Leukotriene Receptor Antagonists

Marzena E. Krawiec, MD, Nizar J. Jarjour, MD


Semin Respir Crit Care Med. 2002;23(4) 

In This Article


LTs are 20 carbon lipid derivatives of arachidonic acid produced in increased amounts in the airways of asthmatics. They were originally linked to asthma and allergic reactions by Kellaway in the 1940s, being described as "slow-reacting substance of anaphylaxis, SRS-A."[8] The term slow-reacting substance of anaphylaxis (SRS-A) was first introduced in 1983 to describe a substance that caused guinea pig lung smooth muscle contraction in the presence of cobra venom.[9] In general, these inflammatory mediators are formed in a multistep process, thereby allowing for various sites of pharmacological intervention. All LTs are synthesized de novo from arachidonic acid (AA) by the action of phospholipases, specifically phospholipase A2, on cell membrane phospholipids following cellular activation. In general, cellular activation is an immunologically initiated, mediator-driven event, although nonimmunologic, nonspecific stimulants such as exercise can also lead to the generation of inflammatory mediators such as the LTs. AA can be metabolized via several pathways, including the 5-LO and cyclo-oxygenase (CO) pathways (Fig. 1).[10] CO metabolizes AA to form prostaglandins and thromboxanes. Conversely, the activation of 5-LO results in the movement of the 5-LO enzyme to the cell membrane, where, in association with FLAP, it produces the unstable molecule LTA4. The 5-LO pathway was originally discovered in 1976 based on animal experiments involving incubated rabbit peritoneal leukocytes with 14C-labeled AA.[10a] Both 5-LO and FLAP have limited cellular distribution resulting in LTA4 production being restricted to cells of myeloid lineage.[11]

Figure 1.

Leukotriene pathway diagram -- the AA (arachidonic acid) cascade. (Adapted from Krawiec and Wenzel[10] with permission.)

The subsequent fate of LTA4 is dependent on the cell and its specific-enzyme system.[11] Unlike 5-LO and FLAP, both LTC4 synthase and LTA4 hydrolase are more widely distributed. In cells containing LTC4 synthase, LTA4 is conjugated with glutathione to produce the cysteinyl-LTs (cysLTs), which include LTC4 and its derivatives LTD4 and LTE4. Additionally, in cells containing LTA4 hydrolase, LTA4 can undergo hydrolysis to form LTB4. Eosinophils, mast cells, and alveolar macrophages contain significant amounts of LTC4 synthase compared with LTA4 hydrolase, whereas the converse is true in neutrophils, monocytes, and macrophages.[12,13,14]

A thioether-linked peptide distinguishes the cysLTs from LTB4. Specifically, this thioether-linked peptide is characterized by glutathione in LTC4, cystinyl-glycine in LTD4, and cysteine in LTE4. Conversely, LTB4 is a dihydroxy derivative of AA that lacks the thioether linkage.

Following synthesis, LTs exert their effects through cell surface receptors. A single LTB4 receptor, known as the BLT receptor, has been identified,[15] whereas there are two types of cysLT receptors in humans, cysLT1 and cysLT2. Studies have detected cysLT1-receptor messenger RNA in the spleen, peripheral blood leukocytes, as well as smooth muscle cells and tissue macrophages in the lung.[16] Evidence of cysLT1-receptors in bronchial smooth muscle would specifically support the bronchoconstrictive nature of the cysLTs. Unlike cysLT1, the more recently identified cysLT2 has a wider distribution and includes lung macrophages, airway smooth muscle cells, cardiac Purkinje fibers, brain, adrenal medullary cells, and peripheral blood leukocytes.[17] The cysLT2 receptor is insensitive to all the commercially available LTRAs; the currently available LTRAs are highly selective for inhibition of the cysLT1 receptor.

The LTs, particularly the cysLTs, have been shown to cause three important biological effects in relation to the classic pathophysiological features of asthma: bronchoconstriction,[3] mucus production in vitro,[18] and inflammatory cell influx.[7] Overall, the cysLTs are 100- to 1000-fold more potent bronchoconstrictors than histamine[19] and up to 10,000 times more potent than methacholine.[20] Even in the nonasthmatic patient, inhalation of a cysLT can induce significant airflow obstruction, whereas there is a significant increase in this effect in the asthmatic patient.[21] In addition to bronchoconstriction, these lipid mediators are known mucus secretagogues in vitro being more potent than both prostaglandins and histamine in the production of airway mucus.[18,22] Finally, inhalation of two cysLTs, LTD4 and LTE4, caused a significant increase in cellular influx in asthmatic airways and sputum.[7,23] Specifically, Laitinen and colleagues demonstrated that eosinophils and neutrophils were significantly increased in the bronchoalveolar lavage (BAL) of patients with mild asthma 4 hours following LTE4 inhalation.[7] Interestingly, the increase in eosinophils was 10 times that of the neutrophils. In contrast, although methacholine inhalation resulted in similar bronchoconstriction, no inflammatory eosinophil or neutrophil influx was identified.

LTB4, unlike the cysLTs, has a much less distinct role in the pathophysiology of asthma. This noncysteinyl LT does not have bronchoconstrictive effects in the airways; however, it has been reported to have an important role in neutrophil (and perhaps eosinophil) chemotaxis and activation,[15,24] along with increasing mucus secretion. In addition, LTB4 has been shown to augment neutrophil survival ex vivo in a concentration-dependent manner.[25] With ß leuketriene receptor (BLT) binding, it results in increased neutrophil chemotaxis, stimulates neutrophil- endothelial interactions, and induces release of mediators, enzymes, and superoxide.[24,26] Therefore, although it may play only a small role in allergic disease, its association with airway inflammation remains strong.[27]


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