Mast cell stabilization + leukotriene axis

Category: immune_innate

Overview

Mast cells release preformed (histamine, tryptase, heparin) + newly synthesized (LTC4, LTD4, LTE4, PGD2, TNF-α) mediators on IgE-FcεRI crosslinking. Cromolyn + nedocromil stabilize mast cells (mechanism debated — possibly Ca²⁺ channel modulation). Leukotrienes (5-LOX pathway from arachidonic acid — cross-link: arachidonic_acid_cascade): LTB4 = chemoattractant; LTC4/D4/E4 (cysteinyl-LTs) = bronchoconstriction + vascular permeability + mucus + airway remodeling. Therapeutic blockade: 5-LOX inhibitor zileuton (blocks LT synthesis); cysteinyl-LT1 receptor antagonists montelukast + zafirlukast (asthma + allergic rhinitis). PDE4-i (roflumilast, apremilast) reduce inflammatory mediator release via cAMP elevation.

Organ Systems

• immune-hematologic
• respiratory

Pathway Steps

1. mast-cell-igE-crosslinking → mediator-release — via FcεRI → SYK → PLCγ → Ca²⁺ → degranulation + de novo LT/PG synthesis. Allergen cross-linking of IgE bound to mast-cell FcεRI triggers degranulation, releasing preformed histamine and proteases plus newly synthesized lipid mediators. This is the central effector event of immediate hypersensitivity (allergy, anaphylaxis).
2. arachidonic-acid → leukotrienes — via 5-LOX → LTA4 → LTB4 (LTA4H) or LTC4 (LTC4S) → LTD4 → LTE4; cross-link: arachidonic_acid_cascade. Mast cells convert arachidonic acid via 5-lipoxygenase to cysteinyl leukotrienes (LTC4/D4/E4) — potent bronchoconstrictors and pro-inflammatory mediators in asthma. This arm is blocked by 5-LOX inhibitors (zileuton) and leukotriene-receptor antagonists (montelukast).

Known Modulators

• cromolyn (inhibitor) — mast cell stabilizer (mechanism debated). inhaled prophylactic for asthma + intranasal/ophthalmic for allergic rhinitis/conjunctivitis; minimal systemic absorption
• zileuton (inhibitor) — 5-lipoxygenase (LT biosynthesis). asthma; blocks all downstream LTs; LFT monitoring; less used due to qid dosing + hepatotoxicity risk
• zafirlukast (inhibitor) — cysteinyl-LT1 receptor. leukotriene-receptor antagonist; asthma + allergic rhinitis; hepatotoxicity signal; modest efficacy vs ICS
• apremilast (inhibitor) — PDE4 (cAMP elevation → reduced TNF/IL-23). oral; plaque psoriasis + PsA + oral ulcers of Behçet; nausea + weight loss + depression tail
• roflumilast (inhibitor) — PDE4. severe COPD with chronic bronchitis phenotype; weight loss + GI side effects limit tolerability

References

• PMID 17978293