Arachidonic Acid Metabolism in Allergic Airway Inflammation

Arachidonic acid is released from cellular membranes in response to allergens and pro-inflammatory stimuli by phospholipase A₂. Once freed, it is metabolised through cyclooxygenase (COX), lipoxygenase (LOX) and cytochrome P450 monooxygenase pathways to yield prostaglandins, thromboxanes, leukotrienes, lipoxins and hydroxyeicosatetraenoic acids. These bioactive lipids orchestrate bronchial smooth muscle tone, vascular permeability, mucous secretion and leukocyte recruitment in the airway. In allergic asthma, an imbalance between pro-inflammatory leukotrienes and counter-regulatory lipoxins and specialised pro-resolving mediators contributes to persistent airway hyperresponsiveness, eosinophilia and tissue remodelling. Understanding the spatio-temporal dynamics of these mediators across epithelial cells, mast cells, eosinophils and macrophages has underpinned the development of leukotriene receptor antagonists and 5-LOX inhibitors. More recently, attention has turned to selective modulation of BLT receptors, enhancement of lipoxin pathways and exploitation of endocannabinoid derivatives as potential adjuncts to steroid and β₂-agonist therapy. These advances offer promise for personalised intervention in severe and steroid-resistant asthma, with implications for global respiratory health.

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Arachidonic Acid Metabolism in Allergic Airway Inflammation publication trend

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Technical terms

Arachidonic acid: A polyunsaturated fatty acid liberated from membrane phospholipids that serves as the precursor for eicosanoid synthesis.

Cyclooxygenase (COX): Enzymes that convert arachidonic acid into prostaglandin H₂, the common precursor for prostaglandins and thromboxanes.

Lipoxygenase (LOX): A family of iron-containing enzymes that oxygenate arachidonic acid to form hydroperoxyeicosatetraenoic acids, leukotrienes and lipoxins.

Leukotriene B₄ (LTB₄): A potent chemoattractant derived from 5-LOX activity that mediates neutrophil recruitment and activation via BLT receptors.

BLT1/BLT2 receptors: G-protein-coupled receptors with differing affinity for LTB₄ and related metabolites, critical for leukocyte signalling in airway inflammation.

NLRP3 inflammasome: A multiprotein complex that activates caspase-1, leading to interleukin-1β maturation and release in innate immune responses.

Specialised pro-resolving mediators: Lipid derivatives such as lipoxins, resolvins and protectins that promote resolution of inflammation and tissue repair.

References

1. Human and Mouse Eosinophils Differ in Their Ability to Biosynthesize Eicosanoids, Docosanoids, the Endocannabinoid 2-Arachidonoyl-glycerol and Its Congeners. Cells (2022).
2. Leukotriene B4 Receptors Are Necessary for the Stimulation of NLRP3 Inflammasome and IL-1β Synthesis in Neutrophil-Dominant Asthmatic Airway Inflammation. Biomedicines (2021).
3. Leukotriene B4 Receptor 2 Mediates the Production of G-CSF That Plays a Critical Role in Steroid-Resistant Neutrophilic Airway Inflammation. Biomedicines (2022).