Postreceptor Mechanisms of Growth Factor Action
Enrique Pimentel in Handbook of Growth Factors, 2017
Leukotrienes display many biological effects and may have a crucial role in inflammatory and hypersensitivity reactions. LTB4 stimulates polymorphonuclear leukocytes and leads to their aggregation and degranulation. LTB4 is also a potent chemotactic and chemokinetic agent for polymorphonuclear leukocytes, eosinophils, and monocytes. LTB4 can stimulate suppressor T lymphocytes and can enhance natural cytotoxic cell activity. It is also a potent bronchoconstrictor. Bioactive leukotrienes induce vasoconstriction of vascular beds and can produce a negative inotropic effect on cardiac muscle fibers. The precise role of leukotrienes in the mechanisms of action of hormones and growth factors is not clear, but they are members of the eicosanoid family of lipids and have numerous interactions with the prostaglandins. The effects of LTB4 on leukocyte function are probably mediated by the synthesis of diverse cytokines. There is evidence that the physiological actions of leukotrienes are mediated by a specific receptor located on the cell surface and that the LTB4 transduction mechanism involves changes in G proteins and alterations in phosphatidylinositol turnover.26 LTB4 may regulate the production of different cytokines by modulating the yield or the function of transcription factors such as the Fos and Jun proteins, which recognize AP-1-containing target genes.27
Leukotriene Receptors in the Airways
Devendra K. Agrawal, Robert G. Townley in Inflammatory Cells and Mediators in Bronchial Asthma, 2020
Three distinct leukotriene receptors (LTC4, LTD4, and LTB4) have been demonstrated; they are defined by their relative sensitivity to leukotrienes and by specific antagonism by chemical substances. These receptors mediate a number of biological responses in the airways of animals and humans. Activation of these receptors by leukotrienes has been implicated in the pathogenesis of allergy, asthma, and other airway inflammatory diseases. LTD4 and LTB4 receptors have received the greatest attention because there is clear evidence of their participation in biological responses, such as bronchospasm and neutrophil activation, respectively. Specific antagonists of the LTD4 and LTB4 receptor have been discovered and advanced into clinical trials for the treatment of airway diseases. In addition, recent studies have led to the subclassification of LTD4 receptors into LTD4α and LTD4β receptor subtypes and LTB4 receptors into LTB4 high- and low-affinity receptor subtypes.
Clinical pharmacology and therapeutics: nonopioids
Nigel Sykes, Michael I Bennett, Chun-Su Yuan in Clinical Pain Management, 2008
When NSAIDs block COX, arachidonic acid degradation is shunted mainly into the production of leukotrienes via lipoxygenase (LOX) (Figure 11.1). Leukotrienes attract neutrophils to inflammatory sites, causing the release of proteolytic enzymes, toxic oxygen radicals, chemokines and cytokines, inducing inflammation.301 They also probably reduce gastric mucosal blood flow, potentiating mucosal damage. Agents which block COX-1, COX-2, and LOX (LOX-COX inhibitors),302 theoretically and experimentally are less gastrotoxic303, 304, 305 and nephrotoxic than nonselective NSAIDs, and have antithrombotic, analgesic, anti-inflammatory, antihyperalgesic, antipyretic, antiasthmatic, and even chondroprotective properties.306 Indeed, licofelone, the first LOX-COX inhibitor, interfered with platelet function in vitro more than acetylsalicylic acid did.307 In rabbits, it also reduced neointimal formation and inflammation.308 Early human trials confirm low gastric toxicity.309
Montelukast, a cysteinyl leukotriene receptor antagonist, exerts local antinociception in animal model of pain through the L-arginine/nitric oxide/cyclic GMP/KATP channel pathway and PPARγ receptors
Published in International Journal of Neuroscience, 2021
Ehsan Alizamani, Behnam Ghorbanzadeh, Reza Naserzadeh, Mohammad Taghi Mansouri
Leukotrienes are eicosanoids that are generated from arachidonic acid by 5-lipoxygenase via biochemical pathways [2]. Leukotrienes are potent pro-inflammatory mediators involved in the pathophysiology of various inflammatory conditions such as asthma, rheumatoid arthritis, ulcerative colitis, and pain [3–5]. Montelukast, cysteinyl leukotriene (CysLT) receptor antagonist, is widely used in the treatment of bronchial asthma [6]. Moreover, montelukast may possess anti-inflammatory properties that are distinct from conventional antagonism of CysLT receptors including interference with activation of the transcription factor, nuclear factor kappa B in inflammatory cells, promotion of sustained production of interleukin-10 or inhibition of P2Y receptors [7,8]. Furthermore, Fermor et al. (2001) demonstrated the role of nitric oxide (NO) in the regulation of Leukotrienes B4 expression [9]. On the other hand, it has been shown that the cysteinyl leukotrienes LTC4 and LTD4, as well as LTB4, activate NO release from human polymorphonuclear granulocytes by surface receptor [10]. Moreover, it has been reported that montelukast reduces the levels of exhaled nitric oxide in patients with mild asthma [11].
Treatment response heterogeneity in asthma: the role of genetic variation
Published in Expert Review of Respiratory Medicine, 2018
Susanne J. H. Vijverberg, Niloufar Farzan, Elise M. A. Slob, Anne H. Neerincx, Anke H. Maitland-van der Zee
Leukotriene modifiers interfere in the leukotriene pathway, which is thought to mediate bronchoconstriction in asthma patients. One of the key enzymes in this pathway is 5-lipoxygenase, which converts arachidonic acid into leukotriene A4 (LTA4). This compound is subsequently modified to leukotriene E4 and D4, which on their turn can bind to leukotriene receptors on leukocytes and lung smooth muscle cells and cause bronchoconstriction. There are two types of leukotriene modifiers (LTM): leukotriene receptor antagonists (LTRA), e.g. montelukast, which prevent the leukotrienes from binding to the cysteinyl leukotriene receptor 1 and leukotriene inhibitors (e.g. zileuton), which inhibit leukotriene production through blockage of 5-lipoxygenase. LTRA are more commonly prescribed for asthma than leukotriene inhibitors.
Emerging drugs for the treatment of sickle cell disease: a review of phase II/III trials
Published in Expert Opinion on Emerging Drugs, 2022
Jules M. Ross, Stéphanie Forté, Denis Soulières
As depicted above, activated leukocytes and proinflammatory mediators appear to contribute to SCD pathogenesis. The role of Canakinumab, a human monoclonal antibody targeting IL-1β, was explored in a proof-of-concept phase II trial and did not reach statistical significance in daily pain scores, however reduced patient-reported fatigue and hospitalization for pain crisis were observed, warranting further exploration (NCT02961218) [82]. In non-asthmatic SCD individuals, use of the inhaled corticosteroid mometasone decreased pain scores and soluble VCAM levels, a surrogate for erythrocyte adhesivity and overall disease severity in the phase II randomized trial IMPROVE (NCT02061202) and effects on vaso-occlusive event rates will be measured in IMPROVE2 (NCT03758950) [83]. Another explored activator of the inflammation cascade is dysbiosis and translocation of gut flora in SCD, contributing to the increased number of circulating aged neutrophils (CANs) in SCD which in turn participate in the endothelial adhesion process [84]. Suggesting a role for intestinal decontamination [85], Rifaximin, an antibiotic inhibiting bacterial RNA polymerase and having a track record of safety in long-term use in liver disease, was trialed in a small single arm study (NCT03719729). A decreased number of CANs and a potentially favorable effect on VOCs frequency and opioids use was observed and Rifaximin is currently the object of further investigations [84]. Other attempts have been made in the modulation of inflammatory response, using omega-3 fatty acids supplementation, leukotrienes antagonists, and statins, with variable successes (see Table 1).
Related Knowledge Centers
- Arachidonic Acid
- Autocrine Signaling
- Eicosapentaenoic Acid
- Enzyme
- Inflammation
- White Blood Cell
- Eicosanoid
- Redox
- Arachidonate 5-Lipoxygenase
- Lipid Signaling