Introduction

Leukotrienes (LTs) are a group of inflammatory mediators that belong to the eicosanoid family. Their synthesis, primarily by leukocytes, is spurred by a variety of immunologic and nonimmunologic stimuli, including antigens, immune complexes, complement, cytokines, osmotic challenges, and pollutants, among others. These molecules collectively serve a variety of purposes aimed at furthering the inflammatory cascade via alterations in vascular permeability, effects on leukocytes, and constriction of smooth muscle. Most notably, the bronchoconstriction that results from the action of leukotrienes plays a vital role in the pathophysiology of asthma, which creates opportunity in the utilization of targeted pharmacotherapy to treat asthma and similar diseases.[1]

Cellular Level

The synthesis of leukotrienes primarily occurs in leukocytes. Different leukocytes tend to predominantly produce a specific leukotriene, either leukotriene B (LTB) or the cysteinyl class of leukotrienes. Neutrophils are the primary synthesizers of LTB and produce little of the cysteinyl leukotrienes. Eosinophils, basophils, and mast cells are the primary producers of the cysteinyl leukotrienes. They have minimal capacity to produce LTB. Macrophages and monocytes serve as intermediaries, having adequate capacity to produce both LTB and the cysteinyl leukotrienes. Other cells typically do not produce significant levels of leukotrienes as they often do not express 5-lipoxygenase or 5-lipoxygenase activating protein (FLAP). However, cells can take up leukotriene A (LTA) produced by leukocytes and then synthesize bioactive leukotrienes if they express more distal enzymes in the metabolic pathway. This process has been termed “transcellular biosynthesis.”[1]

Development

Leukotrienes undergo synthesis via the 5-lipoxygenase pathway of arachidonic acid metabolism. Arachidonic acid is a fatty acid found within the phospholipids that constitute cell membranes. When a stimulus arrives that calls for the production of leukotrienes, phospholipids within our cell membranes metabolize to arachidonic acid via phospholipase A (PLA). The arachidonic acid is then acted on by 5-lipooxygenase in concert with FLAP to yield LTA. Within the cell, LTA is used as the substrate for the production of LTB via hydrolysis or leukotriene C (LTC) via conjugation with glutathione. At this point, LTB and LTC are exported out of the cell via separate transport proteins. Extracellularly, LTC can subsequently undergo hydrolysis to produce leukotriene (LTE). LTC, LTD (an intermediate in LTE synthesis), and LTE are termed cysteinyl leukotrienes.[1]

Mechanism

Leukotrienes exert their effects by binding receptors in an autocrine or paracrine fashion. These receptors are G protein-coupled receptors (GPCR) that, once bound, activate a G protein. Leukotriene receptors either activate the Gq protein, which leads to increases in intracellular calcium, or the Gi protein, which leads to decreases in the intracellular cAMP. Either of these G proteins then signals a cascade of kinase reactions, leading to changes in both transcriptional activity and cellular motility.

The different types of leukotrienes exert both common and distinctive effects. In general, LTB and the cysteinyl leukotrienes exert different effects by separate binding classes of receptors. LTB binds to B leukotriene receptors 1 and 2 (BLT1 and BLT2), respectively. LTB most notably acts as a potent neutrophil chemotactic receptor. This action emphasizes the inflammatory propellant nature of leukotrienes, as neutrophils are the primary produces of LTB as well. The cysteinyl leukotrienes bind to type 1 and type 2 cysteinyl leukotriene receptors (cysLT1 and cysLT2), respectively). cysLT1 primarily mediates airway changes, including bronchoconstriction, airway edema, and mucus secretion. cysLT2, on the other hand, is principally an inflammatory stimulator as it evokes increases in vascular permeability and tissue fibrosis but has little effect on the airways. It is worth noting that leukotriene mediated increases in vascular permeability are 3 to 4 times more potent than histamine.[2]

Collectively, the different types of leukotrienes also exert common effects. Leukotrienes promote the movement of almost all leukocyte types into tissues and amplify the effects of type 2 T helper cells. Additionally, there is a proposal that leukotrienes also exert a negative inotropic influence on the heart, stimulate prostaglandin synthesis in macrophages, and induce gastrointestinal smooth muscle constriction.

Clinical Significance

Research has revealed leukotrienes to play a crucial role in several diseases, most notably asthma. Leukotrienes have several effects that lead to the production of asthma symptoms. First, they promote bronchiole constriction leading to narrowing of the airways. In regards to this, they also promote smooth muscle proliferation, leading to increased responsiveness in airway constriction. Second, they promote leukocyte recruitment and subsequent cytokine release, leading to further inflammation of the airways. Third, they act directly on airway goblet cells to promote mucus secretion. Collectively, these actions produce many of the symptoms seen in asthma. Given the ability of leukotrienes to lead to airway remodeling with increases in goblet cell and smooth muscle proliferation, there has been a suggestion that those who have chronic asthma will especially benefit from anti-leukotriene therapy.[3]

In addition to asthma, leukotrienes have shown to play a role in the development of cardiovascular disease. Researchers have noted that atherosclerotic vascular lesions express the entire biochemical machinery necessary for leukotriene production, including 5-lipooxygenase, FLAP, and other distal enzymes important for leukotriene synthesis. Moreover, levels of 5-lipooxygenase within atherosclerotic vessels correlates with disease severity. Based on animal models, the belief is that increases in leukotrienes promote the attraction of macrophages as well as their differentiation into foam cells. Globally, researchers have found that several different ethnic populations with variants of leukotriene-related genes that lead to overproduction of leukotrienes have an increased incidence of stroke and myocardial infarction. Although anti-leukotriene therapy is not currently standard in the care of cardiovascular disease, increasing evidence supports the role of leukotrienes in its pathogenesis.[4]

Lastly, leukotrienes have a connection to various cancers. Chronic inflammation leads to an increased risk of certain cancers. For example, the chronic inflammation provoked by inflammatory bowel disease (IBD) appears to promote the transformation to colorectal adenocarcinoma. In such patients, these cancers have increased expression of cysLT. Research also shows that LTD promotes the up-regulation of Bcl-2, an anti-apoptotic protein that promotes cell survival. Similar findings also exist with other cancers, including leukemia, lymphomas, esophageal, lung, and skin cancers. These malignancies express increased amounts of 5-lipooxygenase, FLAP, and other enzymes in the leukotriene synthesis pathway. Cell models and animal studies have suggested that anti-leukotriene therapies decrease cancer cell survival and decrease the incidence of certain malignancies.[1]