Role Of Cysteinyl Leukotrienes Research Articles

The Role of Cysteinyl Leukotrienes and Their Receptors in EC-Macrophage Interaction and Therapeutic Implications for Atherosclerosis

The Role of Cysteinyl Leukotrienes and Their Receptors in EC-Macrophage Interaction and Therapeutic Implications for Atherosclerosis

Abstract 6963: Cysteinyl leukotriene receptors promote melanoma progression and metastasis

Abstract Background: Cysteinyl leukotrienes (cys-LTs; LTC4, LTD4, LTE4) are pro-inflammatory mediators mainly produced by hematopoietic cells, which enhance inflammation through their receptors, CysLT1R and CysLT2R. They play a pivotal role in the development of chronic asthma in humans. Recent association of inflammation with cancer has led to immense interest on the role of cysteinyl leukotrienes in cancer progression and metastasis. However, the exact molecular mechanisms regarding how these inflammatory mediators regulate the tumor proliferation and metastasis remain unexplored. A thorough investigation of these precise molecular mechanisms and identification of the specific receptor/s responsible can aid in understanding the therapeutic potential of these receptors in various cancers like melanoma. Since the inhibitors of these receptors are already FDA approved for the treatment of asthma, our goal is to repurpose these drugs to treat melanoma progression. Objective: To determine the mechanistic aspects of how CysLTRs regulate melanoma tumor initiation, progression, and metastasis. Methods: Protein expression by western blotting and ELISA, transcript expression by qPCR, viability, and proliferation by XTT and BrDU, migration using trans-well assay, tumor growth and metastasis were confirmed through in vivo experiments. Results & Conclusion: B16F10 melanoma cells express high CysLT1R compared to CysLT2R and produce endogenous cys-LTs that function in an autocrine signaling pattern. Further, cys-LTs mediated the activation of several signaling proteins such as ERK, p38, AKT, and CREB that are important for melanoma survival and proliferation. Moreover, treatment with CysLTR antagonists significantly reduced melanoma cell proliferation, survival, and migration. Accordingly, we observed a significant reduction in the melanoma tumor volume in vivo in both Cysltr1−/- and Cysltr2−/− mice compared to the WT mice. Interestingly, angiogenesis was significantly reduced in Cysltr2−/- mice but not in Cysltr1−/−.Therefore, we speculate that while both receptors play a crucial role in tumor proliferation in vivo, CysLT2R is the main driver of angiogenesis and metastasis. Therefore, targeting both these receptors using their specific antagonists can offer potential therapy for melanoma progression and metastasis. Citation Format: Emma Elizabeth Sabu Kattuman, Lakshminarayan Reddy Teegala, Somayeh Darzi, Sailaja Paruchuri. Cysteinyl leukotriene receptors promote melanoma progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6963.

Antagonism of cysteinyl leukotrienes and their receptors as a neuroinflammatory target in Alzheimer's disease.

Alzheimer's disease is a complex multifaceted neurodegenerative disorder. It is characterized by the deposition of extracellular amyloid senile plaques and intracellular neurofibrillary tangles leading to progressive dementia and death in aged adult population. Recent emerging research has highlighted a potential pharmacological role of 5-lipoxyenase-cysteinyl leukotriene pathway in molecular pathogenesis of Alzheimer's disease. Although cysteinyl leukotrienes and their receptors have a major clinical role in chronic respiratory inflammation, their roles in chronic neuroinflammation in Alzheimer's disease need a detailed and careful exploration. This review article highlights a novel role of cysteinyl leukotrienes and their receptors in pathophysiology of Alzheimer's disease in order to understand the underlying molecular mechanism. In addition, it summarizes the recent advances in various pre-clinical and clinical strategies used to modulate this pathway for therapeutic targeting of Alzheimer's disease.

Cysteinyl-leukotriene pathway as a new therapeutic target for the treatment of atherosclerosis related to obstructive sleep apnea syndrome

AimsObstructive sleep apnea (OSA) characterized by nocturnal intermittent hypoxia (IH) is associated with atherosclerosis and cysteinyl-leukotrienes (CysLT) pathway activation. We aimed to identify the determinants of CysLT pathway activation and the role of CysLT in OSA-related atherosclerosis. Methods and resultsDeterminants of the urinary excretion of LTE4 (U-LTE4) including history of cardiovascular events, polysomnographic and biological parameters were studied in a cohort of 170 OSA patients and 29 controls, and in a subgroup of OSA patients free of cardiovascular event (n = 136). Mechanisms linking IH, the CysLT pathway and atherogenesis were investigated in Apolipoprotein E deficient (ApoE−/−) mice exposed to 8-week IH.In the whole cohort, U-LTE4 was independently influenced by age, minimal oxygen saturation, and a history of cardiovascular events, and correlated significantly with intima-media thickness. In the subgroup of OSA patients free of cardiovascular event, increased U-LTE4 was increased compared to controls and independently related to hypoxia severity and traditional risk factors aggregated in the 10-year cardiovascular risk score of European Society of Cardiology. In IH mice, atherosclerosis lesion size and mRNA levels of 5-lipoxygenase, 5-lipoxygenase activating protein (FLAP) and CysLT1 receptor were significantly increased. This transcriptional activation was associated with the binding of HIF-1 to the FLAP promoter and was strongly associated with atherosclerosis lesion size. CysLT1 receptor antagonism (montelukast) significantly reduced atherosclerosis progression in IH mice. ConclusionsIH-related CysLT pathway activation contributes to OSA-induced atherogenesis. In the era of personalized medicine, U-LTE4 may be a useful biomarker to identify OSA patients for whom CysLT1 blockade could represent a new therapeutic avenue for reducing cardiovascular risk.

The role of cysteinyl leukotrienes and their receptors in refractory nasal polyps

Leukotriene signaling is essential in many diseases, including asthma, allergic rhinitis, atherosclerosis and inflammatory bowel disease. Nevertheless, the expression of cysteinyl leukotrienes (CysLTs) and its receptors (CYSLTRs) in different types of nasal polyps (NPs), and the role of their antagonist in the treatment of refractory chronic rhinosinusitis with nasal polyps (CRSwNP) are not well understood. The following study investigates the expression of CysLTs and CYSLTRs in different types of NPs, as well as the role of leukotriene receptor antagonist (montelukast) in refractory NPs. Our data showed that CysLTs and CYSLTRs were significantly elevated in CRSwNP group (p < 0.05), particularly in IL-5+NP patients, compared to patients with chronic rhinosinusitis but without NPs (CRSsNP) and the control group. Furthermore, montelukast have shown the ability to inhibit the expression of MUC5AC, TSLP, IL-4, IL-5, IL-13, and TGF-β in NP explants after treatment with Staphylococcal Enterotoxins B (SEB). In addition, the patients treated by additional montelukast have better outcomes compared to those with INCS only. To conclude, our results demonstrate that the inhibition of CysLTs signaling by montelukast decreases the expression of cytokines and mucin in polyp explants, and in turn promotes the recovery in patients with refractory CRSwNP.

TARGET THERAPY OF BRONCHIAL ASTHMA WITH LEUKOTRIENE RECEPTOR AGONISTS

This article describes the features of asthma phenotypes such as asthma in smokers and asthma and obesity. The role of cysteinyl leukotrienes is discussed in the formation of inflammation in these phenotypes of asthma. The leukotriene receptor antagonists, including montelukast are effective in therapy of this category of patients.

Injury-Related Production of Cysteinyl Leukotrienes Contributes to Brain Damage following Experimental Traumatic Brain Injury

The leukotrienes belong to a family of biologically active lipids derived from arachidonate that are often involved in inflammatory responses. In the central nervous system, a group of leukotrienes, known as the cysteinyl leukotrienes, is generated in brain tissue in response to a variety of acute brain injuries. Although the exact clinical significance of this excess production remains unclear, the cysteinyl leukotrienes may contribute to injury-related disruption of the brain-blood barrier and exacerbate secondary injury processes. In the present study, the formation and role of cysteinyl leukotrienes was explored in the fluid percussion injury model of traumatic brain injury in rats. The results showed that levels of the cysteinyl leukotrienes were elevated after fluid percussion injury with a maximal formation 1 hour after the injury. Neutrophils contributed to cysteinyl leukotriene formation in the injured brain hemisphere, potentially through a transcellular biosynthetic mechanism. Furthermore, pharmacological reduction of cysteinyl leukotriene formation after the injury, using MK-886, resulted in reduction of brain lesion volumes, suggesting that the cysteinyl leukotrienes play an important role in traumatic brain injury.

The Role of Leukotrienes in Airway Remodeling

Asthma is an inflammatory disorder of the airways that has been typified by its bronchospastic component. New attention has been directed to the long-term changes in asthmatic airways as indicated by the accelerated rate of lung function decline occurring in these patients despite therapy with inhaled corticosteroids. These structural changes in the airway wall, termed airway remodeling, are now thought to be a key component in the pathophysiology of asthma. Airway remodeling is characterized by thickening of the lamina reticularis with deposition of collagen and other extracellular matrix proteins leading to subepithelial fibrosis and increased airway goblet cells causing mucus hypersecretion. Of note, there is myofibroblast proliferation and increased airway smooth muscle mass caused by both hyperplasia and hypertrophy of smooth muscle cells. While an important role for cysteinyl leukotrienes (CysLTs) in the pathogenesis of airway inflammation and bronchoconstriction in asthma has been well-established, the specific role of CysLTs in airway remodeling is less clear. This aim of this review is to summarize the data from mouse models of asthma as well as limited human studies that demonstrate a key role for CysLTs in allergen-induced mucus hypersecretion, thickening of the lamina reticularis, and subepithelial fibrosis in the lungs. We will also focus on the interaction between CysLTs and cytokines/growth factors that mediate these changes in epithelial cells, smooth muscle cells, vasculature, and other structural components of the lungs in patients with asthma.

Role of cysteinyl leukotrienes in human allergen-specific Th2 responses induced by granulocyte macrophage-colony stimulating factor

The pro-inflammatory cytokine, granulocyte macrophage-colony stimulating factor (GM-CSF), which is elevated in the lungs of atopic asthmatic patients, has been shown to enhance major histocompatibility class II expression of alveolar macrophages (AM). We hypothesized that exposure of AM and monocytes from atopic asthmatic patients to GM-CSF would enhance their antigen presenting function, and investigated putative mechanisms for this effect. Alveolar macrophages were purified from bronchoalveolar lavage by plastic adherence. Monocytes and CD4(+) T cells were purified from peripheral blood by magnetic bead separation. Antigen-presenting cell (APC) were pretreated with GM-CSF, pulsed with allergen and cocultured with autologous T cells. T-cell proliferation was determined by tritiated thymidine incorporation and cytokine production by enzyme-linked immunosorbent assay. Exposure of allergen-pulsed AM and peripheral blood monocytes to GM-CSF significantly increased allergen-specific T-cell proliferation and T helper 2 (Th2) cytokine production. The enhanced response was dependent on costimulation by CD86, but not CD80. Inhibition of the 5-lipoxygenase pathway abrogated GM-CSF-mediated upregulation by monocytes of allergen-specific interleukin-5 (IL-5) and IL-13 cytokine production. Blocking of the cysteinyl leukotriene receptor 1 (cysLT(1)) receptor by a specific receptor antagonist inhibited allergen-specific IL-5 production in response to GM-CSF pretreatment. Exposure to GM-CSF enhanced the capacity of human APC from atopic asthmatic patients to induce allergen-specific Th2 responses by a mechanism involving cysLT. Novel immunotherapies, targeting production of GM-CSF or its actions on APC have the potential, therefore, to prove beneficial in treatment of patients with inflammatory airway disease.

Secretory Phospholipase A2 and Airway Inflammation and Hyperresponsiveness

Phospholipases mediate the release of arachidonic acid from membrane phospholipids, enabling the subsequent metabolism to potent inflammatory mediator products of cyclooxygenase and lipoxygenase enzymes, such as prostaglandins and leukotrienes. Cytosolic phospholipase A2 has long been recognized as important, but newly characterized are secreted A2 isoenzymes. These secretory phospholipases are released into the extracellular compartment on cell activation. Elevated levels have been found in allergic patients after allergen challenge. Earlier investigations in a mouse asthma model utilizing airway challenges with allergen showed an important role for cysteinyl leukotrienes in the airway remodeling process. Utilizing secretory phospholipase knockout mice, group X deficiency significantly diminished the airway goblet cell metaplasia, mucus hypersecretion, increased airway smooth muscle mass, and subepithelial fibrosis observed in wild type mice after allergen challenge. The mechanism is likely through impaired generation of cysteinyl leukotrienes in the knockout mice. Recent human investigation in patients with exercise induced bronchoconstriction is supportive of a role of secretory phospholipase, directing attention to these enzymes as particularly attractive pharmacologic targets in asthma.

Role of cysteinyl leukotrienes in the proliferation and the migration of murine vascular smooth muscle cells in vivo and in vitro

Objective Cysteinyl leukotrienes (Cys-LTs) are proinflammatory lipid mediators generated from arachidonic acid through 5-lipoxygenase (5-LO). It was reported that the 5-LO pathway is associated with vascular smooth muscle cell (VSMC) proliferation and migration; however, the relationship between Cys-LTs and VSMC proliferation and migration remains unclear. Methods: We used a mouse (C57/BL6J) model of femoral artery wire injury, and compared neointimal formation between controls and animals treated with the Cys-LT receptor antagonist, Montelukast (3 mg/kg/day). The effects of Cys-LTs with or without Montelukast on mouse aortic VSMC proliferation and migration were also investigated. Results After wire injury, neointimal hyperplasia was observed, and immunohistochemical analysis demonstrated expression of the Cys-LT receptors (Cys-LT1 and Cys-LT2) and α-smooth muscle actin in the injured arterial walls. RT-PCR analysis revealed that transcription was not altered during the observation period (before, 1, 2 and 4 weeks after injury). Administration of Montelukast significantly inhibited neointimal formation 4 weeks after injury (intima/media ratio; control group 1.94±0.56 versus Montelukast-treated group 0.94±0.26, n =11, P <0.001). In an in vitro study, LTD4, but not LTC4 and LTE4 significantly stimulated VSMC proliferation (1000 nM), and this effect was inhibited by Montelukast (10 μM). LTC4, LTD4 and LTE4 significantly stimulated VSMC migration (1000 nM), and this effect was inhibited by Montelukast (10 μM). Conclusions Our data suggest that Cys-LTs are involved in VSMC proliferation and migration, and a Cys-LT receptor antagonist may have beneficial effects on vascular remodeling after mechanical injury.

Modification of Cysteinyl Leukotriene Receptor Expression in Capsular Contracture

The development of a fibrotic capsule around foreign material in the body is a physiologic reaction undertaken by the body to protect itself from a material it does not recognize. The periprosthetic capsule can pathologically contract, pressing on the implant; it can cause pain, firmness, and sometimes implant extrusion. The pathogenesis of capsular contracture is still unclear, but most reports indicate a multifactorial explanation. The aim of this study is to investigate the role of cysteinyl leukotriene receptors (cysLTR) on the inflammatory cells involved in the development of the capsular contracture. We recruited 20 patients affected by severe capsular contracture (Baker III-IV) and a control group composed of normal patients who had undergone implant substitution. In both groups, we performed a semiquantitative analysis of mRNA encoding for cysLTR1, cysLTR2, tumor necrosis factor-alpha (TNF-alpha) and interleukin 10 (IL-10) on myofibroblasts and macrophages of the periprosthetic capsular tissue. The molecular analysis showed an increase in the cysLTR2, TNF-alpha gene expression but no change in the cysLTR1 and IL-10 genes in patients affected by capsular contracture. These preliminary findings suggest a primary role for cysteinyl leukotrienes in the activation and up-regulation of capsular contraction mechanisms.

Role of cysteinyl-leukotrienes in the pathogenesis of nasal polyposis in patients with asthma

Cysteinyl leukotrienes (CysLTs: leukotrienes C4, D4, and E4) have long been implicated in the pathogenesis of allergic diseases such as asthma. CysLTs are potent bronchoconstrictors that have the additional effects of edema, mucous secretion, and eosinophilic accumulation, and airway remodeling. LTE4 has been identified as a major metabolite of LTC4, and urinary LTE4 (U-LTE4) is considered as the most reliable analytic parameter for monitoring the endogenous synthesis of CysLTs. From our extensive study of U-LTE4 in adult asthma, we identified four factors for hyperleukotrienuria. These factors were aspirin-intolerance, eosinophilic nasal polyposis (ENP), vasculitis, and severe asthma. In ENP there is prominent infiltration of eosinophils in the sinus and polyp tissues, which is linked to adult asthma and aspirin-sensitivity, and ENP is the most important factor for overproduction of CysLTs in asthmatics. We demonstrated that there is a significant decrease in the U-LTE4 concentration after the sinus surgery of asthmatics with and without aspirin intolerance. Recent studies reported that ENP tissue contain and produce a large amount of CysLTs, and there is a close relationship between CysLT production and eosinophil accumulation in ENP. These observations suggest that ENP is not only a local allergic disease, but also a systemic inflammatory disease with CysLT overproduction.

Identification and Functional Characterization of the Hepatic Stellate Cell CD38 Cell Surface Molecule

The activation of hepatic stellate cells (HSCs) is a critical event in hepatic fibrosis, because these cells are the main producers of extracellular matrix proteins in the liver and contribute to the modulation of inflammatory responses via the secretion of several cytokines and the expression of adhesion molecules. The goal of the present study was to characterize cell surface proteins that regulate HSC activation. To this end, a panel of monoclonal antibodies (mAbs) was generated. mAb 14.27 recognized a protein of 45 kd that was highly expressed on HSCs. Affinity purification of this protein followed by sequencing revealed that protein to be CD38. We subsequently demonstrated that CD38 was constitutively expressed by HSCs and that its expression increased after in vitro and in vivo activation. mAb 14.27 induced an increase in cytosolic Ca2+ levels in HSCs, showing that it functions as an agonistic antibody. Moreover, the effects mediated by the CD38 mAb included induction of the proinflammatory cytokine interleukin-6 and up-regulation of the adhesion molecules intercellular adhesion molecule-1, vascular cell adhesion molecule-1, and neural cell adhesion molecule. Collectively, our data suggest that CD38 can act as a regulator of HSC activation and effector functions.

Role of cysteinyl leukotrienes in airway inflammation and responsiveness following RSV infection in BALB/c mice

Cysteinyl leukotrienes (CysLTs) contribute to the development of airway obstruction and inflammation in asthma; however little information is available on the role of these molecules in the pathophysiology of respiratory syncytial virus (RSV) bronchiolitis. This study was designed to evaluate the effects of RSV infection on CysLTs production in a well-established mouse infection model. Furthermore, we assessed the effect of anti-inflammatory agents (a leukotriene receptor antagonist, MK-571, and dexamethasone) on the functional and immune changes induced by RSV infection. Six to 8-wk-old BALB/c mice were infected with human RSV (strain A2). Measurements of airway function were performed using whole body plethysmography. Lung inflammation was assessed by cell counts, measurement of cytokines and CysLTs in bronchoalveolar lavage fluid (BALF) in the absence and presence of treatment with MK-571 or dexamethasone. RSV infection produced a marked increase in CysLTs in the BALF and lung tissue, recruitment of neutrophils and lymphocytes into the airways, increased IFN-gamma levels and airway hyperresponsiveness (AHR). Treatment with MK-571 decreased RSV-induced AHR without affecting the cellular and inflammatory responses to RSV. Dexamethasone decreased AHR and markedly reduced the recruitment of inflammatory cells and production of IFN-gamma. Our findings suggest CysLTs play an important role in the pathogenesis of RSV-induced airway dysfunction. Treatment with MK-571 decreases RSV-induced AHR but does not appear to alter the lung inflammatory responses to RSV. In contrast, dexamethasone decreases RSV-induced AHR but interferes with recruitment of inflammatory cells, resulting in decreased Th1 cytokines (a potentially Th2-prone environment) in this model. These studies support recent reports on the beneficial effects of CysLT receptor antagonist in human trials and provide a model for investigating the role of CysLTs in RSV bronchiolitis.

A possible role for cysteinyl-leukotrienes in non-ionic contrast media induced adverse reactions

Purpose: To test whether mono- or dimeric X-ray contrast media (CM) may induce the de novo production of cysteinyl-leukotriens (cys-LT), that could contribute to allergic/allergy-like side effects. Materials and methods: Leukocytes from 39 patients receiving iopromide or iotrolan for routine CT-examination were analyzed for the production of cys-LT. Histamine levels were analyzed in plasma specimens. One patient with a positive history of a previous CM-reaction did not receive CM-injection. Results: Three patients of the iopromide and five of the iotrolan group showed adverse reactions. Reactors had increased cys-LT values in samples obtained before CM-injection induced by the positive control (anti-FcɛRI antibodies) (6763.7 pg/ml ± 1367.3 versus 2299.8 pg/ml ± 399.2; p < 0.007). Patients with versus without CM-reaction did not differ significantly with respect to their histamine values before CM-administeration. In vitro iopromide ( p < 0.0002) and iotrolan ( p < 0.0008) induced significant cys-LT production as compared to IL-3 stimulation. In vivo both CM induced a significant increase 6 h after CM administration ( p < 0.05). Conclusion: Our findings suggest that both CM seem to induce cys-LT production. As to whether the observed increased values in pre-dose samples of patients with as compared to those without reactions could contribute to identify high risk patients should be investigated in larger patient groups in future.

Role for cysteinyl leukotrienes in allergen-induced change in circulating dendritic cell number in asthma

BackgroundDendritic cells are important antigen-presenting cells. After an allergen inhalation, their numbers rapidly decrease in circulation and increase in the airway mucosa. ObjectiveTo investigate whether allergen-induced changes in the number of circulating dendritic cells are mediated by cysteinyl leukotrienes. MethodsIn a randomized, double-blind, crossover study, we examined the effects of 2 weeks of treatment with pranlukast (a cysteinyl leukotriene 1 [CysLT1] receptor antagonist) 300 mg twice daily and placebo on allergen-induced changes in airway responses and circulating dendritic cells in 15 subjects with mild asthma. We examined by flow cytometry, before and at 3 hours and 24 hours after allergen inhalation, the proportion of myeloid (CD33+) and plasmacytoid (CD123+) dendritic cells (HLA-DR+, CD14–, CD16–) among all peripheral blood mononuclear cells. The fraction of dendritic cells expressing CysLT1 receptor was also determined. ResultsCompared with placebo, pranlukast significantly attenuated both the maximum early (by 55%) and the late (by 39%) asthma responses, the allergen-induced methacholine airway hyperresponsiveness, and the increase in macrophage inflammatory protein 1α and 3α in induced sputum. A significantly greater proportion of CD33+ cells (55%) expressed CysLT1 receptor compared with CD123+ cells (11%). Consistent with this, pranlukast prevented the allergen-induced decrease in CD33+ dendritic cells at 3 hours postallergen (mean Δ from baseline, +4.4%) compared with placebo (mean Δ, −8.4; P < .05), but not CD123+ cells. ConclusionPretreatment with pranlukast attenuated allergen-induced airway responses and the decrease in circulating myeloid dendritic cells, demonstrating a novel role of cysteinyl leukotrienes in dendritic cell trafficking.

The role of leukotrienes in nasal allergy

Objective This review focuses on the role of cysteinyl leukotrienes (cysLTs) in nasal allergy. The purpose was to provide knowledge of the role of cysLTs in the pathophysiology of nasal allergy and the role of antileukotrienes in the treatment of nasal allergies. Materials and methods We conducted a literature review. Results The proinflammatory effects of cysLTs have been well described in asthma. Antileukotrienes have proved to be an effective anti-inflammatory treatment for asthma patients. Similar to pathogenesis of asthma, cysLTs exert potent inflammatory effects in the upper airways and play a role in the pathogenesis of allergic rhinitis and other nasal allergies. Conclusion Antileukotriene treatment appears to be beneficial in nasal allergies. Allergic rhinitis is a complex, IgE-mediated inflammatory disease of the upper airways. It is the most common allergic disease, occurring in 10% to 30% of adults and up to 30% of children. It may be perennial or seasonal. Sneezing, itching, watery rhinorrhea, and nasal obstruction are classic symptoms. It may impair cognition, school/work performance and productivity, behavior, mood, and quality of life. On physical examination, clear secretions, nasal congestion, pink-bluish nasal mucosa, the allergic salute, and allergic shiners may be detected. Allergic rhinitis is a common comorbid condition with asthma, sinusitis, otitis media, nasal polyposis, and respiratory infections.

Studies on the Experimental Allergic Rhinitis Induced by Japanese Cedar Pollen — Role of Cysteinyl Leukotrienes in Nasal Allergic Symptoms

AbstractFor Abstract see ChemInform Abstract in Full Text.

Cysteinyl leukotrienes in porcine acute allergic airway reactions: bronchial and vascular effects.

The role of cysteinyl leukotrienes (cysLTs) in the acute allergic airway reaction in the pig was investigated, with focus on the effects on the bronchial circulation, and compared with histamine-induced effects. 31 barrier-bred pigs were used, of which 24 pigs were actively-sensitised to Ascaris suum. Leukotriene D(4) (LTD(4)) and histamine were injected intravenously (i.v.) and given as an aerosol to non-sensitised pigs. Seventeen animals, sensitised to Ascaris suum, were challenged with Ascaris antigen aerosol. The effect of MK-571, a CysLT(1)-receptor antagonist, on LTD(4)- and allergen-induced responses were investigated. LTD(4) (2 nmol/kg) i.v. injection increased the airways resistance (R(aw)) by 46 +/- 20% and reduced bronchial vascular conductance (BVC) by 38 +/- 2%. Both these effects were blocked by MK-571 (0.1 mg/kg i.v.). Histamine injections (i.v.) in equimolar doses caused similar dose-dependent increases in R(aw), (22 +/- 7%) but induced vasodilatation and an increase in BVC (22 +/- 8%). Aerosolised LTD(4) (4 nmol/kg) caused a decrease in BVC but did not affect R(aw). In sensitised pigs, challenge with Ascaris aerosol led to an acute increase in Raw (198 +/- 57%) and increase in BVC (62 +/- 35%). MK-571 (0.5 mg/kg i.v.) pre-treatment did not significantly affect these responses (n = 9). LTD(4) causes constriction of the pig bronchi and of the bronchial circulation via activation of the CysLT(1) receptor and may counteract histamine-induced vasodilatory effects. However, in the allergen-induced acute airway response in the pig, cysLTs do not seem to be important bronchoconstrictive mediators.