Importance of the leukotriene B4-BLT1 and LTB4-BLT2 pathways in asthma

Abstract

For several decades, the leukotriene pathways have been implicated as playing a central role in the pathophysiology of asthma. The presence and elevation of numerous metabolites in the blood, sputum, and bronchoalveolar lavage fluid from asthmatics or experimental animals adds support to this notion. However, targeting of the leukotriene pathways has had, in general, limited success. The single exception in asthma therapy has been targeting of the cysteinyl leukotriene receptor 1, which clinically has proven effective but only in certain clinical situations. Interference with 5-lipoxygenase has had limited success, in part due to adverse drug effects. The importance of the LTB4-BLT1 pathway in asthma pathogenesis has extensive experimental support and findings, albeit limited, from clinical samples. The LTB4-BLT1 pathway was shown to be important as a neutrophil chemoattractant. Despite observations made more than two decades ago, the LTB4-BLT1 pathway has only recently been shown to exhibit important activities on subsets of T lymphocytes, both as a chemoattractant and on lymphocyte activation, as well as on dendritic cells, the major antigen presenting cell in the lung. The role of BLT2 in asthma remains unclear. Targeting of components of the LTB4-BLT1 pathway offers innovative therapeutic opportunities especially in patients with asthma that remain uncontrolled despite intensive corticosteroid treatment.

CD8+Tc2 cells: underappreciated contributors to severe asthma

“…BLT1 is the high-affinity receptor for leukotriene B4 expressed on a variety of cell types [114]. In allergen-sensitised and -challenged mice, it was the CD8 + BLT1 + and not the CD8 + BLT1 − T-cell subset that was associated with IL-13-mediated asthma and dependent on LTB4 release from mast cells [115][116][117][118].…”

Trichomonas vaginalis‐secreted cysteinyl leukotrienes promote migration, degranulation and MCP‐1 production in mast cells

“…1,6,7 In addition, mast cells express various receptors that recognize pathogen-secreted molecules. 6,7 Mast cells highly express receptors for lipid mediators, 16,17 (Figure 2). These results are consistent with those of a previous study, which reported that MCP-1/CCL2 stored within the intracellular granules at the resting state is rapidly secreted via exocytosis upon stimulation such as PMA, histamine and forskolin.…”

“…16 LTB 4 interacts with both high-affinity (BLT1) and low-affinity receptors (BLT2). 17 Additionally, CysLTs reportedly interact with the CysLT1 (CysLT1R) and CysLT2 receptors (CysLT2R). 16 Previously, we had reported that T vaginalis-secreted LTB 4 induces exocytotic degranulation, migration and IL-8 secretion in mast cells through an LTB 4 receptor, BLT1.…”

G Protein–Coupled Receptors in Asthma Therapy: Pharmacology and Drug Action

“…Besides CysLTs, another leukotriene, LTB 4 , which does not contain a glutathione moiety, has been implicated in the inflammatory process of asthma (Gelfand, 2017). There are two GPCRs for LTB 4 , leukotriene receptor (BLT 1 ) as the high-affinity receptor and BLT 2 as the low-affinity receptor.…”