The mast cell and the cysteinyl leukotrienes

Novartis Found Symp. 2005;271:166-75; discussion 176-8, 198-9. doi: 10.1002/9780470033449.ch13.

Abstract

The mast cell has been a fundamental focus for nearly half a century in the effort to understand the biology of the cysteinyl leukotrienes (cysLTs). My initial interest in the cysLTs, once termed the slow reacting substance of anaphylaxis (SRS-A), was based on the findings of others that this activity was elaborated by lung tissue and constricted bronchial smooth muscle in the presence of an antihistamine. We now know that leukotriene C4 (LTC4) is formed when arachidonic acid is cleaved from membrane phospholipids, and metabolized to an epoxide intermediate, LTA4 that in turn is conjugated to reduced glutathione by an integral membrane protein, LTC4 synthase. The LTC4 is exported in an energy-dependent step and subjected to extracellular cleavage of the glutamic acid and then the glycine to provide LTD4 and LTE4, respectively. Mice with targeted disruption of the LTC4S gene are partially protected against plasma leakage elicited in the ear by adaptive immune mast cell activation or in the peritoneal cavity by microbial carbohydrate stimulation of the macrophages. Such mice are also partially protected against pulmonary fibrosis after intratracheal administration of bleomycin. A strain with targeted disruption of the CysLT1 receptor gene is protected against the pathobiological insults that augment microvascular permeability, whereas a strain with targeted disruption of the CysLT2 receptor gene is protected against pulmonary fibrosis. Thus, the expression of these receptors on endothelium, smooth muscle and cells of the haematopoietic lineage such as mast cells, macrophages, and granulocytes extends the possible role of this lipid mediator pathway to both acute and chronic inflammation.

Publication types

  • Review

MeSH terms

  • Anaphylaxis / immunology
  • Animals
  • Cysteine / immunology*
  • Cytokines / immunology
  • Glutathione Transferase / genetics
  • Glutathione Transferase / metabolism
  • Humans
  • Immunologic Factors*
  • Inflammation / metabolism
  • Leukotrienes / immunology*
  • Mast Cells / immunology*
  • Membrane Proteins / metabolism
  • Receptors, Leukotriene / metabolism
  • Signal Transduction / physiology

Substances

  • Cytokines
  • Immunologic Factors
  • Leukotrienes
  • Membrane Proteins
  • Receptors, Leukotriene
  • cysteinyl-leukotriene
  • Glutathione Transferase
  • leukotriene-C4 synthase
  • Cysteine
  • leukotriene D4 receptor