chromatin-associated proteins with a high content of acidic and basic amino acids.Eur J Biochem. 1973; 38: 14-19Crossref PubMed Scopus (595) Google Scholar One member of this family of proteins, high mobility group box 1 (HMGB1), has a molecular mass of ∼28 kDa7Goodwin GH Sanders C Johns EW A new group of chromatin-associated proteins with a high content of acidic and basic amino acids.Eur J Biochem. 1973; 38: 14-19Crossref PubMed Scopus (595) Google Scholar, 8Sanders C A method for the fractionation of the high-mobility-group non-histone chromosomal proteins.Biochem Biophys Res Commun. 1977; 78: 1034-1042Crossref PubMed Scopus (87) Google Scholar and is capable of bending DNA by virtue of a conserved DNA binding domain, the HMG1 box.9Thomas JO Travers AA HMG1 and 2, and related ‘architectural’ DNA-binding proteins.Trends Biochem Sci. 2001; 26: 167-174Abstract Full Text Full Text PDF PubMed Scopus (553) Google Scholar HMGB1 also facilitates the binding of several regulatory protein complexes to DNA, particularly members of the nuclear hormone-receptor family,10Prendergast P Onate SA Christensen K Edwards DP Nuclear accessory factors enhance the binding of progesterone receptor to specific target DNA.J Steroid Biochem Mol Biol. 1994; 48: 1-13Crossref PubMed Scopus (35) Google Scholar, 11Zhang CC Krieg S Shapiro DJ HMG-1 stimulates estrogen response element binding by estrogen receptor from stably transfected HeLa cells.Mol Endocrinol. 1999; 13: 632-643Crossref PubMed Google Scholar V(D)J recombinases,12Ciubotaru M Schatz DG Synapsis of recombination signal sequences located in cis and DNA underwinding in V(D)J recombination.Mol Cell Biol. 2004; 24: 8727-8744Crossref PubMed Scopus (13) Google Scholar and the tumor suppressor proteins p53 and p73.13Stros M Muselikova-Polanska E Pospisilova S Strauss F High-affinity binding of tumor-suppressor protein p53 and HMGB1 to hemicatenated DNA loops.Biochemistry. 2004; 43: 7215-7225Crossref PubMed Scopus (63) Google Scholar In 1999, Wang and colleagues14Wang H Bloom O Zhang M Vishnubhakat JM Ombrellino M Che J Frazier A Yang H Ivanova S Borovikova L Manogue KR Faist E Abraham E Andersson J Andersson U Molina PE Abumrad NN Sama A Tracey KJ HMG-1 as a late mediator of endotoxin lethality in mice.Science. 1999; 285: 248-251Crossref PubMed Scopus (2965) Google Scholar identified HMGB1 as a cytokine-like mediator of lipopolysaccharide (LPS)-induced mortality in mice. Subsequently, these findings were extended by Yang and colleagues,15Yang H Ochani M Li J Tanovic M Harris HE Susarla S Ulloa L Wang H DiRaimo R Czura CJ Wang H Warren HS Fink MP Fenton MJ Andersson U Tracey KJ Reversing established sepsis with antagonists of endogenous HMGB1.Proc Natl Acad Sci USA. 2004; 101: 296-301Crossref PubMed Scopus (976) Google Scholar who showed that HMGB1 is also a mediator of lethality in mice rendered septic by the induction of polymicrobial bacterial peritonitis. Additional studies documented that extracellular HMGB1 can promote tumor necrosis factor release from mononuclear cells16Andersson U Wang H Palmblad K Aveberger AC Bloom O Erlandsson-Harris H Janson A Kokkola R Zhang M Yang H Tracey KJ High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes.J Exp Med. 2001; 192: 565-570Crossref Scopus (1230) Google Scholar and increase the permeability of Caco-2 cell monolayers.17Sappington PL Yang R Yang H Tracey KJ Delude RL Fink MP HMGB1 B box increases the permeability of Caco-2 enterocytic monolayers and impairs intestinal barrier function in mice.Gastroenterology. 2002; 123: 790-802Abstract Full Text Full Text PDF PubMed Scopus (282) Google Scholar One of the most interesting features of HMGB1 as a cytokine-like mediator of inflammation is that this protein is released much later in the inflammatory process than are the classical alarm-phase cytokines such as tumor necrosis factor and interleukin-1β. In mice, for example, injection of a bolus dose of LPS elicits a monophasic spike in circulating tumor necrosis factor that peaks in ∼90 minutes of the proinflammatory challenge and is over by 4 hours.18Zuckerman SH Shellhaas J Butler LD Differential regulation of lipopolysaccharide-induced interleukin 1 and tumor necrosis factor synthesis: effects of endogenous and exogenous glucocorticoids and the role of the pituitary-adrenal axis.Eur J Immunol. 1989; 19: 301-305Crossref PubMed Scopus (306) Google Scholar The peak in interleukin-1β concentration occurs somewhat later; ie, 4 to 6 hours after the injection of LPS.19Zuckerman SH Evans GF Butler LD Endotoxin tolerance: independent regulation of interleukin-1 and tumor necrosis factor expression.Infect Immun. 1991; 59: 2774-2780Crossref PubMed Google Scholar In contrast, after injecting mice with LPS, circulating levels of HMGB1 are not elevated until 16 hours after the proinflammatory stimulus but remain elevated for more than 30 hours.14Wang H Bloom O Zhang M Vishnubhakat JM Ombrellino M Che J Frazier A Yang H Ivanova S Borovikova L Manogue KR Faist E Abraham E Andersson J Andersson U Molina PE Abumrad NN Sama A Tracey KJ HMG-1 as a late mediator of endotoxin lethality in mice.Science. 1999; 285: 248-251Crossref PubMed Scopus (2965) Google Scholar Furthermore, treatment with neutralizing anti-HMGB1 antibodies14Wang H Bloom O Zhang M Vishnubhakat JM Ombrellino M Che J Frazier A Yang H Ivanova S Borovikova L Manogue KR Faist E Abraham E Andersson J Andersson U Molina PE Abumrad NN Sama A Tracey KJ HMG-1 as a late mediator of endotoxin lethality in mice.Science. 1999; 285: 248-251Crossref PubMed Scopus (2965) Google Scholar, 15Yang H Ochani M Li J Tanovic M Harris HE Susarla S Ulloa L Wang H DiRaimo R Czura CJ Wang H Warren HS Fink MP Fenton MJ Andersson U Tracey KJ Reversing established sepsis with antagonists of endogenous HMGB1.Proc Natl Acad Sci USA. 2004; 101: 296-301Crossref PubMed Scopus (976) Google Scholar or various pharmacological agents that block HMGB1 secretion, such as nicotine20Wang H Liao H Ochani M Justiniani M Lin X Yang L Al-Abed Y Wang H Metz C Miller EJ Tracey KJ Ulloa L Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis.Nat Med. 2004; 10: 1216-1221Crossref PubMed Scopus (986) Google Scholar or ethyl pyruvate,21Ulloa L Ochani M Yang H Halperin D Yang R Czura CJ Fink MP Tracey KJ Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation.Proc Natl Acad Sci USA. 2002; 99: 12351-12356Crossref PubMed Scopus (539) Google Scholar is effective in preventing LPS- or sepsis-induced lethality, even when therapy is started 4 to 24 hours after the initiation of the disease process. Because of the delayed release kinetics, HMGB1 is a very attractive drug target for the development of new therapeutic agents for the management of severe sepsis. The treatment window for an anti-HMGB1 therapy should be longer than is the case for therapeutic agents directed at more proximal mediators of the inflammatory cascade (eg, tumor necrosis factor or interleukin-1β). HMGB1 is actively secreted by immunostimulated macrophages,14Wang H Bloom O Zhang M Vishnubhakat JM Ombrellino M Che J Frazier A Yang H Ivanova S Borovikova L Manogue KR Faist E Abraham E Andersson J Andersson U Molina PE Abumrad NN Sama A Tracey KJ HMG-1 as a late mediator of endotoxin lethality in mice.Science. 1999; 285: 248-251Crossref PubMed Scopus (2965) Google Scholar, 22Rendon-Mitchell B Ochani M Li J Han J Wang H Susarla S Czura C Mitchell RA Chen G Sama AE Tracey KJ Wang H IFN-gamma induces high mobility group box 1 protein release partly through a TNF-dependent mechanism.J Immunol. 2003; 170: 3890-3897PubMed Google Scholar, 23Gardella S Andrei C Ferrera D Lotti LV Torrisi MR Bianchi ME Rubartelli A The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway.EMBO Rep. 2002; 3: 995-1001Crossref PubMed Scopus (751) Google Scholar, 24Bonaldi T Talamo F Scaffidi P Perrera D Porto A Bachi A Rubartelli A Agresti A Bianchi ME Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion.EMBO J. 2003; 22: 5551-5560Crossref PubMed Scopus (1006) Google Scholar natural killer cells,25Semino C Angelini G Poggi A Rubartelli A NK/iDC interaction results in IL-18 secretion by DCs at the synaptic cleft followed by NK cell activation and release of the DC maturation factor HMGB1.Blood. 2005; 106: 609-616Crossref PubMed Scopus (272) Google Scholar plasmacytoid dendritic cells,26Dumitriu IE Baruah P Bianchi ME Manfredi AA Rovere-Querini P Requirement of HMGB1 and RAGE for the maturation of human plasmacytoid dendritic cells.Eur J Immunol. 2005; 35: 2184-2190Crossref PubMed Scopus (170) Google Scholar pituicytes,27Wang H Vishnubhakat JM Bloom O Zhang M Ombrellino M Sama A Tracey KJ Proinflammatory cytokines (tumor necrosis factor and interleukin 1) stimulate release of high mobility group protein-1 by pituicytes.Surgery. 2002; 126: 389-392Abstract Full Text Full Text PDF Scopus (275) Google Scholar and enterocytes.28Liu S Stolz DB Sappington PL Macias CA Killeen ME Tenhunen JJ Delude RL Fink MP HMGB1 is secreted by immunostimulated enterocytes and contributes to cytomix-induced hyperpermeability of Caco-2 monolayers.Am J Physiol. 2006; 290: C990-C999Crossref Scopus (126) Google Scholar Like members of the interleukin-1 family of cytokines, the primary amino acid sequence of HMGB1 lacks a signal peptide. Accordingly, secretion of HMGB1 by macrophages or monocytes presumably occurs via a nonclassical secretory pathway. Indeed, when monocytes are activated by exposure to LPS, HMGB1 relocalizes from the nucleus into cytoplasmic organelles that belong to the endolysosomal compartment.23Gardella S Andrei C Ferrera D Lotti LV Torrisi MR Bianchi ME Rubartelli A The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway.EMBO Rep. 2002; 3: 995-1001Crossref PubMed Scopus (751) Google Scholar In the past few years, numerous agents have been shown to be capable of blocking HMGB1 secretion by immunostimulated cells, including various nicotinic cholinergic agonists20Wang H Liao H Ochani M Justiniani M Lin X Yang L Al-Abed Y Wang H Metz C Miller EJ Tracey KJ Ulloa L Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis.Nat Med. 2004; 10: 1216-1221Crossref PubMed Scopus (986) Google Scholar, 29Pavlov VA Ochani M Yang LH Gallowitsch-Puerta M Ochani K Lin X Levi J Parrish WR Rosas-Ballina M Czura CJ Larosa GJ Miller EJ Tracey KJ Al-Abed Y Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis.Crit Care Med. 2007; 35: 1139-1144Crossref PubMed Scopus (283) Google Scholar; stearoyl lysophosphatidylcholine30Chen G Li J Qiang X Czura CJ Ochani M Ochani K Ulloa L Yang H Tracey KJ Wang P Sama AE Wang H Suppression of HMGB1 release by stearoyl lysophosphatidylcholine: an additional mechanism for its therapeutic effects in experimental sepsis.J Lipid Res. 2005; 46: 623-627Crossref PubMed Scopus (111) Google Scholar; ethyl pyruvate21Ulloa L Ochani M Yang H Halperin D Yang R Czura CJ Fink MP Tracey KJ Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation.Proc Natl Acad Sci USA. 2002; 99: 12351-12356Crossref PubMed Scopus (539) Google Scholar; the serine protease inhibitor nafamostat mesilate31Hagiwara S Iwasaka H Matumoto S Noguchi T Nafamostat mesilate inhibits high-mobility group box 1 by lipopolysaccharide stimulation in murine macrophage raw 264.7.Shock. 2007; 27: 429-435Crossref PubMed Scopus (12) Google Scholar; several steroid-like pigments (tanshinone I, tanshinone IIA, and cryptotanshinone), derived from a Chinese medicinal herb, Danshen (Salvia miltiorrhiza)32Li W Li J Ashok M Wu R Chen D Yang L Yang H Tracey KJ Wang P Sama AE Wang H A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinflammatory mediator, high mobility group box 1.J Immunol. 2007; 178: 3856-3864PubMed Google Scholar; and the diuretic ethacrynic acid, as well as other drugs, which are known to be phase 2 enzyme inducers.33Killeen ME Englert JA Stolz DB Song M Han Y Delude RL Kellum JA Fink MP The phase 2 enzyme inducers, ethacrynic acid. DL-sulforaphane and oltipraz, inhibit LPS-induced HMGB1 secretion by RAW 2647 cells.J Pharmacol Exp Ther. 2006; 316: 1070-1079Crossref PubMed Scopus (44) Google Scholar Now, two endogenous neuropeptides with known anti-inflammatory activities, vasoactive intestinal peptide (VIP) and urocortin, have been shown to inhibit active secretion of HMGB1 by LPS-stimulated murine macrophages.4Chorny A Delgado M Neuropeptides rescue mice from lethal sepsis by downregulating the secretion of the late-acting inflammatory mediator high mobility group box 1.Am J Pathol. 2008; 172: 1287-1292Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar As is the case with almost all previously identified inhibitors of HMGB1 release from immunostimulated macrophages, both VIP and urocortin interfere in some way with a key step in the secretion process, namely nuclear-to-cytoplasmic translocation of the protein. And, importantly, like several other known inhibitors of HMGB1 secretion,20Wang H Liao H Ochani M Justiniani M Lin X Yang L Al-Abed Y Wang H Metz C Miller EJ Tracey KJ Ulloa L Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis.Nat Med. 2004; 10: 1216-1221Crossref PubMed Scopus (986) Google Scholar, 21Ulloa L Ochani M Yang H Halperin D Yang R Czura CJ Fink MP Tracey KJ Ethyl pyruvate prevents lethality in mice with established lethal sepsis and systemic inflammation.Proc Natl Acad Sci USA. 2002; 99: 12351-12356Crossref PubMed Scopus (539) Google Scholar, 29Pavlov VA Ochani M Yang LH Gallowitsch-Puerta M Ochani K Lin X Levi J Parrish WR Rosas-Ballina M Czura CJ Larosa GJ Miller EJ Tracey KJ Al-Abed Y Selective alpha7-nicotinic acetylcholine receptor agonist GTS-21 improves survival in murine endotoxemia and severe sepsis.Crit Care Med. 2007; 35: 1139-1144Crossref PubMed Scopus (283) Google Scholar, 30Chen G Li J Qiang X Czura CJ Ochani M Ochani K Ulloa L Yang H Tracey KJ Wang P Sama AE Wang H Suppression of HMGB1 release by stearoyl lysophosphatidylcholine: an additional mechanism for its therapeutic effects in experimental sepsis.J Lipid Res. 2005; 46: 623-627Crossref PubMed Scopus (111) Google Scholar, 32Li W Li J Ashok M Wu R Chen D Yang L Yang H Tracey KJ Wang P Sama AE Wang H A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinflammatory mediator, high mobility group box 1.J Immunol. 2007; 178: 3856-3864PubMed Google Scholar treatment with VIP or urocortin improves survival in mice with lethal sepsis, even when treatment is delayed for many hours after the onset of infection. However, unlike other pharmacological inhibitors of HMGB1 secretion, which have been shown to improve survival in septic mice, VIP and urocortin are endogenous substances. Thus, as pointed out by Chorny and Delgado,4Chorny A Delgado M Neuropeptides rescue mice from lethal sepsis by downregulating the secretion of the late-acting inflammatory mediator high mobility group box 1.Am J Pathol. 2008; 172: 1287-1292Abstract Full Text Full Text PDF PubMed Scopus (68) Google Scholar endogenous release of VIP and/or urocortin might serve a counterregulatory role in vivo to modulate the proinflammatory effects of HMGB1 secretion. Activation of the cholinergic anti-inflammatory pathway, mediated via increased efferent traffic through the vagus nerve, might serve a similar counterregulatory role.34Czura CJ Friedman SG Tracey KJ Neural inhibition of inflammation: the cholinergic anti-inflammatory pathway.J Endotoxin Res. 2003; 9: 409-413Crossref PubMed Google Scholar, 35Huston JM Gallowitsch-Puerta M Ochani M Ochani K Yuan R Rosas-Ballina M Ashok M Goldstein RS Chavan S Pavlov VA Metz CN Yang H Czura CJ Wang H Tracey KJ Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis.Crit Care Med. 2007; 35: 2762-2768Crossref PubMed Scopus (231) Google Scholar Treating septic mice with either VIP or urocortin decreases circulating HMGB1 concentration and improves survival. Although it is certainly plausible that these two effects of treatment with VIP or urocortin are mechanistically related, data from the present set of experiments are insufficient to establish this causal linkage. It is conceivable, for example, that administration of the peptides triggers another process, activation of the vagal cholinergic anti-inflammatory pathway comes to mind,34Czura CJ Friedman SG Tracey KJ Neural inhibition of inflammation: the cholinergic anti-inflammatory pathway.J Endotoxin Res. 2003; 9: 409-413Crossref PubMed Google Scholar, 35Huston JM Gallowitsch-Puerta M Ochani M Ochani K Yuan R Rosas-Ballina M Ashok M Goldstein RS Chavan S Pavlov VA Metz CN Yang H Czura CJ Wang H Tracey KJ Transcutaneous vagus nerve stimulation reduces serum high mobility group box 1 levels and improves survival in murine sepsis.Crit Care Med. 2007; 35: 2762-2768Crossref PubMed Scopus (231) Google Scholar and this other process is the proximate cause of the salutary effects observed in septic mice after the administration of VIP or urocortin. Infusion of an anti-coagulant protein, recombinant human activated protein C, has been shown to improve survival in patients with severe sepsis,36Bernard GR Vincent J-L Laterre PF LaRosa SP Dhainaut J-F Lopez-Rodriguez A Steingrub JS Garber GE Helterbrand JD Ely EW Fisher Jr, CJ Efficacy and safety of recombinant human activated protein C for severe sepsis.N Engl J Med. 2001; 344: 699-709Crossref PubMed Scopus (5070) Google Scholar and this agent has been approved by regulatory agencies in the United States and elsewhere for the treatment of selected cases of severe sepsis. Nevertheless, the clinical adoption of recombinant human activated protein C has been relatively slow, possibly because of concerns about its cost,37Costa V Brophy JM Drotrecogin alfa (activated) in severe sepsis: a systematic review and new cost-effectiveness analysis.BMC Anesthesiol. 2007; 7: 5Crossref PubMed Scopus (18) Google Scholar safety,38Castelli EE Culley CM Fink MP Challenge and rechallenge: drotrecogin alfa (activated)-induced prolongation of activated partial thromboplastin time in a patient with severe sepsis.Pharmacotherapy. 2005; 25: 1147-1150Crossref PubMed Scopus (7) Google Scholar, 39Kanji S Perreault MM Chant C Williamson D Burry L Evaluating the use of Drotrecogin alfa (activated) in adult severe sepsis: a Canadian multicenter observational study.Intensive Care Med. 2007; 33: 517-523Crossref PubMed Scopus (75) Google Scholar and/or efficacy.40Mackenzie AF Activate protein C: do more survive?.Intensive Care Med. 2005; 31: 1624-1626Crossref PubMed Scopus (59) Google Scholar Accordingly, there remains a need for new and better therapeutic approaches for the management of severe sepsis. One approach worth considering in this regard is the therapeutic administration of the endogenous peptides, VIP or urocortin. VIP infused into normal human volunteers has been shown to cause a range of adverse effects, including diarrhea and tachycardia.41Keller J Mueller-Wolf JC Ahmadi-Simab K Fibbe C Rosien U Layer P Do elevated plasma vasoactive intestinal polypeptide (VIP) levels cause small intestinal motor disturbances in humans?.Dig Dis Sci. 2005; 50: 276-282Crossref PubMed Scopus (13) Google Scholar Whether these side effects would occur in septic patients, or be tolerable in the context of treating a life-threatening illness, remains to be determined. Infusion of urocortin into normal human volunteers seems to be better tolerated,42Davis ME Pemberton CJ Yandle TG Laichbury JG Rademaker MT Nicholls MG Frampton CM Richards AM Urocortin-1 infusion in normal humans.Clin Endocrinol Metab. 2004; 89: 1402-1409Crossref Scopus (82) Google Scholar and, therefore, this neuropeptide might be a more promising candidate for further development as an adjuvant therapeutic for severe sepsis. Antiprion Prophylaxis by Gene Transfer of a Soluble Prion AntagonistThe American Journal of PathologyVol. 172Issue 5PreviewPrion diseases are untreatable neurodegenerative disorders characterized by accumulation of PrPSc, an aggregated isoform of the normal prion protein PrPC. Here, we delivered the soluble prion antagonist PrP-Fc2 to the brains of mice by lentiviral gene transfer. Although naïve mice developed scrapie at 175 ± 5 days postintracerebral prion inoculation (dpi), gene transfer before inoculation delayed disease onset by 72 ± 4 days. At 170 days postintracerebral prion inoculation, PrPSc accumulation and prion infectivity in PrPFc-treated brains were reduced by 3.6 and 4.2 logs, respectively. Full-Text PDF