LTB4, acting at the BLT1 receptor, is a potent chemoattractant for T lymphocytes, neutrophils, eosinophils, monocytes, and possibly mast cells. LTB4 also contributes to activation of neutrophils and eosinophils, and to monocyte-endothelial adhesion. The cysteinyl leukotrienes are potent chemoattractants for eosinophils and T lymphocytes. Cysteinyl leukotrienes may also generate distinct sets of cytokines through activation of mast cell cysLT1 and cysLT2. At higher concentrations, these leukotrienes also promote eosinophil adherence, degranulation, cytokine or chemokine release, and oxygen radical formation. Cysteinyl leukotrienes also contribute to inflammation by increasing endothelial permeability, thus promoting migration of inflammatory cells to the site of inflammation. The leukotrienes have been strongly implicated in the pathogenesis of inflammation, especially in chronic diseases such as asthma and inflammatory bowel disease.
Lipoxins have diverse effects on leukocytes, including activation of monocytes and macrophages and inhibition of neutrophil, eosinophil, and lymphocyte activation. Both lipoxin A and lipoxin B inhibit natural killer cell cytotoxicity.
B. Heart and Smooth Muscle 1. Cardiovascular—12(S)-HETE promotes vascular smooth muscle cell proliferation and migration at low concentrations; it may play a role in myointimal proliferation that occurs after vascular injury such as that caused by angioplasty. Its stereoisomer, 12(R)-HETE, is not a chemoattractant, but is a potent inhibitor of the Na+/K+-ATPase in the cornea. In vascular smooth muscle LTB4 may cause vasoconstriction as well as smooth muscle cell migration and proliferation, possibly contributing to atherosclerosis and injury-induced neointimal proliferation. LTC4 and LTD4 reduce myocardial contractility and coronary blood flow, leading to depression of cardiac output. Lipoxin A and lipoxin B exert coronary vasoconstrictor effects in vitro. In addition to their vasodilatory action, EETs may reduce cardiac hypertrophy as well as systemic and pulmonary vascular smooth muscle proliferation and migration.
2.
Gastrointestinal—Human colonic epithelial cells synthesize LTB4, a chemoattractant for neutrophils. The colonic mucosa of patients with inflammatory bowel disease contains substantially increased amounts of LTB4. It appears that activation of the BLT2 receptor, possibly by agonists other than LTB4, is protective in colonic epithelium and contributes to maintenance of barrier function.
3.
Airways—The cysteinyl leukotrienes, particularly LTC4 and LTD4, are potent bronchoconstrictors and cause increased micro-vascular permeability, plasma exudation, and mucus secretion in the airways. Controversies exist over whether the pattern and specificity of the leukotriene receptors differ in animal models and humans. LTC4-specific receptors have not been found in human lung tissue, whereas both highand low-affinity LTD4 receptors are present.
C. Renal System