The mast cell and the cysteinyl leukotrienes

摘要

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 C_4 (LTC_4) is formed when arachidonic acid is cleaved from membrane phos-pholipids, and metabolized to an epoxide intermediate, LTA_4 that in turn is conjugated to reduced glutathione by an integral membrane protein, LTC_4 synthase. The LTC_4 is exported in an energy-dependent step and subjected to extracellular cleavage of the glu-tamic acid and then the glycine to provide LTD_4 and LTE_4, respectively. Mice with targeted disruption of the LTC_4S 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 CysLT_1 receptor gene is protected against the pathobiological insults that augment microvascular permeability, whereas a strain with targeted disruption of the CysLT_2 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.