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• W2079478719 abstract "•Aberrant LM levels contribute to immune dysfunction in CI.•Aberrance reflects dysregulation of inflammatory resolution pathways or their failure.•Targeted manipulation of LMs restores immune competence and outcomes in animal models.•Stratified resolution-based immunomodulatory strategies hold therapeutic potential. Sepsis, trauma, burns, and major surgical procedures activate common systemic inflammatory pathways. Nosocomial infection, organ failure, and mortality in this patient population are associated with a quantitatively different reprioritization of the circulating leukocyte transcriptome to the initial inflammatory insult, greater in both magnitude and duration, and secondary to multiple observed defects in innate and adaptive immune function. Dysregulation of inflammatory resolution processes and associated bioactive lipid mediators (LMs) mechanistically contribute to this phenotype. Recent data indicate the potential efficacy of therapeutic interventions that either reduce immunosuppressive prostaglandins (PGs) or increase specialized proresolving LMs. Here, we reassess the potential for pharmacological manipulation of these LMs as therapeutic approaches for the treatment of critical illness (CI). Sepsis, trauma, burns, and major surgical procedures activate common systemic inflammatory pathways. Nosocomial infection, organ failure, and mortality in this patient population are associated with a quantitatively different reprioritization of the circulating leukocyte transcriptome to the initial inflammatory insult, greater in both magnitude and duration, and secondary to multiple observed defects in innate and adaptive immune function. Dysregulation of inflammatory resolution processes and associated bioactive lipid mediators (LMs) mechanistically contribute to this phenotype. Recent data indicate the potential efficacy of therapeutic interventions that either reduce immunosuppressive prostaglandins (PGs) or increase specialized proresolving LMs. Here, we reassess the potential for pharmacological manipulation of these LMs as therapeutic approaches for the treatment of critical illness (CI). Inflammation unites CISystemic inflammation is nearly ubiquitous in CI, uniting the leading causes of intensive care (ICU) admission [1Wunsch H. et al.Comparison of medical admissions to intensive care units in the United States and United Kingdom.Am. J. Respir. Crit. Care Med. 2011; 183: 1666-1673Crossref PubMed Scopus (163) Google Scholar]. Induced by infectious and noninfectious stimuli with approximately equal frequency [2Dulhunty J.M. et al.Does severe non-infectious SIRS differ from severe sepsis? Results from a multi-centre Australian and New Zealand intensive care unit study.Intensive Care Med. 2008; 34: 1654-1661Crossref PubMed Scopus (64) Google Scholar], the host inflammatory reaction is driven by common mediators and shared signaling pathways [3Xu J. et al.Extracellular histones are major mediators of death in sepsis.Nat. Med. 2009; 15: 1318-1321Crossref PubMed Scopus (1017) Google Scholar, 4Zhang Q. et al.Circulating mitochondrial DAMPs cause inflammatory responses to injury.Nature. 2010; 464: 104-107Crossref PubMed Scopus (2406) Google Scholar]. Critically ill patients are now understood to experience a highly coordinated, reproducible response at the transcriptomic, metabolomic, and proteomic level, regardless of the inflammatory source [5Langley R.J. et al.An integrated clinico-metabolomic model improves prediction of death in sepsis.Sci. Transl. Med. 2013; 5: 195ra195Crossref Scopus (302) Google Scholar, 6Tang B.M. et al.Gene-expression profiling of gram-positive and gram-negative sepsis in critically ill patients.Crit. Care Med. 2008; 36: 1125-1128Crossref PubMed Scopus (82) Google Scholar, 7Xiao W. et al.A genomic storm in critically injured humans.J. Exp. Med. 2011; 208: 2581-2590Crossref PubMed Scopus (760) Google Scholar].Adverse clinical outcomes are associated with a quantitative dysregulation of the inflammatory profile in both magnitude and duration [7Xiao W. et al.A genomic storm in critically injured humans.J. Exp. Med. 2011; 208: 2581-2590Crossref PubMed Scopus (760) Google Scholar]. Predominance and prolongation of anti-inflammatory processes mechanistically contribute to multiple defects in the innate and adaptive immune system, and consequent vulnerability to nosocomial [hospital-acquired infection (HAI)] [8Perl M. et al.Contribution of anti-inflammatory/immune suppressive processes to the pathology of sepsis.Front. Biosci. 2006; 11: 272-299Crossref PubMed Scopus (45) Google Scholar, 9Hotchkiss R.S. et al.Immunosuppression in sepsis: a novel understanding of the disorder and a new therapeutic approach.Lancet Infect. Dis. 2013; 13: 260-268Abstract Full Text Full Text PDF PubMed Scopus (925) Google Scholar] and CI-induced immune dysfunction (CIIID) [10Fullerton J.N. et al.Pathways mediating resolution of inflammation: when enough is too much.J. Pathol. 2013; 231: 8-20Crossref PubMed Scopus (49) Google Scholar]. In total, ∼30% of CI patients will contract HAI; a rate six times greater than on standard wards [11Burgmann H. et al.Impact of nosocomial infections on clinical outcome and resource consumption in critically ill patients.Intensive Care Med. 2010; 36: 1597-1601Crossref PubMed Scopus (46) Google Scholar, 12Vincent J.L. Nosocomial infections in adult intensive-care units.Lancet. 2003; 361: 2068-2077Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar]. HAI in this setting is associated with a twofold greater inpatient mortality risk and a case mortality in excess of 50% [11Burgmann H. et al.Impact of nosocomial infections on clinical outcome and resource consumption in critically ill patients.Intensive Care Med. 2010; 36: 1597-1601Crossref PubMed Scopus (46) Google Scholar, 13Alberti C. et al.Epidemiology of sepsis and infection in ICU patients from an international multicentre cohort study.Intensive Care Med. 2002; 28: 108-121Crossref PubMed Scopus (711) Google Scholar]. Causative pathogens are most commonly bacterial; however, fungal infections (particularly Candida spp.) are increasing in incidence [12Vincent J.L. Nosocomial infections in adult intensive-care units.Lancet. 2003; 361: 2068-2077Abstract Full Text Full Text PDF PubMed Scopus (453) Google Scholar]. Viral infection, especially reactivation, poses an additional risk, and polymicrobial infection is common.LMs, including eicosanoids and the more recently discovered ‘specialized pro-resolution lipid mediators’ (SPMs), are key signaling molecules in the resolution of inflammation, playing a pivotal role in regulating the inflammatory profile and promoting return to homeostasis [14Serhan C.N. Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?.Am. J. Pathol. 2010; 177: 1576-1591Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar]. Their dysregulation in any of several dimensions may have pathogenic consequences (Box 1), with failure of resolution leading to chronic inflammation and excess tissue damage being best recognized [14Serhan C.N. Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?.Am. J. Pathol. 2010; 177: 1576-1591Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar, 15Nathan C. Ding A. Nonresolving inflammation.Cell. 2010; 140: 871-882Abstract Full Text Full Text PDF PubMed Scopus (1380) Google Scholar]. The potential active contribution of LMs to an anti-inflammatory, immunosuppressive phenotype has, until recently, received little attention [10Fullerton J.N. et al.Pathways mediating resolution of inflammation: when enough is too much.J. Pathol. 2013; 231: 8-20Crossref PubMed Scopus (49) Google Scholar].Box 1LMs: background and pathogenic potentialAA (20:6, ω-6), docosahexaenoic acid (22:6, ω-3) and eicosapentaenoic acid (20:5, ω-3) are polyunsaturated fatty acids that form the substrates for the enzymatic generation of several groups of bioactive LMs. Eicosanoids – the generic term for a group of bioactive lipids containing 20 carbons derived from AA – are divided into several separate mediator families, the major groups being the PGs, LTs and LXs. More recently discovered ω-3-derived SPM families include Rvs, protectins, and maresins. LMs represent vital endogenous biochemical determinants of inflammatory kinetics and the principle mediators of resolution.The ability of NSAIDs to reduce the primary symptoms and signs of inflammation via COX inhibition and hence PG suppression has led to a common assumption that they, and in turn eicosanoids in general, are universally proinflammatory. This represents a grossly simplified view. These lipid mediators are variably constitutive and inducible, expressed widely yet in a cell-type- and tissue-specific manner, and their actions are diverse, multifaceted, and vary down to the receptor level. Individual molecules have been shown to variably exert pro- and anti-inflammatory effects along with pro-resolution properties in a context-dependent manner.Given their immunomodulatory potency and diversity of action, for an effective and self-limited inflammatory reaction to be facilitated, eicosanoid generation must be localized, balanced, proportionate, and timely. Disturbance in any of these dimensions in isolation, or more likely combination, may contribute adversely to disease states. Several pathogenic aberrations may be hypothesized:1)Location of action.•Compartment leakage or altered distribution of generation. Endocrine as opposed to typical autocrine or paracrine activity.2)Increased or decreased concentration.•Altered synthesis, via host, pathogen or iatrogenic intervention, through modulation of substrate or enzymatic process.•Promotion or loss of catabolism (local or systemic) or the failure of feedback loops. Altered bioavailability or protein binding (e.g., albumin).3)Deranged temporal profile of production.•Failure or dysregulation of eicosanoid class switching [64Levy B.D. et al.Lipid mediator class switching during acute inflammation: signals in resolution.Nat. Immunol. 2001; 2: 612-619Crossref PubMed Scopus (1084) Google Scholar, 65Serhan C.N. Savill J. Resolution of inflammation: the beginning programs the end.Nat. Immunol. 2005; 6: 1191-1197Crossref PubMed Scopus (1757) Google Scholar].4)Up- or downregulation of receptors, alteration in receptor profile, including distribution.5)Modification of action (e.g., co-stimulation – additive, synergistic, or anergic) by other stimuli/mediators in the surrounding inflammatory milieu.In broad terms, two key patterns may result from the above. First, deficient or failed resolution where either an insufficient concentration of LM are available to facilitate inflammatory termination, or their action is inadequate. This has been recently discussed in varying inflammatory conditions [14Serhan C.N. Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?.Am. J. Pathol. 2010; 177: 1576-1591Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar]. Second, a state we describe as injurious resolution may exist. Here, an excessive immunoregulatory effect is exerted by eicosanoids involved in the initiation or control of resolution, rendering host defenses locally or systemically compromised [10Fullerton J.N. et al.Pathways mediating resolution of inflammation: when enough is too much.J. Pathol. 2013; 231: 8-20Crossref PubMed Scopus (49) Google Scholar].Observational studies have related LM-modifying aspirin and statin administration, as well as nonsteroidal anti-inflammatory drugs (NSAIDs), to clinical benefit in the CI population (Box 2) [16Eisen D.P. Manifold beneficial effects of acetyl salicylic acid and nonsteroidal anti-inflammatory drugs on sepsis.Intensive Care Med. 2012; 38: 1249-1257Crossref PubMed Scopus (45) Google Scholar], and compelling clinical data support the use of targeted immunomodulatory therapy [17Meisel C. et al.Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial.Am. J. Respir. Crit. Care Med. 2009; 180: 640-648Crossref PubMed Scopus (450) Google Scholar, 18Hall M.W. et al.Immunoparalysis and nosocomial infection in children with multiple organ dysfunction syndrome.Intensive Care Med. 2011; 37: 525-532Crossref PubMed Scopus (198) Google Scholar]. This information, coupled with a more advanced appreciation of how inflammatory resolution pathways, and LMs in particular, may affect immune competence (and be used to modify it) in CI, necessitates a reappraisal of the clinical validity of these drugs.Box 2Observational and mechanistic data supporting therapeutic LM manipulationRegular use of aspirin in patients who develop community-acquired pneumonia has been associated with lower ICU requirement (odds ratio 0.19, 95% confidence interval 0.04–0.87) and shorter in-patient stay (13.9±6.2 vs. 18.2±10.2 days) [86Winning J. et al.Anti-platelet drugs and outcome in severe infection: clinical impact and underlying mechanisms.Platelets. 2009; 20: 50-57Crossref PubMed Scopus (92) Google Scholar]. In a general CI patient set prior prescription and consumption of aspirin and statins has been linked with reduced severity of illness (development of severe sepsis, acute lung injury, or adult respiratory distress syndrome) and mortality in a multivariate analysis [83O’Neal Jr, H.R. et al.Prehospital statin and aspirin use and the prevalence of severe sepsis and acute lung injury/acute respiratory distress syndrome.Crit. Care Med. 2011; 39: 1343-1350Crossref PubMed Scopus (149) Google Scholar]. Aspirin administration within 24 h of SIRS recognition has been separately linked with a significant decrease in mortality in all such ICU patients of –6.2% (absolute risk difference after propensity matching), and an even greater mortality reduction in those with proven sepsis of –14.8% (27.4% aspirin vs. 42.2% no aspirin) [84Eisen D.P. et al.Acetyl salicylic acid usage and mortality in critically ill patients with the systemic inflammatory response syndrome and sepsis.Crit. Care Med. 2012; 40: 1761-1767Crossref PubMed Scopus (90) Google Scholar]. Independently, a near 50% reduction in the risk of inpatient mortality in septic patients given aspirin during their ICU admission has been described [88Otto G.P. et al.Effects of low-dose acetylsalicylic acid and atherosclerotic vascular diseases on the outcome in patients with severe sepsis or septic shock.Platelets. 2012; 24: 480-485Crossref PubMed Scopus (51) Google Scholar], with similar levels of benefits potentially resulting from utilization of alternative NSAIDs in addition (ibuprofen, diclofenac, or indomethacin) [85Sossdorf M. et al.Benefit of low-dose aspirin and non-steroidal anti-inflammatory drugs in septic patients.Crit. Care. 2013; 17: 402Crossref PubMed Scopus (39) Google Scholar]. NSAID benefit is however lost if coadministered with aspirin [85Sossdorf M. et al.Benefit of low-dose aspirin and non-steroidal anti-inflammatory drugs in septic patients.Crit. Care. 2013; 17: 402Crossref PubMed Scopus (39) Google Scholar], and concerns regarding delayed presentation [89Legras A. et al.A multicentre case-control study of nonsteroidal anti-inflammatory drugs as a risk factor for severe sepsis and septic shock.Crit. Care. 2009; 13: R43Crossref PubMed Scopus (37) Google Scholar] and side effects persist [84Eisen D.P. et al.Acetyl salicylic acid usage and mortality in critically ill patients with the systemic inflammatory response syndrome and sepsis.Crit. Care Med. 2012; 40: 1761-1767Crossref PubMed Scopus (90) Google Scholar]. The cause of clinical improvement is likely multifactorial and suggested to be secondary to antithrombotic (antiplatelet), anti-inflammatory effects and augmentation of inflammatory resolution pathways [16Eisen D.P. Manifold beneficial effects of acetyl salicylic acid and nonsteroidal anti-inflammatory drugs on sepsis.Intensive Care Med. 2012; 38: 1249-1257Crossref PubMed Scopus (45) Google Scholar, 87Winning J. et al.Antiplatelet drugs and outcome in mixed admissions to an intensive care unit.Crit. Care Med. 2010; 38: 32-37Crossref PubMed Scopus (74) Google Scholar]. This is re-enforced via positive interactions with statins [83O’Neal Jr, H.R. et al.Prehospital statin and aspirin use and the prevalence of severe sepsis and acute lung injury/acute respiratory distress syndrome.Crit. Care Med. 2011; 39: 1343-1350Crossref PubMed Scopus (149) Google Scholar] and other antiplatelet agents [86Winning J. et al.Anti-platelet drugs and outcome in severe infection: clinical impact and underlying mechanisms.Platelets. 2009; 20: 50-57Crossref PubMed Scopus (92) Google Scholar, 87Winning J. et al.Antiplatelet drugs and outcome in mixed admissions to an intensive care unit.Crit. Care Med. 2010; 38: 32-37Crossref PubMed Scopus (74) Google Scholar].Mechanistically, aspirin and statins exert their immunomodulatory actions through increased synthesis of bioactive SPMs from all three PUFAs (Figure 3). Both may modify COX-2 – aspirin via serine acetylation, and statins via cysteine S-nitrosylation – to generate 15R-hydroxyeicosatetraenoic acid, which is subsequently converted by 5-LOX into 15-epi-LXA4 (aspirin-triggered LX, ATL). Aspirin may in addition upregulate expression of the ATL receptor ALX (FPRL1) [42Morris T. et al.Effects of low-dose aspirin on acute inflammatory responses in humans.J. Immunol. 2009; 183: 2089-2096Crossref PubMed Scopus (233) Google Scholar], and promote the generation of aspirin-triggered Rvs (17R-epimers) and protectins (e.g., aspirin-triggered protectin D1). Glucocorticoids have also been demonstrated to increase SPM generation [79Perretti M. et al.Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor.Nat. Med. 2002; 8: 1296-1302Crossref PubMed Scopus (368) Google Scholar]. The effects of these molecules in models of CI are discussed in the main text.Here, we summarize contemporary preclinical and clinical data describing the effects of modulating LMs in CI syndromes, predominantly sepsis. We describe the pathogenic contribution of two distinct yet interlinked patterns of dysregulation to CIIID, namely injurious and failed inflammatory resolution, and discuss therapeutic opportunities presented by LM manipulation.CI: a failure of resolution?ω-3-Derived SPMs from different series appear to have individually separate yet collectively beneficial effects on multiple modalities of immune function. Evidence indicates that a paucity of these LMs contributes to derangement of the inflammatory profile and CIIID, with therapeutic replacement restoring or augmenting immune function. In the next sections we discuss data relating to specific LMs of the resolvin (Rv) and protectin series, and later the lipoxin (LX) and leukotriene (LT) families in interventional animal models of infection/inflammation.Defining features of SPM bioaction include the ability to: (i) counter-regulate mediators that summon leukocytes, in particular polymorphonuclear cells (PMNs, neutrophils), to an inflamed site; (ii) dampen pain; (iii) stimulate nonphlogistic monocyte recruitment; and (iv) activate macrophages to efferocytose apoptotic granulocytes and clear both pathogens and tissue debris [14Serhan C.N. Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?.Am. J. Pathol. 2010; 177: 1576-1591Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar]. Despite being part of the endogenous anti-inflammatory process via action (i), with associated prevention of inflammatory amplification, it is attributes (iii) and (iv) in tandem with promotion of phagocyte trafficking to lymph nodes [19Schwab J.M. et al.Resolvin E1 and protectin D1 activate inflammation-resolution programmes.Nature. 2007; 447: 869-874Crossref PubMed Scopus (935) Google Scholar] that distinguishes them from classical anti-inflammatory mediators such as interleukin (IL)-10 or IL-1 receptor antagonist [14Serhan C.N. Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?.Am. J. Pathol. 2010; 177: 1576-1591Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar].SPMs have repeatedly been demonstrated to lack an immunosuppressive action, and indeed to augment host-directed antimicrobial defenses [20Spite M. et al.Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis.Nature. 2009; 461: 1287-1291Crossref PubMed Scopus (512) Google Scholar]. These molecules stimulate mucosal production of bactericidal peptides [21Canny G. et al.Lipid mediator-induced expression of bactericidal/permeability-increasing protein (BPI) in human mucosal epithelia.Proc. Natl. Acad. Sci. U.S.A. 2002; 99: 3902-3907Crossref PubMed Scopus (244) Google Scholar] and enhance bacterial phagocytosis by PMNs and macrophages, working synergistically with antibiotics, to increase their therapeutic action and hence bacterial clearance [22Chiang N. et al.Infection regulates pro-resolving mediators that lower antibiotic requirements.Nature. 2012; 484: 524-528Crossref PubMed Scopus (465) Google Scholar]. They have further been shown to suppress nuclear viral mRNA transcript export, and hence replication, reducing mortality from influenza infection [23Morita M. et al.The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza.Cell. 2013; 153: 112-125Abstract Full Text Full Text PDF PubMed Scopus (321) Google Scholar]: a potentially novel therapeutic addition to standard antivirals, focused on modifying host immune capability, avoiding the problems posed by these infectious agents diversity, variability and capacity to evolve.Rvs and protectinsRvE1 administered prior to a murine model of aspiration pneumonia (hydrochloric acid with subsequent Escherichia coli challenge) was associated with a reduction in proinflammatory cytokines, decreased pulmonary PMN accumulation, enhanced bacterial clearance, and improved survival [24Seki H. et al.The anti-inflammatory and proresolving mediator resolvin E1 protects mice from bacterial pneumonia and acute lung injury.J. Immunol. 2010; 184: 836-843Crossref PubMed Scopus (173) Google Scholar]. El Kebir and colleagues have further described the ability of RvE1 to promote resolution of established infective and sterile models of murine lung injury [25El Kebir D. et al.Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation.Proc. Natl. Acad. Sci. U.S.A. 2012; 109: 14983-14988Crossref PubMed Scopus (198) Google Scholar]. Mechanistically, RvE1 was noted to enhance NADPH-oxidase reactive oxygen species generation and promote phagocytosis-induced neutrophil apoptosis (with subsequent efferocytosis by macrophages) via the LTB4 receptor BLT1. Increased activation of caspase-8 and caspase-3 in tandem with attenuation of both extracellular signal-regulated kinase (ERK) and Akt-mediated apoptosis-suppressing signals shifting the balance of pro-/anti-survival information toward apoptosis via induction of mitochondrial dysfunction. In addition, RvE1, at concentrations as low as 1 nM, enhances macrophage phagocytosis, with the products of its metabolism continuing to exert pro-resolution properties but with reduced bioactivity in vivo [26Hong S. et al.Resolvin E1 metabolome in local inactivation during inflammation-resolution.J. Immunol. 2008; 180: 3512-3519Crossref PubMed Scopus (89) Google Scholar].RvD1 pretreatment prior to lipopolysaccharide (LPS)-induced acute lung injury is protective, improving pathological changes and survival [27Wang B. et al.Resolvin D1 protects mice from LPS-induced acute lung injury.Pulm. Pharmacol. Ther. 2011; 24: 434-441Crossref PubMed Scopus (145) Google Scholar]. The central mechanism appears to be suppression of nuclear factor (NF)-κB activation in a partly peroxisome proliferator-activated receptor (PPAR)γ-dependent manner, with associated reduction in downstream signaling/transcriptomic alteration [28Liao Z. et al.Resolvin D1 attenuates inflammation in lipopolysaccharide-induced acute lung injury through a process involving the PPARgamma/NF-kappaB pathway.Respir. Res. 2012; 13: 110Crossref PubMed Scopus (118) Google Scholar]. RvD2, but not its isomer trans-RvD2, has been shown specifically to improve survival in murine polymicrobial sepsis (cecal-ligation and puncture; CLP). Its actions appear multifaceted – modulating leukocyte–endothelium interactions in a direct (adhesion receptor expression) and indirect manner (endothelial NO production), altering the cytokine profile [reduced IL-17, IL-10, PGE2 and LTB4], and enhancing bacterial phagocytosis and intraphysosomal vacuolar production of reactive oxygen species [20Spite M. et al.Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis.Nature. 2009; 461: 1287-1291Crossref PubMed Scopus (512) Google Scholar]. More recently, the ability of RvD2 to restore neutrophil directionality, prevent CIIID, and thus increase survival from a secondary septic challenge post-burn injury has been demonstrated [29Kurihara T. et al.Resolvin D2 restores neutrophil directionality and improves survival after burns.FASEB J. 2013; 27: 2270-2281Crossref PubMed Scopus (65) Google Scholar].Discrete specialized pro-resolution mediators are unlikely to be produced in isolation and have overlapping proresolving actions. RvE1, aspirin-triggered (ATL, 15-epi-lipoxin A4) and protectin D1 may independently rescue cyclo-oxygenase (COX)- and lipoxygenase (LOX)-derived ‘resolution deficits’ in vitro and in vivo, with actions extending to promotion of phagocyte trafficking away from the primary inflammatory site [19Schwab J.M. et al.Resolvin E1 and protectin D1 activate inflammation-resolution programmes.Nature. 2007; 447: 869-874Crossref PubMed Scopus (935) Google Scholar]. The ability to bind and act as agonists on alternate SPM receptors (e.g., RvD1 on the LXA4 receptor [27Wang B. et al.Resolvin D1 protects mice from LPS-induced acute lung injury.Pulm. Pharmacol. Ther. 2011; 24: 434-441Crossref PubMed Scopus (145) Google Scholar]) may provide one pharmacological explanation for this phenomenon. However, despite their common actions the source of different classes of SPMs in inflammation appears diverse. Recent evidence suggests that RvE1 and 2 are synthesized by PMNs via the 5-LOX pathway [30Tjonahen E. et al.Resolvin E2: identification and anti-inflammatory actions: pivotal role of human 5-lipoxygenase in resolvin E series biosynthesis.Chem. Biol. 2006; 13: 1193-1202Abstract Full Text Full Text PDF PubMed Scopus (198) Google Scholar], whereas eosinophils are responsible for generation of 12/15-LOX-derived mediators protectin D1 and the newly discovered RvE3 [31Yamada T. et al.Eosinophils promote resolution of acute peritonitis by producing proresolving mediators in mice.FASEB J. 2011; 25: 561-568Crossref PubMed Scopus (112) Google Scholar, 32Isobe Y. et al.Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid.J. Biol. Chem. 2012; 287: 10525-10534Crossref PubMed Scopus (178) Google Scholar]. Deficiency of these cell types in the resolution phase may lead to impaired biosynthesis with deleterious consequences [31Yamada T. et al.Eosinophils promote resolution of acute peritonitis by producing proresolving mediators in mice.FASEB J. 2011; 25: 561-568Crossref PubMed Scopus (112) Google Scholar]. The same may be true of polyunsaturated fatty acids at the inflammatory site.Experimentally, the ω-3 Rv precursors eicosapentaenoic and docosahexaenoic acids have been demonstrated to increase in exudates during the resolution phase; being both plasma (partially bound to leaked albumin) and locally derived [14Serhan C.N. Novel lipid mediators and resolution mechanisms in acute inflammation: to resolve or not?.Am. J. Pathol. 2010; 177: 1576-1591Abstract Full Text Full Text PDF PubMed Scopus (331) Google Scholar, 33Kasuga K. et al.Rapid appearance of resolvin precursors in inflammatory exudates: novel mechanisms in resolution.J. Immunol. 2008; 181: 8677-8687Crossref PubMed Scopus (202) Google Scholar]. Indirect evidence to support the therapeutic benefit of increasing this SPM series concentration in humans comes from the addition of fish oils to parenteral nutrition in septic patients. A raised plasma eicosapentaenoic concentration was observed along with modification of the cytokine profile, and small physiological and clinical benefits in a recent randomized clinical trial [34Barbosa V.M. et al.Effects of a fish oil containing lipid emulsion on plasma phospholipid fatty acids, inflammatory markers, and clinical outcomes in septic patients: a randomized, controlled clinical trial.Crit. Care. 2010; 14: R5Crossref PubMed Scopus (135) Google Scholar].LTs and LXsTherapeutic use of the arachidonic acid (AA)-derived LX series may also be beneficial. Post-insult treatment with LXA4 has been demonstrated to limit inhaled LPS-induced lung injury [35Jin S.W. et al.Posttreatment with aspirin-triggered lipoxin A4 analog attenuates lipopolysaccharide-induced acute lung injury in mice: the role of heme oxygenase-1.Anesth. Analg. 2007; 104: 369-377Crossref PubMed Scopus (112) Google Scholar], and to reduce pro- and anti-inflammatory cytokine production, enhance macrophage recruitment, reduce blood bacterial load, and improve mortality in a rat CLP model [36Walker J. et al.Lipoxin a4 increases survival by decreasing systemic inflammation and bacterial load in sepsis.Shock. 2011; 36: 410-416Crossref PubMed Scopus (98) Google Scholar]. In this later study, macrophage recruitment was increased without impairing phagocytic function, and systemic inflammation" @default.
• W2079478719 created "2016-06-24" @default.
• W2079478719 creator A5024695885 @default.
• W2079478719 creator A5059667674 @default.
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• W2079478719 date "2014-01-01" @default.
• W2079478719 modified "2023-10-18" @default.
• W2079478719 title "Lipid mediators in immune dysfunction after severe inflammation" @default.
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