Rodrigo Arrangoiz MS, MD, FACS, FSSO

Leukotrienes:
- Are a family of potent inflammatory lipid mediators:
  - Derived from arachidonic acid in white blood cells (leukocytes) and other immune cells
- Produced rapidly in response to injury, infection, or allergens
- Leukotrienes:
  - Act as local hormones:
    - That help regulate immune and inflammatory responses
Biosynthesis pathway:
- Leukotrienes are produced through the 5-lipoxygenase (5-LO) pathway
- An increase in intracellular calcium:
  - Activates the enzyme phospholipase A2 (cPLA2):
    - Which releases arachidonic acid (AA) from cell membrane phospholipids
- AA is converted into an unstable epoxide intermediate:
  - Leukotriene A4 (LTA4):
    - Through a two-step process catalyzed by the 5-lipoxygenase enzyme.
  - LTA4 then branches into two main pathways:
    - Leading to the formation of two distinct classes of leukotrienes:
      - LTB4:
        
        An LTA4 hydrolase enzyme converts LTA4 into leukotriene B4 (LTB4):
        
        LTB4 is primarily involved in recruiting neutrophils and other leukocytes to inflammatory sites
      - Cysteinyl leukotrienes:
        
        A separate enzyme, LTC4 synthase, conjugates LTA4 with glutathione to create:
        
        Leukotriene C4 (LTC4):
        
        LTC4 is subsequently metabolized into leukotriene D4 (LTD4) and leukotriene E4 (LTE4) by other enzymes
Functions of leukotrienes :
- Leukotrienes exert their effects by binding to G-protein-coupled receptors (GPCRs) on the surface of target cells
- LTB4:
  - Acts as a potent chemoattractant:
    - Recruiting immune cells like neutrophils, eosinophils, and T-cells to inflamed tissues
    - It is also involved in the initial sensitization phase of allergic responses
- Cysteinyl Leukotrienes (CysLTs): The CysLTs (LTC4, LTD4, and LTE4) cause:
  - Bronchoconstriction
  - Increased vascular permeability:
    - Leading to swelling (edema) and the leakage of plasma and immune cells into tissues
  - Mucus production:
    - Stimulating the release of excess mucus, particularly in the airways
Role in inflammatory diseases:
- Because of their role in promoting inflammation:
  - Leukotrienes are implicated in a number of chronic inflammatory and allergic diseases
- Asthma:
  - Overproduction of CysLTs is a major cause of the airway inflammation and bronchoconstriction seen in asthma, particularly exercise-induced asthma and aspirin-sensitive asthma
- Allergic rhinitis:
  - CysLTs contribute to nasal congestion, mucus production, and other symptoms associated with hay fever
- Rheumatoid arthritis and inflammatory bowel disease:
  - The pro-inflammatory effects of leukotrienes have been linked to these and other conditions
- Cardiovascular disease:
  - Recent research suggests leukotrienes also play a role in cardiovascular diseases like atherosclerosis
Clinical applications:
- The central role of leukotrienes in inflammation makes them a target for medications called leukotriene modifiers
- 5-Lipoxygenase inhibitors:
  - Drugs like zileuton block the 5-LO enzyme, preventing the synthesis of all leukotrienes (LTB4 and CysLTs)
- Leukotriene receptor antagonists (LTRAs):
  - Drugs like montelukast (Singulair) and zafirlukast (Accolate) block CysLTs from binding to their receptors
  - These are primarily used to manage asthma and allergic rhinitis.
- By interfering with the leukotriene pathway:
  - These drugs can help manage symptoms associated with inflammatory and allergic conditions