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Medical Hypotheses 80 (2013) 297–299
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Is sepsis a pro-resolution deficiency disorder? Undurti N. Das UND Life Sciences, 13800 Fairhill Road, #321, Shaker Heights, OH 44120, USA School of Biotechnology, Jawaharlal Nehru Technological University, Kakinada-533 003, India
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Article history: Received 31 July 2012 Accepted 5 December 2012
a b s t r a c t Sepsis is due to a systemic inflammatory response to both infectious and non-infectious disorders; and when it leads to hypotension and organ dysfunction, septic shock occurs. Mortality in sepsis is due to multiple organ dysfunction. The early stages of sepsis are characterized by excessive generation of inflammatory mediators; however, as sepsis develops into chronic severe sepsis, immunosuppression dominates. Despite several advances in our understanding of the pathogenesis of sepsis both its prevention and management remains elusive. It is proposed that sepsis is due to failure of production of appropriate amounts of pro-resolution bioactive lipids such as lipoxins, resolvins, protectins, maresins and nitrolipids that suppress inappropriate inflammation, production of pro-inflammatory cytokines, free radical generation, and leukocyte activation and enhance resolution of inflammation and wound healing. Ó 2012 Elsevier Ltd. All rights reserved.
Introduction Sepsis is common and accounts for more than 200, 000 deaths per year in the USA alone. The number of patients with sepsis is increasing, partly due to its high prevalence among elderly patients and the age of the population [1–3]. Sepsis is due to a systemic inflammatory response to both infectious and non-infectious disorders. When sepsis causes hypotension and organ dysfunction, it results in septic shock [4] and death is due to multiple organ dysfunction. Several mediators that participate in the pathobiology of sepsis include: human leukocyte antigen-DR (HLA-DR), tumor necrosis factor-a (TNF-a), interleukin-1 (IL-1), IL-2, IL-4, IL-6, IL-8, IL-10, high mobility group box-1 (HMGB1) protein, adhesion molecules, CD11b/CD18, x-3 fatty acids, eicosanoids, and high-density lipoprotein (HDL) and reactive oxygen species (ROS) [4–11].
The immune response in sepsis and critical illness Patients with sepsis have difficulty clearing infections; show reduced and delayed hypersensitivity. They are also susceptible to nosocomial infections [12–15]. Common mutations in TLR-4 (Toll-like receptor) are associated with differences in LPS (lipopolysaccharide) responsiveness in humans, suggesting that gene-sequence changes can alter host response to environmental stress such as infections that could render some to develop sepsis while others do not [14,16]. This indicates that elaboration of adequate amounts of inflammationresolving bioactive molecules could limit infection and injury E-mail address:
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and restore normal function and recovery from sepsis. In this context, it is noteworthy that TLRs regulate free radical generation, macrophage and leukocyte function, modulate eicosanoid synthesis and thus, play a critical role in inflammation and immune response [17–22]. TLRs, pro- and anti-inflammatory bioactive lipids and sepsis Polyunsaturated fatty acids (PUFAs) form precursors to both pro- and anti-inflammatory bioactive lipids and have modulatory influence on the expression of TLRs. For example, COX-2 (cyclooxygenase-2) mediated high production of PGE2 and, to a lesser extent, other prostanoids after LPS stimulation. In contrast, LPS down-regulated COX-1 in a MyD88-dependent fashion, and COX-1 deficiency increased prostaglandin E2 (PGE2) production following LPS stimulation in astrocytes. Thus, LPS stimulated COX-2-dependent production of prostanoids and suggest that coordinated down-regulation of COX-1 facilitates PGE2 production after TLR-4 activation [23,24]. PUFA supplementation especially of AA (arachidonic acid, 20:4 x-6) and DHA (docosahexaenoic acid, 22:6 x-3) reduced the incidence of inflammatory condition necrotizing enterocolitis (NEC) and inhibited intestinal TLR-4 gene expression and thus, ameliorated NEC [25,26]. It is noteworthy that administration of resolvins and protectin D1, which are derived from DHA and have potent anti-inflammatory actions, reduced the number of infiltrating leukocytes and blocked TLR-mediated activation of macrophages and reduced interstitial fibrosis after ischemia–reperfusion-induced kidney injury [27,28].These results suggest that a co-ordinated synthesis, release and action of proand anti-inflammatory molecules need to occur to induce appropriate amount of inflammatory process and subsequent resolution of infection, inflammation and restore cell/tissue/organ function to
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Fig. 1. Scheme showing relationship among infection, LPS, PUFAs, eicosanoids, cytokines, ROS and sepsis and septic shock. During infection/injury/surgery (especially following abdominal surgery), gut barrier function is disrupted leading to the absorption of endotoxins (LPS) from the gut into the circulation. LPS activates monocytes, macrophages and leukocytes leading to the release of pro-inflammatory cytokines: TNF-, IL-6, MIF, HMGB1 that, in turn, incite excess of free radicals, nitric oxide and proinflammatory eicosanoids: prostaglandins, thromboxanes and leukotrienes, which lead to hypoglycemia, hypotension, decreased tissue perfusion and tissue injury that results in sepsis and septic shock. Lipoxins, resolvins, protectins, maresins and nitrolipids have anti-inflammatory actions by virtue of their ability to suppress production of TNF-, IL-6, MIF, HMGB1, free radicals, inducible nitric oxide and pro-inflammatory eicosanoids. Lipoxins, resolvins, protectins, maresins and nitrolipids may also restore gut barrier function, eliminate invading micro-organisms, and suppress the activation of macrophages and leukocytes and thus, are of benefit in the prevention and management of sepsis and septic shock.
normal. This is supported by the observation that resolvin D2, a potent anti-inflammatory compound derived from DHA, has stereoselective actions in reducing excessive neutrophil trafficking to inflammatory loci, decreased leukocyte–endothelial interactions in vivo by endothelial-dependent nitric oxide production, and by direct modulation of leukocyte adhesion receptor expression. Resolvin D2 suppressed and improved survival in the mice model of microbial sepsis initiated by caecal ligation and puncture (CLP) [29]. Flavocoxid, a dual inhibitor of cyclooxygenase (COX-2) and 5-lipoxygenase (5-LOX), has been shown to possess antiinflammatory activity in LPS-stimulated rat macrophages in vitro by reducing nuclear factor (NF)-jB activity and COX-2, 5-LOX and inducible nitric oxide synthase (iNOS) expression. In a murine model of CLP-induced polymicrobial sepsis, flavocoxid improved survival and reduced the expression of NF-jB, COX-2, 5-LOX, TNF-a and IL-6; reduced blood LTB4, PGE2, TNF-a and IL-6 and increased IL-10 production and LXA4 serum levels and also showed protection against the histologic damage induced by CLP and reduced the myeloperoxidase (MPO) activity in the lung and liver [30]. These results [29,30] support the proposal that sepsis could be a pro-resolving deficiency disorder and that methods designed to enhance the levels of anti-inflammatory bioactive lipids LXA4 and resolvin D2 protect against sepsis and septic shock. Sepsis as a pro-resolution deficiency disorder Based on the preceding discussion, I propose that sepsis and septic shock are due to failure of timely generation and action of anti-inflammatory and pro-resolution molecules: lipoxins, resolvins, protectins, maresins and nitrolipids. Thus, the balance between inflammation and resolution is disturbed more in favor of proinflammatory events in sepsis. It is likely that even after the inciting agent responsible for the initiation of inflammation is removed; inappropriate inflammation continues simply because resolution failed to occur that leads to delay in the healing/repair process and so tissue/organ damage continues and sepsis persists.
It was reported that inhaled LPS-induced lung injury in mice can be markedly diminished by the administration of 15-epi-16parafluoro-phenoxy lipoxin A4 by increasing heme oxygenase-1 (HO-1) activity that, in turn, augmented carbon monoxide (CO) generation [31]. Administration of LXA4 (40 lg/kg, i.p.) 5 h after surgery to CLP rats lived longer than 48 h and attenuated tissue injury after 8 days [32]. In this study, LXA4 reduced plasma IL-6, monocyte chemoattractant protein 1 and IL-10 levels by suppressing NF-jB activation and reduced blood bacterial load by enhancing macrophage recruitment without affecting phagocytic ability. These results are similar to those seen with resolvin D2, which decreased IL-17 and IL-10, PGE2 and LTB4 but enhanced leukocyte Escherichia coli phagocytosis that was accompanied by an increase in intracellular ROS [29] that led to increased survival rates among CLP-operated mice treated with resolvin D2. Thus, both LXA4 and resolvin D2 increased survival in sepsis by simultaneously reducing systemic inflammation as well as bacterial spread [29–32]. These results are in support of the proposal that a deficiency of pro-resolution molecules play a significant role in sepsis. Testing the hypothesis This proposal can be verified by measuring the plasma and urinary levels of lipoxins, resolvins, protectins, maresins and nitrolipids in patients at various stages of sepsis and correlating their levels with the degree of severity of sepsis and multiorgan dysfunction. Based on the evidences presented above and the role of LXA4 and LTs and PGs in inflammation, it is logical to suggest that a deficiency of LXA4, protectin D2 and other bioactive lipids that have anti-inflammatory actions and/or an excess of LTs and PGs that possess pro-inflammatory property initiate and perpetuate inflammation in sepsis. Plasma and urinary levels of LXA4 and LTs can be measured and correlated with progression of sepsis. If the plasma and urinary LXA4, resolvin D2, protectin D1 levels revert to normal or are slowly increasing with/without a decrease in the plasma and
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U.N. Das / Medical Hypotheses 80 (2013) 297–299
urinary levels of LTs, it can be considered as an indication that the patient is responding to treatment. The urinary levels of LXA4, resolvins and protectins and LTs can be compared to the clinical picture and APCHE score to know the progress of sepsis. Since lipoxins, resolvins, protectins, maresins and nitrolipids are all anti-inflammatory lipid molecules derived from various PUFAs and have a role in the resolution of inflammation, it is predicted that they all may have a significant role in the prevention and recovery from sepsis and septic shock. In order to ascertain their role in sepsis, it is essential to develop reliable, robust and simple methods (though it is possible to measure them by LC-MS and MSMS techniques) to estimate their levels in the plasma and urine and other body fluids. Conclusion The proposal that sepsis and septic shock could be due to a deficiency of anti-inflammatory and pro-resolution lipoxins, resolvins, protectins, maresins and nitrolipids and excess production of proinflammatory LTs and PGs is supported by the observation that in experimental animals LXA4 and its analogues attenuated sepsis induced by LPS and other stimuli [29–32]. It is noteworthy that lipoxins, resolvins, protectins and maresins are not only antiinflammatory in nature but also enhance wound healing, resolve inflammation and possess cytoprotective and neuroprotective actions [33,34] (see Fig. 1). Hence, it is likely that when the local concentrations of lipoxins, resolvins, protectins and maresins are low, it could lead to continued inflammation and tissue damage whereas when their levels are enhanced inappropriate inflammation will be suppressed leading to healing and cytoprotection. In addition, lipoxins, resolvins, protectins and maresins enhance stem cell survival, proliferation and differentiation [34–37] that could aid in healing and augment recovery process in sepsis. Hence, efforts made to enhance the levels of lipoxins, resolvins, protectins and maresins or use of their synthetic analogues that are more stable and potent in their action may prove to be of significant benefit in the prevention and management of sepsis and septic shock. Conflict of interest statement None. References [1] Angus 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;29:1303–10. [2] Le Gall JR, Alberti C, Brun Buisson C. Epidemiology of infection and sepsis in intensive care unit patients. Bull Acad Natl Med 2004;188:1115–25. [3] Melamed A, Sorvillo FJ. The burden of sepsis-associated mortality in the United States from 1999 to 2005: an analysis of multiple-cause-of-death data. Crit Care 2009;13:R28. [4] Das UN. Can sepsis and other critical illnesses be predicted and prognosticated? Adv Sepsis 2006;5:52–9. [5] Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med 2003;348:138–50. [6] Kinasewitz GT, Yan BS, Basson B, Comp P, Russell JA, Cariou A, et al. For the PROWESS Sepsis Study Group. Universal changes in biomarkers of coagulation and inflammation occur in patients with severe sepsis, regardless of causative micro-organism [ISRCTN74215569]. Crit. Care 2004;8:R82–90. [7] Tracey KJ, Beutler B, Lowry SF, Merryweather J, Wolpe S, Milsark IW, et al. Shock and tissue injury induced by recombinant human cachectin. Science 1986;234:470–4. [8] Tracey KJ, Fong Y, Hesse DG, Manogue KR, Lee AT, Kuo GC, et al. Anti-cachectin/ TNF monoclonal antibodies prevent septic shock during lethal bacteraemia. Nature 1987;330:662–4. [9] Karlsson S, Pettilä V, Tenhunen J, Laru-Sompa R, Hynninen M, Ruokonen E. HMGB1 as a predictor of organ dysfunction and outcome in patients with severe sepsis. Intensive Care Med 2008;34:1046–53. [10] Yang H, Ochani M, Li J, Qiang X, Tanovic M, Harris HE, et al. Reversing established sepsis with antagonists of endogenous high mobility group box-1. Proc Natl Acad Sci USA 2004;101:296–301.
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