Allergy Asthma Immunol Res.  2016 Nov;8(6):481-490. 10.4168/aair.2016.8.6.481.

Eicosanoid Mediators in the Airway Inflammation of Asthmatic Patients: What is New?

• Sanak M

• KMID: 2349987
• DOI: http://doi.org/10.4168/aair.2016.8.6.481

Abstract

Lipid mediators contribute to inflammation providing both pro-inflammatory signals and terminating the inflammatory process by activation of macrophages. Among the most significant biologically lipid mediators, these are produced by free-radical or enzymatic oxygenation of arachidonic acid named "eicosanoids". There were some novel eicosanoids identified within the last decade, and many of them are measurable in clinical samples by affordable chromatography-mass spectrometry equipment or sensitive immunoassays. In this review, we present some recent advances in understanding of the signaling by eicosanoid mediators during asthmatic airway inflammation. Eicosanoid profiling in the exhaled breath condensate, induced sputum, or their metabolites measurements in urine is complementary to the cellular phenotyping of asthmatic inflammation. Special attention is paid to aspirin-exacerbated respiratory disease, a phenotype of asthma manifested by the most profound changes in the profile of eicosanoids produced. A hallmark of this type of asthma with hypersensitivity to non-steroid anti-inflammatory drugs (NSAIDs) is to increase biosynthesis of cysteinyl leukotrienes on the systemic level. It depends on transcellular biosynthesis of leukotriene C₄ by platelets that adhere to granulocytes releasing leukotriene A₄. However, other abnormalities are also reported in this type of asthma as a resistance to anti-inflammatory activity of prostaglandin E₂ or a robust eosinophil interferon-γ response resulting in cysteinyl leukotrienes production. A novel mechanism is also discussed in which an isoprostane structurally related to prostaglandin E₂ is released into exhaled breath condensate during a provoked asthmatic attack. However, it is concluded that any single eicosanoid or even their complex profile can hardly provide a thorough explanation for the mechanism of asthmatic inflammation.

Keyword

Eicosanoids; asthma; aspirin exacerbated respiratory disease

MeSH Terms

Arachidonic Acid
Asthma
Eicosanoids
Eosinophils
Granulocytes
Humans
Hypersensitivity
Immunoassay
Inflammation*
Isoprostanes
Leukotrienes
Macrophages
Oxygen
Phenotype
Spectrum Analysis
Sputum
Arachidonic Acid
Eicosanoids
Isoprostanes
Leukotrienes
Oxygen

Figure

• 

  Fig. 1 Chemical structure and numbering of carbon atoms in polyusnaturatedfaty acid precursor of oxylipins. Gamma-linolenic acid (GLA), precursor of prostaglandin-1 series. This is not metabolized to leukotrienes but prostanoids: prostaglandin E1 or thromboxane A1 has an anti-inflammatory activity. Arachidonic acid (ARA): common precursor of the most active biologically prostanoids and leukotrienes. Eicosapentaenoic (EPA) and docosahexaenoic (DHA) acids are ω-3 polyunsaturated fatty acids. EPA is a precursor of prostanoid-3 series, leukotrienes-5 series, or resolvin E1. DHA is a precursor of resolvins, protectins D, and maresins with proresolving activity.

• 

  Fig. 2 Arachidonic acid is a substrate for lipoxygenase and cyclooxygenases. While 5-lipooxygenase (5-LO) is expressed in myeloid cells (neutrophils, basophils, eosinophils, platelets, and mast cells), 12-LO and 15-LO are expressed in epithelia, keratinocytes,eosinophils, and monocytes/macrophages. Both cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) produce the common precursors (PGH2) of prostaglandins thromboxane and prostacyclin.

• 

  Fig. 3 A 5-LO product, 5-HETE, or its unstable precursor 5-HpETE is oxidized by the same enzyme to leukotriene A4 (LTA4). In neutrophils and monocytes, LTA4 hydrolase reduces LTA4 to leukotriene B4 (LTB4). Cells expressing leukotriene C4 synthase (eosinophils, mast cells, and platelets) produce leukotriene C4 (LTC4). This cysteinyl leukotriene is metabolized to leukotriene D4 (LTD4) and leukotriene E4 (LTE4) by various petidases.

• 

  Fig. 4 During induction of cyclooxygenase-2 expression, a cis-isomer of prostaglandin E2 (PGE2) is produced. A. The chemical structure of PGE2 having trans conformation of aliphatic chains at the cyclopentane ring. B. 8-iso-PGE2 with cis-conformation. C. Human bronchial epithelial cells were cultured at the presence of interleukin-1β (recombinant IL-1β 3ng/mL) or bacterial lipopolysaccharide (Pseudomonas aeruginosa LPS, 1β g/mL), and 8-iso-PGE2 accumulated in the culture medium with a peak concentration between 3 and 18 hours, depending on the stimulus.

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