[Good Pharm NOWㅣPopular] Leukotrienes: Essential Mediators in Inflammation and Disease

[Good Pharm NOWㅣPopular] Leukotrienes: Essential Mediators in Inflammation and Disease

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Introduction

Leukotrienes are potent lipid mediators that play a crucial role in various physiological and pathological processes, particularly in inflammation and allergic reactions. They are synthesized from arachidonic acid through the 5-lipoxygenase (5-LO) pathway and exert their biological effects by binding to specific receptors on target cells. Leukotrienes have been implicated in the pathogenesis of several diseases, including asthma, allergic rhinitis, inflammatory bowel disease, and cardiovascular disorders. Understanding their biology and developing therapeutic strategies to modulate their activity hold promise for treating these conditions.

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Biosynthesis of Leukotrienes

Leukotrienes are derived from the essential fatty acid arachidonic acid, which is released from membrane phospholipids by the enzyme phospholipase A2. Arachidonic acid is then metabolized by the 5-LO pathway, which consists of the following enzymes:

  • 5-lipoxygenase (5-LO)
  • 5-lipoxygenase activating protein (FLAP)
  • Leukotriene A4 synthase (LTA4S)
  • Leukotriene B4 synthase (LTB4S)
  • Leukotriene C4 synthase (LTC4S)

The initial step in the 5-LO pathway is the conversion of arachidonic acid to 5-hydroperoxyeicosatetraenoic acid (5-HPETE) by 5-LO. FLAP is required for the optimal activity of 5-LO. 5-HPETE is then converted to leukotriene A4 (LTA4) by LTA4S. LTA4 is an unstable intermediate that can be further metabolized to different leukotrienes depending on the specific synthase enzymes present. LTB4S converts LTA4 to leukotriene B4 (LTB4), while LTC4S converts LTA4 to leukotriene C4 (LTC4).

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Types of Leukotrienes

There are several types of leukotrienes, each with distinct biological properties:

  • Leukotriene B4 (LTB4): LTB4 is a potent chemotactic factor that attracts neutrophils and other inflammatory cells to sites of infection or injury. It also promotes adhesion of these cells to endothelial cells and stimulates their degranulation, releasing inflammatory mediators.
  • Leukotriene C4 (LTC4): LTC4 is a bronchoconstrictor and mucus secretagogue, contributing to the airway obstruction and excessive mucus production characteristic of asthma and allergic rhinitis.
  • Leukotriene D4 (LTD4): LTD4 is also a bronchoconstrictor and mucus secretagogue, similar to LTC4.
  • Leukotriene E4 (LTE4): LTE4 is a vasodilator and pro-inflammatory mediator that can contribute to hypotension and tissue edema.
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Receptors for Leukotrienes

Leukotrienes exert their biological effects by binding to specific G protein-coupled receptors (GPCRs):

  • BLT1 receptor: Binds LTB4 and is expressed on neutrophils, monocytes, macrophages, and endothelial cells.
  • BLT2 receptor: Also binds LTB4 and is expressed on mast cells, eosinophils, and basophils.
  • CysLT1 receptor: Binds LTC4, LTD4, and LTE4 and is expressed on airway smooth muscle cells, vascular smooth muscle cells, and endothelial cells.
  • CysLT2 receptor: Binds LTC4, LTD4, and LTE4 and is expressed on eosinophils and macrophages.
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Biological Activities of Leukotrienes

Leukotrienes have a wide range of biological activities, including:

  • Inflammation: Leukotrienes are potent pro-inflammatory mediators that promote the recruitment and activation of inflammatory cells
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