Abstract
Because of its neutrophil-activating properties, interleukin-8 (IL-8) may play an important role in the pathophysiology of sepsis. We measured circulating IL-8 levels in 47 patients with clinical sepsis. Levels on admission were elevated in 42 of the 47 patients (89%) and were comparable in patients with gram-positive or gram-negative infections. Patients with shock had significantly higher IL-8 levels than normotensive patients (P = 0.0014, Wilcoxon-Mann-Whitney test), whereas no differences in IL-8 levels were found between patients with or without adult respiratory distress syndrome. Patients who died had higher IL-8 levels on admission than the patients who survived. The largest differences in IL-8 levels between survivors and nonsurvivors was found when only patients with positive cultures were considered (P = 0.0342). IL-8 levels appeared to correlate significantly with lactate levels and inversely with leukocyte and platelet numbers and mean arterial pressure. In addition, the IL-8 level in the sepsis patients was found to correlate significantly with levels of IL-6, elastase-alpha 1-antitrypsin, and C3a. Serial observations revealed that in most patients IL-8 levels decreased, irrespective of the outcome. Thus, our results demonstrate that IL-8 levels are increased in most patients with sepsis and correlate with some important clinical, biochemical, and inflammatory parameters. These findings suggest a role for IL-8 in the pathophysiology of sepsis.
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- Abbink J. J., Nuijens J. H., Eerenberg A. J., Huijbregts C. C., Strack van Schijndel R. J., Thijs L. G., Hack C. E. Quantification of functional and inactivated alpha 2-macroglobulin in sepsis. Thromb Haemost. 1991 Jan 23;65(1):32–39. [PubMed] [Google Scholar]
- Alexander H. R., Doherty G. M., Buresh C. M., Venzon D. J., Norton J. A. A recombinant human receptor antagonist to interleukin 1 improves survival after lethal endotoxemia in mice. J Exp Med. 1991 Apr 1;173(4):1029–1032. doi: 10.1084/jem.173.4.1029. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Baggiolini M., Walz A., Kunkel S. L. Neutrophil-activating peptide-1/interleukin 8, a novel cytokine that activates neutrophils. J Clin Invest. 1989 Oct;84(4):1045–1049. doi: 10.1172/JCI114265. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Beutler B., Cerami A. Cachectin: more than a tumor necrosis factor. N Engl J Med. 1987 Feb 12;316(7):379–385. doi: 10.1056/NEJM198702123160705. [DOI] [PubMed] [Google Scholar]
- Beutler B., Milsark I. W., Cerami A. C. Passive immunization against cachectin/tumor necrosis factor protects mice from lethal effect of endotoxin. Science. 1985 Aug 30;229(4716):869–871. doi: 10.1126/science.3895437. [DOI] [PubMed] [Google Scholar]
- Bobrow M. N., Harris T. D., Shaughnessy K. J., Litt G. J. Catalyzed reporter deposition, a novel method of signal amplification. Application to immunoassays. J Immunol Methods. 1989 Dec 20;125(1-2):279–285. doi: 10.1016/0022-1759(89)90104-x. [DOI] [PubMed] [Google Scholar]
- Bone R. C. The pathogenesis of sepsis. Ann Intern Med. 1991 Sep 15;115(6):457–469. doi: 10.7326/0003-4819-115-6-457. [DOI] [PubMed] [Google Scholar]
- Brakenhoff J. P., Hart M., Aarden L. A. Analysis of human IL-6 mutants expressed in Escherichia coli. Biologic activities are not affected by deletion of amino acids 1-28. J Immunol. 1989 Aug 15;143(4):1175–1182. [PubMed] [Google Scholar]
- Brakenhoff J. P., Hart M., De Groot E. R., Di Padova F., Aarden L. A. Structure-function analysis of human IL-6. Epitope mapping of neutralizing monoclonal antibodies with amino- and carboxyl-terminal deletion mutants. J Immunol. 1990 Jul 15;145(2):561–568. [PubMed] [Google Scholar]
- Carveth H. J., Bohnsack J. F., McIntyre T. M., Baggiolini M., Prescott S. M., Zimmerman G. A. Neutrophil activating factor (NAF) induces polymorphonuclear leukocyte adherence to endothelial cells and to subendothelial matrix proteins. Biochem Biophys Res Commun. 1989 Jul 14;162(1):387–393. doi: 10.1016/0006-291x(89)92009-3. [DOI] [PubMed] [Google Scholar]
- Cohen A. B., MacArthur C., Idell S., Maunder R., Martin T., Dinarello C. A., Griffith D., McLarty J. A peptide from alveolar macrophages that releases neutrophil enzymes into the lungs in patients with the adult respiratory distress syndrome. Am Rev Respir Dis. 1988 May;137(5):1151–1158. doi: 10.1164/ajrccm/137.5.1151. [DOI] [PubMed] [Google Scholar]
- Colditz I., Zwahlen R., Dewald B., Baggiolini M. In vivo inflammatory activity of neutrophil-activating factor, a novel chemotactic peptide derived from human monocytes. Am J Pathol. 1989 Apr;134(4):755–760. [PMC free article] [PubMed] [Google Scholar]
- Collins P. D., Jose P. J., Williams T. J. The sequential generation of neutrophil chemoattractant proteins in acute inflammation in the rabbit in vivo. Relationship between C5a and proteins with the characteristics of IL-8/neutrophil-activating protein 1. J Immunol. 1991 Jan 15;146(2):677–684. [PubMed] [Google Scholar]
- Gimbrone M. A., Jr, Obin M. S., Brock A. F., Luis E. A., Hass P. E., Hébert C. A., Yip Y. K., Leung D. W., Lowe D. G., Kohr W. J. Endothelial interleukin-8: a novel inhibitor of leukocyte-endothelial interactions. Science. 1989 Dec 22;246(4937):1601–1603. doi: 10.1126/science.2688092. [DOI] [PubMed] [Google Scholar]
- Girardin E., Grau G. E., Dayer J. M., Roux-Lombard P., Lambert P. H. Tumor necrosis factor and interleukin-1 in the serum of children with severe infectious purpura. N Engl J Med. 1988 Aug 18;319(7):397–400. doi: 10.1056/NEJM198808183190703. [DOI] [PubMed] [Google Scholar]
- Hack C. E., De Groot E. R., Felt-Bersma R. J., Nuijens J. H., Strack Van Schijndel R. J., Eerenberg-Belmer A. J., Thijs L. G., Aarden L. A. Increased plasma levels of interleukin-6 in sepsis. Blood. 1989 Oct;74(5):1704–1710. [PubMed] [Google Scholar]
- Hack C. E., Hannema A. J., Eerenberg-Belmer A. J., Out T. A., Aalberse R. C. A C1-inhibitor-complex assay (INCA): a method to detect C1 activation in vitro and in vivo. J Immunol. 1981 Oct;127(4):1450–1453. [PubMed] [Google Scholar]
- Hack C. E., Nuijens J. H., Felt-Bersma R. J., Schreuder W. O., Eerenberg-Belmer A. J., Paardekooper J., Bronsveld W., Thijs L. G. Elevated plasma levels of the anaphylatoxins C3a and C4a are associated with a fatal outcome in sepsis. Am J Med. 1989 Jan;86(1):20–26. doi: 10.1016/0002-9343(89)90224-6. [DOI] [PubMed] [Google Scholar]
- Hechtman D. H., Cybulsky M. I., Fuchs H. J., Baker J. B., Gimbrone M. A., Jr Intravascular IL-8. Inhibitor of polymorphonuclear leukocyte accumulation at sites of acute inflammation. J Immunol. 1991 Aug 1;147(3):883–892. [PubMed] [Google Scholar]
- Heflin A. C., Jr, Brigham K. L. Prevention by granulocyte depletion of increased vascular permeability of sheep lung following endotoxemia. J Clin Invest. 1981 Nov;68(5):1253–1260. doi: 10.1172/JCI110371. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Heinzel F. P. The role of IFN-gamma in the pathology of experimental endotoxemia. J Immunol. 1990 Nov 1;145(9):2920–2924. [PubMed] [Google Scholar]
- Helle M., Boeije L., de Groot E., de Vos A., Aarden L. Sensitive ELISA for interleukin-6. Detection of IL-6 in biological fluids: synovial fluids and sera. J Immunol Methods. 1991 Apr 8;138(1):47–56. doi: 10.1016/0022-1759(91)90063-l. [DOI] [PubMed] [Google Scholar]
- Heremans H., Van Damme J., Dillen C., Dijkmans R., Billiau A. Interferon gamma, a mediator of lethal lipopolysaccharide-induced Shwartzman-like shock reactions in mice. J Exp Med. 1990 Jun 1;171(6):1853–1869. doi: 10.1084/jem.171.6.1853. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Huber A. R., Kunkel S. L., Todd R. F., 3rd, Weiss S. J. Regulation of transendothelial neutrophil migration by endogenous interleukin-8. Science. 1991 Oct 4;254(5028):99–102. doi: 10.1126/science.1718038. [DOI] [PubMed] [Google Scholar]
- Ismail G., Morganroth M. L., Todd R. F., 3rd, Boxer L. A. Prevention of pulmonary injury in isolated perfused rat lungs by activated human neutrophils preincubated with anti-Mo1 monoclonal antibody. Blood. 1987 Apr;69(4):1167–1174. [PubMed] [Google Scholar]
- Martich G. D., Danner R. L., Ceska M., Suffredini A. F. Detection of interleukin 8 and tumor necrosis factor in normal humans after intravenous endotoxin: the effect of antiinflammatory agents. J Exp Med. 1991 Apr 1;173(4):1021–1024. doi: 10.1084/jem.173.4.1021. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Michie H. R., Manogue K. R., Spriggs D. R., Revhaug A., O'Dwyer S., Dinarello C. A., Cerami A., Wolff S. M., Wilmore D. W. Detection of circulating tumor necrosis factor after endotoxin administration. N Engl J Med. 1988 Jun 9;318(23):1481–1486. doi: 10.1056/NEJM198806093182301. [DOI] [PubMed] [Google Scholar]
- Morrison D. C., Ulevitch R. J. The effects of bacterial endotoxins on host mediation systems. A review. Am J Pathol. 1978 Nov;93(2):526–618. [PMC free article] [PubMed] [Google Scholar]
- Natanson C., Eichenholz P. W., Danner R. L., Eichacker P. Q., Hoffman W. D., Kuo G. C., Banks S. M., MacVittie T. J., Parrillo J. E. Endotoxin and tumor necrosis factor challenges in dogs simulate the cardiovascular profile of human septic shock. J Exp Med. 1989 Mar 1;169(3):823–832. doi: 10.1084/jem.169.3.823. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nuijens J. H., Abbink J. J., Wachtfogel Y. T., Colman R. W., Eerenberg A. J., Dors D., Kamp A. J., Strack van Schijndel R. J., Thijs L. G., Hack C. E. Plasma elastase alpha 1-antitrypsin and lactoferrin in sepsis: evidence for neutrophils as mediators in fatal sepsis. J Lab Clin Med. 1992 Feb;119(2):159–168. [PubMed] [Google Scholar]
- Nuijens J. H., Eerenberg-Belmer A. J., Huijbregts C. C., Schreuder W. O., Felt-Bersma R. J., Abbink J. J., Thijs L. G., Hack C. E. Proteolytic inactivation of plasma C1- inhibitor in sepsis. J Clin Invest. 1989 Aug;84(2):443–450. doi: 10.1172/JCI114185. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Nuijens J. H., Huijbregts C. C., Cohen M., Navis G. O., de Vries A., Eerenberg A. J., Bakker J. C., Hack C. E. Detection of activation of the contact system of coagulation in vitro and in vivo: quantitation of activated Hageman factor-C-1-inhibitor and kallikrein-C-1-inhibitor complexes by specific radioimmunoassays. Thromb Haemost. 1987 Aug 4;58(2):778–785. [PubMed] [Google Scholar]
- Nuijens J. H., Huijbregts C. C., Eerenberg-Belmer A. J., Abbink J. J., Strack van Schijndel R. J., Felt-Bersma R. J., Thijs L. G., Hack C. E. Quantification of plasma factor XIIa-Cl(-)-inhibitor and kallikrein-Cl(-)-inhibitor complexes in sepsis. Blood. 1988 Dec;72(6):1841–1848. [PubMed] [Google Scholar]
- Ohlsson K., Björk P., Bergenfeldt M., Hageman R., Thompson R. C. Interleukin-1 receptor antagonist reduces mortality from endotoxin shock. Nature. 1990 Dec 6;348(6301):550–552. doi: 10.1038/348550a0. [DOI] [PubMed] [Google Scholar]
- Okusawa S., Gelfand J. A., Ikejima T., Connolly R. J., Dinarello C. A. Interleukin 1 induces a shock-like state in rabbits. Synergism with tumor necrosis factor and the effect of cyclooxygenase inhibition. J Clin Invest. 1988 Apr;81(4):1162–1172. doi: 10.1172/JCI113431. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Parrillo J. E., Parker M. M., Natanson C., Suffredini A. F., Danner R. L., Cunnion R. E., Ognibene F. P. Septic shock in humans. Advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med. 1990 Aug 1;113(3):227–242. doi: 10.7326/0003-4819-113-3-227. [DOI] [PubMed] [Google Scholar]
- Patterson C. E., Barnard J. W., Lafuze J. E., Hull M. T., Baldwin S. J., Rhoades R. A. The role of activation of neutrophils and microvascular pressure in acute pulmonary edema. Am Rev Respir Dis. 1989 Oct;140(4):1052–1062. doi: 10.1164/ajrccm/140.4.1052. [DOI] [PubMed] [Google Scholar]
- Peveri P., Walz A., Dewald B., Baggiolini M. A novel neutrophil-activating factor produced by human mononuclear phagocytes. J Exp Med. 1988 May 1;167(5):1547–1559. doi: 10.1084/jem.167.5.1547. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Redl H., Schlag G., Bahrami S., Schade U., Ceska M., Stütz P. Plasma neutrophil-activating peptide-1/interleukin-8 and neutrophil elastase in a primate bacteremia model. J Infect Dis. 1991 Aug;164(2):383–388. doi: 10.1093/infdis/164.2.383. [DOI] [PubMed] [Google Scholar]
- Schröder J. M., Mrowietz U., Morita E., Christophers E. Purification and partial biochemical characterization of a human monocyte-derived, neutrophil-activating peptide that lacks interleukin 1 activity. J Immunol. 1987 Nov 15;139(10):3474–3483. [PubMed] [Google Scholar]
- Schröder J. M. The monocyte-derived neutrophil activating peptide (NAP/interleukin 8) stimulates human neutrophil arachidonate-5-lipoxygenase, but not the release of cellular arachidonate. J Exp Med. 1989 Sep 1;170(3):847–863. doi: 10.1084/jem.170.3.847. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Starnes H. F., Jr, Pearce M. K., Tewari A., Yim J. H., Zou J. C., Abrams J. S. Anti-IL-6 monoclonal antibodies protect against lethal Escherichia coli infection and lethal tumor necrosis factor-alpha challenge in mice. J Immunol. 1990 Dec 15;145(12):4185–4191. [PubMed] [Google Scholar]
- Suffredini A. F., Harpel P. C., Parrillo J. E. Promotion and subsequent inhibition of plasminogen activation after administration of intravenous endotoxin to normal subjects. N Engl J Med. 1989 May 4;320(18):1165–1172. doi: 10.1056/NEJM198905043201802. [DOI] [PubMed] [Google Scholar]
- Tracey K. J., Beutler B., Lowry S. F., Merryweather J., Wolpe S., Milsark I. W., Hariri R. J., Fahey T. J., 3rd, Zentella A., Albert J. D. Shock and tissue injury induced by recombinant human cachectin. Science. 1986 Oct 24;234(4775):470–474. doi: 10.1126/science.3764421. [DOI] [PubMed] [Google Scholar]
- Tracey K. J., Fong Y., Hesse D. G., Manogue K. R., Lee A. T., Kuo G. C., Lowry S. F., Cerami A. Anti-cachectin/TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature. 1987 Dec 17;330(6149):662–664. doi: 10.1038/330662a0. [DOI] [PubMed] [Google Scholar]
- Tracey K. J., Lowry S. F., Fahey T. J., 3rd, Albert J. D., Fong Y., Hesse D., Beutler B., Manogue K. R., Calvano S., Wei H. Cachectin/tumor necrosis factor induces lethal shock and stress hormone responses in the dog. Surg Gynecol Obstet. 1987 May;164(5):415–422. [PubMed] [Google Scholar]
- Van Damme J., Van Beeumen J., Opdenakker G., Billiau A. A novel, NH2-terminal sequence-characterized human monokine possessing neutrophil chemotactic, skin-reactive, and granulocytosis-promoting activity. J Exp Med. 1988 Apr 1;167(4):1364–1376. doi: 10.1084/jem.167.4.1364. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Van Zee K. J., DeForge L. E., Fischer E., Marano M. A., Kenney J. S., Remick D. G., Lowry S. F., Moldawer L. L. IL-8 in septic shock, endotoxemia, and after IL-1 administration. J Immunol. 1991 May 15;146(10):3478–3482. [PubMed] [Google Scholar]
- Waage A., Brandtzaeg P., Halstensen A., Kierulf P., Espevik T. The complex pattern of cytokines in serum from patients with meningococcal septic shock. Association between interleukin 6, interleukin 1, and fatal outcome. J Exp Med. 1989 Jan 1;169(1):333–338. doi: 10.1084/jem.169.1.333. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Westwick J., Li S. W., Camp R. D. Novel neutrophil-stimulating peptides. Immunol Today. 1989 May;10(5):146–147. doi: 10.1016/0167-5699(89)90164-3. [DOI] [PubMed] [Google Scholar]
- Yoshimura T., Matsushima K., Tanaka S., Robinson E. A., Appella E., Oppenheim J. J., Leonard E. J. Purification of a human monocyte-derived neutrophil chemotactic factor that has peptide sequence similarity to other host defense cytokines. Proc Natl Acad Sci U S A. 1987 Dec;84(24):9233–9237. doi: 10.1073/pnas.84.24.9233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- van Deventer S. J., Büller H. R., ten Cate J. W., Aarden L. A., Hack C. E., Sturk A. Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways. Blood. 1990 Dec 15;76(12):2520–2526. [PubMed] [Google Scholar]
- van der Poll T., Büller H. R., ten Cate H., Wortel C. H., Bauer K. A., van Deventer S. J., Hack C. E., Sauerwein H. P., Rosenberg R. D., ten Cate J. W. Activation of coagulation after administration of tumor necrosis factor to normal subjects. N Engl J Med. 1990 Jun 7;322(23):1622–1627. doi: 10.1056/NEJM199006073222302. [DOI] [PubMed] [Google Scholar]
- van der Poll T., Levi M., Büller H. R., van Deventer S. J., de Boer J. P., Hack C. E., ten Cate J. W. Fibrinolytic response to tumor necrosis factor in healthy subjects. J Exp Med. 1991 Sep 1;174(3):729–732. doi: 10.1084/jem.174.3.729. [DOI] [PMC free article] [PubMed] [Google Scholar]