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Review
, 35 (1), 12-21

Lipid Mediators in Immune Dysfunction After Severe Inflammation

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Review

Lipid Mediators in Immune Dysfunction After Severe Inflammation

James N Fullerton et al. Trends Immunol.

Abstract

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).

Keywords: cyclooxygenase; eicosanoids; immunosuppression; prostaglandins; resolution of inflammation; sepsis.

Figures

Figure 1
Figure 1
Immunomodulatory effects of two broad classes of lipid mediators throughout the inflammatory response. Persistence or excessive levels of cyclooxygenase-derived prostanoids and leukotrienes due to a failure to class-switch may contribute to injurious resolution. Here, mediators designed to promote inflammatory resolution multimodally drive an immunosuppressive, anti-inflammatory phenotype leading to susceptibility to secondary nosocomial infections (highlighted in red). Predominantly ω-3 polyunsaturated fatty acid lipoxygenase-derived specialized proresolving lipid mediators nonphlogistically augment key processes in inflammatory resolution. An absence or deficit of these eicosanoids may lead to chronic inflammation, failure of pathogen clearance, and both local or distal tissue damage.
Figure 2
Figure 2
Proposed dysregulation of resolution-phase lipid mediators in critical illness. Solid lines indicate the normal inflammatory profile, with an early rise in cyclooxygenase (COX)-derived prostaglandins (PGs) and 5-lipoxygenase-derived leukotriene B4, which trigger a subsequent rise in specialized proresolving lipid mediators (SPMs) including lipoxins, resolvins, and protectins. Dashed lines display the altered profile of eicosanoids in critical illness-induced immune dysfunction, with persistence of early-phase lipid mediators that exert negative immunomodulatory effects and a paucity or relative insufficiency of SPMs, which nonphlogistically augment several key resolution pathways including bacterial clearance. The combination of this dual defect contributes to vulnerability to hospital-acquired infection. Identification of aberrant eicosanoid profiles in critically ill patients may allow their therapeutic correction or antagonism to ameliorate effector cell functional impairment as indicated by the dotted lines.
Figure 3
Figure 3
Potential therapeutic interventions to modify resolution defects and improve innate effector cell functionality in critical illness. Targets on the left of the diagram (red) describe means of reducing excessive or prolonged production of immunosuppressive COX-generated PGs or antagonizing their action. Targets on the right (blue) indicate means of supplementing and/or augmenting levels of SPMs that nonphlogistically enhance multiple effector modalities. AA, arachidonic acid; ATL, aspirin-triggered lipoxin (15-epi-LXA4); COX, cyclooxygenase; EP2/4, E prostanoid 2/4 receptor; LOX, lipoxygenase; LT, leukotriene; LX, lipoxin; PD, protectin; PG, prostaglandin; PPAR, peroxisome proliferator-activated receptor; Rv, resolvin; SPM, specialized proresolving lipid mediator.

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