Subscribe to RSS
DOI: 10.1055/s-0041-100391
Sepsis und Multiorganversagen – Pathophysiologie der Sepsis
Pathophysiology of SepsisPublication History
Publication Date:
27 February 2015 (online)
![](https://www.thieme-connect.de/media/ains/201502/lookinside/thumbnails/10.1055-s-0041-100391-1.jpg)
Zusammenfassung
Unser Verständnis der Ursachen und pathophysiologischen Grundlagen der Sepsis war im Laufe der Zeit einem stetigen Wandel unterworfen. Nach heutigem Verständnis handelt es sich bei der Sepsis um eine Immunpathologie, die zwar durch eine Infektion ausgelöst wird, deren klinisches Bild jedoch maßgeblich von der Reaktion des Wirtsorganismus bestimmt wird. Die Sepsis ist daher weder als rein pro-, noch als anti-inflammatorisches Syndrom zu verstehen. Vielmehr kommt es im Verlauf zu einer Überlagerung verschiedener Mechanismen des Immunsystems. Während in einer frühen Phase der Sepsis die überschießende (proinflammatorische) Immunreaktion dominiert, kommt es schnell zu einer antiinflammatorischen Kompensation dieser Reaktion, welche oftmals in einer Immundysfunktion mit konsekutiver Anfälligkeit für Sekundärinfektionen resultiert. Die vorliegende Übersichtsarbeit soll einen Überblick über die breite Palette an molekularen Mechanismen geben, die dem klinischen Bild der Sepsis zugrunde liegen.
Abstract
Our understanding of the causes and pathophysiological basis of sepsis has been subject to constant change over the last decades. In today's understanding, sepsis is primarily a pathology of the immune system, triggered by an underlying infection but perpetuated by the host's response itself. Thereby, sepsis should not be categorized to be either a sole pro- or anti-inflammatory syndrome, but rather as a variable continuum of overlaying immune mechanisms. While a overshooting immune reaction predominates in early sepsis, this reaction is rapidly compensated, often leading to a immune dysfunction, rendering the host susceptible for secondary infections. This review aims to provide the reader with an overview of the broad molecular mechanisms contributing to the clinical picture of sepsis.
Kernaussagen
-
Sepsis ist eine Immunpathologie, ausgelöst durch eine Infektion und getragen durch die Immunreaktion des Organismus.
-
Der Verlauf der Erkrankung ist sowohl abhängig von der individuellen Prädisposition des Patienten als auch von der Infektion.
-
Im Schwerpunkt der Pathogenese stehen die Zellen des angeborenen Immunsystems.
-
Pro- und anti-inflammatorische Mechanismen koexistieren in der Sepsis.
-
Aufgrund der engen Interaktion von Gerinnungs- und Immunsystem sowie des Endothels kommt es zur Beeinträchtigung der Hämodynamik und daraus resultierend zum Funktionsverlust zahlreicher Organe.
-
In der späten Phase der Sepsis dominiert oftmals eine Immunparalyse, welche die Entstehung von Sekundärinfektionen begünstigt.
-
Biomarker-gestützte, individualisierte Therapieverfahren können zu einer Rekonstituierung der Immunhomöostase führen.
-
Sepsis ist eine interdisziplinäre Herausforderung von Ärzten und Wissenschaftlern.
- 1 Thomas L. Germs. New England Journal of Medicine 1972; 287: 553-555
- 2 Bone RC, Bone RC, Balk RA et al. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. The ACCP/SCCM Consensus Conference Committee. American College of Chest Physicians/Society of Critical Care Medicine. Chest 1992; 101: 1644-1655
- 3 Czura CJ. Merinoff symposium 2010: sepsis-speaking with one voice. Molecular medicine (Cambridge, Mass) 2011; 17: 2-3
- 4 Marshall JC. The PIRO (predisposition, insult, response, organ dysfunction) model: Toward a staging system for acute illness. Virulence 2014; 5: 27-35
- 5 Takeuchi O, Akira S. Pattern Recognition Receptors and Inflammation. Cell 2010; 140: 805-820
- 6 Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. Journal of Leukocyte Biology 2006; 81: 1-5
- 7 Wang H, Yang H, Czura CJ et al. HMGB1 as a late mediator of lethal systemic inflammation. American journal of respiratory and critical care medicine 2001; 164: 1768-1773
- 8 Janko C, Janko C, Filipović M et al. Redox Modulation of HMGB1-Related Signaling. Antioxidants & Redox Signaling. DOI: 10.1089/ars.2013.5179. 130319100953002 2013;
- 9 Kovach MA, Standiford TJ. The function of neutrophils in sepsis. Current Opinion in Infectious Diseases 2012; 25: 321-327
- 10 Kaplan MJ, Radic M. Neutrophil Extracellular Traps: Double-Edged Swords of Innate Immunity. The Journal of Immunology 2012; 189: 2689-2695
- 11 Opal SM, Scannon PJ, Vincent JL et al. Relationship between plasma levels of lipopolysaccharide (LPS) and LPS-binding protein in patients with severe sepsis and septic shock. The Journal of infectious diseases 1999; 180: 1584-1589
- 12 Park BS, Song DH, Kim HM et al. The structural basis of lipopolysaccharide recognition by the TLR4–MD-2 complex. Nature 2009; 458: 1191-1195
- 13 Aksoy E, Taboubi S, Torres D et al. The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock. Nature immunology 2012; 13: 1045-1054
- 14 Hagar JA, Powell DA, Aachoui Y et al. Cytoplasmic LPS Activates Caspase-11: Implications in TLR4-Independent Endotoxic Shock. Science (New York, NY) 2013; 341: 1250-1253
- 15 Oberholzer A, Steckholzer U, Kurimoto M et al. Interleukin-18 plasma levels are increased in patients with sepsis compared to severely injured patients. Shock (Augusta, Ga) 2001; 16: 411-414
- 16 Schroder K, Tschopp J. The Inflammasomes. Cell 2010; 140: 821-832
- 17 Khokha R, Khokha R, Murthy A et al. Metalloproteinases and their natural inhibitors in inflammation and immunity. Nature Reviews Immunology 2013; 13: 649-665
- 18 Ward PA. The harmful role of c5a on innate immunity in sepsis. Journal of innate immunity 2010; 2: 439-445
- 19 Klöckner U, Rueckschloss U, Grossmann C et al. Inhibition of cardiac pacemaker channel hHCN2 depends on intercalation of lipopolysaccharide into channel-containing membrane microdomains. The Journal of physiology 2014; 592: 1199-1211
- 20 Müller-Werdan U. Tumor Necrosis Factorα(TNFα) is Cardiodepressant in Pathophysiologically Relevant Concentrations Without Inducing Inducible Nitric Oxide-(NO)-Synthase (iNOS) or Triggering Serious Cytotoxicity. Journal of molecular and cellular cardiology 1997; 29: 2915-2923
- 21 Werdan K, Hettwer S, Bubel S et al. Septic circulatory shock and septic cardiomyopathy. Der Internist 2009; 50: 799-809
- 22 Li Q, Zhang Q, Wang C et al. Disruption of tight junctions during polymicrobial sepsis in vivo. The Journal of Pathology 2009; 218: 210-221
- 23 van der Poll T, van der Poll T, Boer JDd et al. The effect of inflammation on coagulation and vice versa. Current Opinion in Infectious Diseases 2011; 24: 273-278
- 24 Machiedo GW, Powell RJ, Rush BF et al. The incidence of decreased red blood cell deformability in sepsis and the association with oxygen free radical damage and multiple-system organ failure. Archives of Surgery 1989; 124: 1386-1389
- 25 Steppan J, Hofer S, Funke B et al. Sepsis and major abdominal surgery lead to flaking of the endothelial glycocalix. The Journal of surgical research 2011; 165: 136-141
- 26 Fink MP. Bench-to-bedside review: Cytopathic hypoxia. Critical care (London, England) 2002; 6: 491-499
- 27 Levy RJ, Dillon S, Piel DA et al. Evidence of myocardial hibernation in the septic heart. Critical care medicine 2005; 33: 2752-2756
- 28 Hotchkiss RS, Swanson PE, Freeman BD et al. Apoptotic cell death in patients with sepsis, shock, and multiple organ dysfunction. Critical care medicine 1999; 27: 1230-1251
- 29 Marshall JC. Why have clinical trials in sepsis failed?. Trends in Molecular Medicine 2014; 20: 195-203
- 30 Bone RC, Yang H, Grodzin CJ et al. Sepsis: a new hypothesis for pathogenesis of the disease process. Chest 1997; 112: 235-243
- 31 Otto GP, Sossdorf M, Claus RA et al. The late phase of sepsis is characterized by an increased microbiological burden and death rate. Critical care (London, England) 2011; 15
- 32 Walton AH, Muenzer JT, Rasche D et al. Reactivation of Multiple Viruses in Patients with Sepsis. PloS one 2014; 9
- 33 Torgersen C, Moser P, Luckner G et al. Macroscopic Postmortem Findings in 235 Surgical Intensive Care Patients with Sepsis. Anesthesia & Analgesia 2009; 108: 1841-1847
- 34 Cavaillon J-M, Annane D. Compartmentalization of the inflammatory response in sepsis and SIRS. Journal of Endotoxin Research 2006; 12: 151-170
- 35 Froon AHM, Bemelmans MHA, Greve JW et al. Increased plasma concentrations of soluble tumor necrosis factor receptors in sepsis syndrome: Correlation with plasma creatinine values. Critical Care Medicine 1994; 22: 803-809
- 36 Bopp C, Hofer S, Weitz J et al. sRAGE is elevated in septic patients and associated with patients outcome. The Journal of surgical research 2008; 147: 79-83
- 37 Bopp C, Sprick MR, Hofer S et al. Soluble TREM-1 is not suitable for distinguishing between systemic inflammatory response syndrome and sepsis survivors and nonsurvivors in the early stage of acute inflammation. European journal of anaesthesiology 2009; 26: 504-507
- 38 Hotchkiss RS, Nicholson DW. Apoptosis and caspases regulate death and inflammation in sepsis. Nature Reviews Immunology 2006; 6: 813-822
- 39 Boomer JSJ, Boomer JSJ, To KK et al. Immunosuppression in patients who die of sepsis and multiple organ failure. JAMA : the journal of the American Medical Association 2011; 306: 2594-2605
- 40 Monneret G, Monneret G, Debard A-L et al. Marked elevation of human circulating CD4+CD25+ regulatory T cells in sepsis-induced immunoparalysis. Critical care medicine 2003; 31: 2068-2071
- 41 Cuenca AG, Delano MJ, Kelly-Scumpia KM et al. A paradoxical role for myeloid-derived suppressor cells in sepsis and trauma. Molecular medicine (Cambridge, Mass) 2011; 17: 281-292
- 42 Biswas SK, Biswas SK, Lopez-Collazo E et al. Endotoxin tolerance: new mechanisms, molecules and clinical significance. Trends in immunology 2009; 30: 475-487
- 43 Ertel W, Kremer JP, Kenney J et al. Downregulation of proinflammatory cytokine release in whole blood from septic patients. Blood 1995; 85: 1341-1347
- 44 Monneret G, Venet F, Pachot A et al. Monitoring immune dysfunctions in the septic patient: a new skin for the old ceremony. Molecular medicine (Cambridge, Mass) 2008; 14: 64-78
- 45 Boomer JS, Boomer JS, Shuherk-Shaffer J et al. A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis. Critical Care 2012; 16
- 46 Bo L, Wang F, Zhu J et al. Granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage colony stimulating factor (GM-CSF) for sepsis: a meta-analysis. Critical Care 2011; 15
- 47 Winters BD, Eberlein M, Leung J et al. Long-term mortality and quality of life in sepsis: A systematic review. Critical care medicine DOI: 10.1097/CCM.0b013e3181d8cc1d. 2010;
- 48 Hotchkiss RS, Monneret G, Payen D. Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach. The Lancet Infectious Diseases 2013; 13: 260-268