Physiology, Leukotrienes


Article Author:
Brian Cuzzo


Article Editor:
Sarah Lappin


Editors In Chief:
Laurie Graham
Andrew Wilt
Mary Cataletto


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Nazia Sadiq
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Phillip Hynes
Komal Shaheen
Sandeep Sekhon


Updated:
10/27/2018 12:31:41 PM

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 an important role in the pathophysiology of asthma. This creates opportunity in the utilization of targeted pharmacotherapy to treat asthma and similar diseases. [1]

Cellular

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 and 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, it is possible for cells to 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 are synthesized 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, phospholipid within our cell membranes is metabolized 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 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 be subsequently hydrolyzed 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 receptor 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 receptor (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, it has been proposed that leukotrienes also exert a negative inotropic effect on the heart, stimulate prostaglandin synthesis in macrophages, and induce gastrointestinal smooth muscle constriction.

Clinical Significance

Leukotrienes have been revealed to play a crucial role in several diseases, most notably asthma. Leukotrienes have a number of 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, it has been suggested that those suffering from chronic asthma especially will benefit from anti-leukotriene therapy. [3]

In addition to asthma, leukotrienes have been found to play a role in the development of cardiovascular disease. It has been 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, it has been shown that levels of 5-lipooxygenase within atherosclerotic vessels correlates with disease severity. Based on animal models, it is believed that increases in leukotrienes promote the attraction of macrophages as well as their differentiation into foam cells. Globally, it has been 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 been noted to have a connection to various cancers. It is known that chronic inflammation leads to an increased risk of certain cancers. For example, the chronic inflammation provoked by inflammatory bowel disease (IBD) is believed to promote transformation to colorectal adenocarcinoma. In such patients, it has been found that these cancers have increased expression of cysLT. It has also been shown that LTD promotes the up-regulation of Bcl-2, an anti-apoptotic protein that promotes cell survival. Similar findings have also been shown in other cancers including leukemia, lymphomas, esophageal, lung, and skin cancers. These malignancies have been shown to 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]


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Physiology, Leukotrienes - Questions

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Leukotrienes are synthesized from what molecule?



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Which of the following is considered a slow-reacting substance of anaphylaxis?



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What is the main end product of the lipoxygenase pathway?



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What causes nonsteroidal anti-inflammatory drug (NSAID)-induced asthma?



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The arachidonic acid cascade is initiated by two enzymes: cyclooxygenases and lipoxygenase. Which item listed is the primary end-product of lipoxygenase metabolism of arachidonic acid and is clinically relevant to asthma and its treatment?



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An animal model is being studied to determine the signaling cascade of LTB4 in mouse neutrophils. Which of the following substances would most likely increase in intracellular concentration as a result of LTB4 ligating BLT1?



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An 8-year-old male has experienced increasing shortness of breath for the past 2 months. His shortness of breath is worse at night and is associated with a cough and rhinitis. Albuterol inhaler use relieves his symptoms. Which of the following inflammatory mediators is most directly responsible for the symptoms of his underlying diagnosis?



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Which of the following is not a component believed to underly the promotion of malignant transformation seen in the setting of chronic inflammation?



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An experimental drug is designed to inhibit phospholipase A2. Which of the following molecules will subsequently be reduced in patients receiving this drug?



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A knockout mouse model is designed to remove the gene responsible for FLAP (5-lipoxygenase-activating protein) production. Which of the following molecules will not decrease in concentration?



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Physiology, Leukotrienes - References

References

Peters-Golden M,Henderson WR Jr, Leukotrienes. The New England journal of medicine. 2007 Nov 1     [PubMed]
Hammarström S, Leukotrienes. Annual review of biochemistry. 1983     [PubMed]
Montuschi P, Role of Leukotrienes and Leukotriene Modifiers in Asthma. Pharmaceuticals (Basel, Switzerland). 2010 Jun 2     [PubMed]
Colazzo F,Gelosa P,Tremoli E,Sironi L,Castiglioni L, Role of the Cysteinyl Leukotrienes in the Pathogenesis and Progression of Cardiovascular Diseases. Mediators of inflammation. 2017     [PubMed]

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