Leucotrienos urinarios en pacientes pediátricos con trastorno respiratorio del sueño secundario a hiperplasia adenoamigdalina / Urinary leukotrienes in pediatric patients with sleep disordered breathing secondary to adenotonsillar hypertrophy

RESUMEN Introducción: El trastorno respiratorio del sueño (TRS) afecta al 2% a 3% de la población pediátrica, siendo la hiperplasia adenoamigdalina (HAA) su principal causa. Se ha observado un aumento en los niveles de leucotrienos excretados en orina (LTU) en estos pacientes, los cuales se correlacionarían con la severidad de la enfermedad. Objetivo: Determinar el nivel de LTU en niños con TRS e HAA antes y después de adenoamigdalectomía (AA), y en controles sanos. Correlacionar los niveles de LTU con los síntomas de TRS. Material y método: Estudio prospectivo. Se incluyeron pacientes con TRS e HAA (n =12) y controles sanos (n =12). Se determinó la concentración de LTU en ambos grupos de forma basal y un mes después de cirugía en el grupo con TRS. Resultados: No hubo diferencias en los niveles de LTU antes y después de AA. Tampoco existieron diferencias entre el grupo control y grupo TRS previo a la cirugía. No se encontró asociación entre LTU y la severidad de síntomas respiratorios. Conclusión: Los LTU no se encuentran elevados en pacientes con TRS e HAA, no disminuyen luego de AA y no se correlacionan con la severidad de los síntomas. La medición de LTU no sería una herramienta útil en la evaluación de pacientes con TRS. Nuevos estudios son necesarios para evaluar el rol de los leucotrienos en esta enfermedad.

ABSTRACT Introduction: Sleep disorder breathing (SDB) affects 2%-3% of the pediatric population, being adenotonsillar hyperplasia (ATH) its main cause. An increase in the levels of urinary leukotrienes (ULT) has been measured in these patients, which could be correlated with the severity of the disease. Aim: To determine the level of ULT in children with SDB and ATH before and after adenotonsillectomy, and healthy controls. To correlate the levels of ULT with symptoms of SDB. Material and method: prospective study. SDB and ATH patients (n =12) and healthy controls (n =12) were included. The concentration of ULT in both groups was determined, before surgery and after a month of surgery. Results: There were no differences in the levels of ULT before and after tonsillectomy in the studied group. There were also no differences between the control group and the SDB group. No association was observed between the level of ULT and the severity of respiratory symptoms. Conclusions: ULT are not elevated in patients with SDB and ATH and they do not decrease after adenotonsillectomy. ULT are not correlated with the severity of the symptoms of SDB. The measurement of ULT would not be a useful tool in the evaluation of patients with SDB. New studies are needed to assess the role of the role of leukotrienes in this disease.

Complementary Participation of Genetics and Epigenetics in Development of NSAID-exacerbated Respiratory Disease

Nonsteroidal anti-inflammatory drug (NSAID)-exacerbated respiratory disease (NERD) has attracted a great deal of attention because of its association with severe asthma. However, it remains widely underdiagnosed in asthmatics as well as the general population. Upon pharmacological inhibition of cyclooxygenase 1 by NSAIDs, production of anti-inflammatory prostaglandin E2 and lipoxins ceases, while release of proinflammatory cysteinyl leukotrienes increases. To determine the underlying mechanisms, many studies have attempted to elucidate the genetic variants, such as single nucleotide polymorphisms, responsible for alterations of prostaglandins and leukotrienes, but the results of these genetic studies could not explain the whole genetic pathogenesis of NERD. Accordingly, the field of epigenetics has been introduced as an additional contributor to genomic alteration underlying the development of NERD. Recently, changes in CpG methylation, as one of the epigenetic components, have been identified in target tissues of NERD. This review discusses in silico analyses of both genetic and epigenetic components to gain a better understanding of their complementary roles in the development of NERD. Although the molecular mechanisms underlying NERD pathogenesis remain poorly understood, genetic and epigenetic variations play significant roles. Our results enhance the understanding of the genetic and epigenetic mechanisms involved in the development of NERD and suggest new approaches toward better diagnosis and management.

Genes and Pathways Regulating Decline in Lung Function and Airway Remodeling in Asthma

Asthma is a common disorder of the airways characterized by airway inflammation and by decline in lung function and airway remodeling in a subset of asthmatics. Airway remodeling is characterized by structural changes which include airway smooth muscle hypertrophy/hyperplasia, subepithelial fibrosis due to thickening of the reticular basement membrane, mucus metaplasia of the epithelium, and angiogenesis. Epidemiologic studies suggest that both genetic and environmental factors may contribute to decline in lung function and airway remodeling in a subset of asthmatics. Environmental factors include respiratory viral infection-triggered asthma exacerbations, and tobacco smoke. There is also evidence that several asthma candidate genes may contribute to decline in lung function, including ADAM33, PLAUR, VEGF, IL13, CHI3L1, TSLP, GSDMB, TGFB1, POSTN, ESR1 and ARG2. In addition, mediators or cytokines, including cysteinyl leukotrienes, matrix metallopeptidase-9, interleukin-33 and eosinophil expression of transforming growth factor-β, may contribute to airway remodeling in asthma. Although increased airway smooth muscle is associated with reduced lung function (i.e. forced expiratory volume in 1 second) in asthma, there have been few long-term studies to determine how individual pathologic features of airway remodeling contribute to decline in lung function in asthma. Clinical studies with inhibitors of individual gene products, cytokines or mediators are needed in asthmatic patients to identify their individual role in decline in lung function and/or airway remodeling.

Emerging Therapies in Chronic Spontaneous Urticaria

Chronic spontaneous urticaria (CSU) is characterized by typically short-lived and fleeting wheals, angioedema or both, which occur spontaneously and persist for longer than 6 weeks. This term is applied to the most common subtype of chronic urticaria. The underlying pathophysiology for CSU involves mast cell and basophil degranulation with release of histamine, leukotrienes, prostaglandins and other inflammatory mediators. Although a variety of treatments exist, many patients do not tolerate or benefit from the existing therapies and even require more effective treatments. Omalizumab is currently the only licensed biologic for antihistamine-refractory CSU, and novel drugs are under development. This article reviews its current status regarding pathogenesis and approach to treatment as well as therapeutic agents that are under development for the treatment of CSU.

Diverse characters of Brennan’s paw incision model regarding certain parameters in the rat / 대한통증학회지

BACKGROUND: Brennan’s rodent paw incision model has been extensively used for understanding mechanisms underlying postoperative pain in humans. However, alterations of physiological parameters like blood pressure and heart rate, or even feeding and drinking patterns after the incision have not been documented as yet. Moreover, though eicosanoids like prostaglandins and leukotrienes contribute to inflammation, tissue levels of these inflammatory mediators have never been studied. This work further investigates the antinociceptive effect of protein C after intra-wound administration. METHODS: Separate groups of Sprague–Dawley rats were used for quantitation of cyclooxygenase (COX) activity and leukotriene B4 level by enzyme-linked immunosorbent assay, as well as estimation of cardiovascular parameters and feeding and drinking behavior after paw incision. In the next part, rats were subjected to incision and 10 μg of protein C was locally administered by a micropipette. Both evoked and non-evoked pain parameters were then estimated. RESULTS: COX, particularly COX-2 activity and leukotriene B4 levels increased after incision. Hemodynamic parameters were normal. Feeding and drinking were affected on days 1 and 3, and on day 1, respectively. Protein C attenuated non-evoked pain behavior alone up to day 2. CONCLUSIONS: Based upon current observations, Brennan’s rodent paw incision model appears to exhibit a prolonged period of nociception similar to that after surgery, with minimal interference of physiological parameters. Protein C, which is likely converted to activated protein C in the wound, attenuated the guarding score, which probably represents pain at rest after surgery in humans.

Nonsteroidal anti-inflammatory drug hypersensitivity in the Asia-Pacific

Nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity reactions (HSRs) are often nonimmunologically mediated reactions which present with immediate HSR type manifestations. These are mediated by cyclooxygenase inhibition resulting in shunting towards the excessive production of leukotrienes. Important disease associations include asthma, nasal polyposis, and chronic spontaneous urticaria, especially among adults. The European Network on Drug Allergy/Global Allergy and Asthma European Network 2013 classification of NSAID HSR comprises nonselective HSR i.e., NSAID exacerbated respiratory disease (NERD), NSAIDs exacerbated cutaneous disease (NECD), NSAIDs induced urticarial-angioedema (NIUA); and selective (allergic) HSR i.e., single NSAID induced urticaria/angioedema or anaphylaxis, NSAIDs-induced delayed HSR. Much of the literature on genetic associations with NSAID HSR originate from Korea and Japan; where genetic polymorphisms have been described in genes involved in arachidonic acid metabolism, basophil/mast cell/eosinophil activation, various inflammatory mediators/cytokines, and different HLA genotypes. The Asian phenotype for NSAID HSR appears to be predominantly NIUA with overlapping features in some adults and children. NECD also appears to be more common than NERD, although both are not common in the Asian paediatric population. Between adults and children, children seem to be more atopic, although over time when these children grow up, it is likely that the prevalence of atopic adults with NSAID HSR will increase. Low-dose aspirin desensitization has been shown to be effective in the treatment of coronary artery disease, especially following percutaneous coronary intervention.

Role of the route of leukotrienes in an experimental model of oral mucositis induced by 5-fluorouracil

Abstract Purpose: To investigate the participation of cysteinyl leukotrienes in the pathophysiology of oral mucositis. Methods: Oral mucositis was induced in hamsters using 5-fluorouracil (5-FU; 60 and 40 mg/kg; i.p., on days 1 and 2, respectively, and with excoriations in jugal mucosa on day 4). Montelukast (10, 20, or 40 mg/kg/d; gavage), MK886 (3 mg/kg/d, i.p.), or saline or celecoxib (7.5 mg/kg/d; i.p.) was administered 1 h prior to 5-FU and daily, until the fourth (MK886) or tenth day, when the animals were euthanized and their jugal mucosa was collected for macroscopic, histopathological, and immunohistochemical evaluation. Results: Neither montelukast nor MK-886 prevented the oral mucositis induced by 5-FU, as observed by histopathological evaluation. In addition, we did not find significant differences in the expression of inducible nitric oxide synthase-2, cyclooxygenase-2, or interleukin (IL)-1β between the experimental and control groups. However, we did observe a significant decrease in tumor necrosis factor (TNF)-α expression for all doses of montelukast; we also observed a significant decrease in IL-10 with 40 mg/kg/d and MK 886. Conclusions: Cysteinyl leukotrienes do not play an important role in experimental oral mucositis induced by 5-FU. There is a modulating action specifically on TNF-α.

Urticária crônica exacerbada por anti-inflamatórios não esteroidais e resposta aos antileucotrienos / Nonsteroidal anti-inflammatory drug-exacerbated chronic urticaria and response to antileukotrienes

Introdução: Pacientes com urticária crônica espontânea (UCE) frequentemente exacerbam com o uso de anti-inflamatórios não esteroidais (AINEs), que são medicamentos que inibem a ciclooxigenase 1 (COX-1) e levam a um desvio para produção de leucotrienos. Os antileucotrienos seriam uma opção terapêutica para aqueles que não respondam aos anti-histamínicos (AH1). Objetivo: O objetivo deste estudo foi avaliar a eficácia dos antileucotrienos nos pacientes com UCE exacerbada ou não pelos AINEs que não responderam apenas aos AH1. Método: Estudo retrospectivo com análise de prontuários eletrônicos de pacientes com UCE em seguimento ambulatorial. Todos os pacientes foram interrogados sobre a história de exacerbação ou não da UCE por AINEs. Além dos AH1, o montelucaste foi introduzido para todos os pacientes, em algum momento do acompanhamento. Foram avaliadas a resposta ao antileucotrieno e a presença da associação desta resposta à história de exacerbação com AINE. Resultados: Sessenta e dois pacientes participaram do estudo. A média de idade foi de 48,4 anos, sendo 82,3% do sexo feminino. Destes, 35 pacientes (56,5%) referiam piora da urticária com uso de AINEs, e, destes, 77,1% responderam ao antileucotrieno associado ao AH1. Dentre os 27 pacientes que não apresentavam UCE exacerbada por AINE, 48,1% obtiveram boa resposta ao uso de antileucotrieno associado ao AH1. Conclusão: A resposta ao antileucotrieno foi superior e estatisticamente significante (p = 0,031) no grupo de pacientes com UCE exacerbada por AINE. Portanto, a associação dos antileucotrienos aos AH1 seria uma opção eficaz e segura, sendo que essa associação se torna ainda mais relevante em pacientes que UC exacerbada por AINEs.

Introduction: Patients with chronic spontaneous urticaria (CSU) frequently show symptom exacerbation after the use of nonsteroidal anti-inflammatory drugs (NSAIDs) ­ drugs that inhibit cyclooxygenase-1 (COX-1) and affect leukotriene production. Antileukotrienes are considered a therapeutic option for patients who do not respond to antihistamines (AH1). Objective: The aim of this study was to assess the effectiveness of antileukotrienes in patients with CSU exacerbated or not by NSAIDs. Methods: In this retrospective study, the electronic charts of CSU outpatients were analyzed. All patients were inquired about history of CSU exacerbation or not by NSAIDs. In addition to AH1, treatment with montelukast was introduced to all patients at some point during follow-up. Response to antileukotriene treatment and association between treatment response and history of NSAID exacerbation were evaluated. Results: A total of 62 patients participated in the study. Mean age was 48.4 years, and 82.3% were female. Thirtyfive patients (56.5%) reported worsening of urticaria with the use of NSAIDs; 77.1% of these patients responded to antileukotriene combined with AH1. Of the 27 patients with no history of CSU exacerbation with NSAIDs, 48.1% showed a favorable response to antileukotrienes associated with AH1. Conclusion: Response to antileukotriene treatment was higher and statistically significant (p=0.031) in patients with NSAID-exacerbated CSU. Therefore, the association of antileukotrienes with AH1 could be a safe and effective treatment option, especially for patients with NSAIDexacerbated CSU.

Mecanismos intracelulares induzidos por leucotrienos durante a diferenciação osteogênica / Leukotriene-induced intracellular mechanisms during osteogenic differentiation

Os leucotrienos (LTs) são mediadores inflamatórios derivados da via 5- lipoxigenase (5-LO), com contribuição relevante na reabsorção óssea. Neste estudo investigamos o papel dos LTs na diferenciação osteogênica e o seu impacto na osteoclatogênese. Assim, foi avaliado o perfil ósseo dos camundongos 129/Sv (WT) e 5-LO Knockout (5-LO KO) por meio de microtomografia computadorizada, evidenciando maior densidade óssea vertebral e trabéculas mais espessas em machos 5-LO KO. Após isso, osteoblastos primários (OBL) foram isolados e cultivados para determinar a atividade de fosfatase alcalina (ALP) e o potencial de mineralização. Resultados mostraram que OBL KO possui maior atividade de ALP e mineralização, em todos os períodos quando comparados com WT. Em adição, o tratamento com os LTs B4 e D4 inibiu a deposição de cálcio. Os inibidores da síntese de LTs e os antagonistas do BLT1/2 foram efetivos em recuperar a formação dos nódulos mineralizados. A cinética do Alox5 apresentou um aumento da expressão nos períodos de maior diferenciação celular em OBL WT. Além disso, a expressão de OCN, MMPs 2 e 9 e RANKL foram aumentadas em células 5-LO KO em quase todos os períodos avaliados. Em geral, o estímulo com LTs, seus inibidores e antagonistas diminuiu a expressão de Sp7, Col1a1, Opg e MMP-9 e aumentou RANKL em células KO. A sinalização por meio de segundos mensageiros também foi avaliada. Células 5-LO KO apresentam menor concentração de cálcio intracelular (Ca2+i) em relação ao WT. No período de 14 dias, o estímulo com LTD4 inibiu a liberação Ca2+i independente da linhagem, em relação ao controle. Os níveis de cAMP foram menores em OBL 5- LO KO, em todos os grupos tratados ou controle. LTD4 diminuiu a concentração de cAMP, mas não LTB4, em OBL 5-LO KO. O estudo também quantificou a produção de LTB4 e outros eicosanoides em osteoblastos mostrando a sua capacidade de síntese. A análise proteômica revelou 89 proteínas com expressão diminuída em OBL 5-LO KO, de um total de 154, sendo a maioria relacionada ao citoesqueleto e ao metabolismo energético. Também foram identificadas 59 proteínas exclusivas em OBL 5-LO KO e 06 unicamente expressas em células WT, revelando as diferenças intrínsecas de cada animal. O perfil osteoclastogênico de camundongos WT vs. 5-LO KO mostrou diferenças significativas na análise fenotípica, TRAP e na expressão gênica de células derivadas da linhagem monocítica-macrofágica. Após o estímulo com M-CSF e RANKL, as células WT apresentaram osteoclastos gigantes multinucleados, porém, células 5-LO KO apresentaram uma população de células com formas e tamanhos variáveis, e menor grau de maturação. Em adição, os LTsexógenos não modularam a atividade da TRAP. O meio condicionado proveniente dos OBL WT e KO, retardaram o processo de formação dos osteoclastos. A análise da expressão gênica em osteoclastos mostrou diminuição da expressão de Alox5, Il- 1b, Il-6 e TNFa em células 5-LO KO. BLT1/2, CysLt1 e os marcadores da diferenciação Acp5, Ctsk e Nfact1 não apresentaram diferenças entre os animais. Em adição, o LTB4 diminuiu a expressão do Alox5 e a Il-1b foi aumentada em osteoclastos WT. Assim, os resultados demonstram que os LTs são capazes de modular o metabolismo ósseo, e a ausência do gene da 5-LO está relacionada ao maior perfil osteogênico.(AU)

Leukotrienes (LTs) are inflammatory mediators derived from the 5-lipoxygenase (5-LO) pathway, with a relevant contribution in bone resorption. In this study we investigated the role of LTs in osteogenic differentiation and its impact on osteoclastogenesis.Thus, the bone profile of the 129/Sv (WT) and 5-LO Knockout mice (5-LO KO) was evaluated by computerized microtomography, showing higher vertebral bone density and thicker trabeculae in 5-LO KO males. After that, primary osteoblasts (OBL) were isolated and cultured to determine alkaline phosphatase activity (ALP) and mineralization potential. Results showed that OBL KO has higher ALP activity and mineralization, in all periods when compared with WT. In addition, the treatment with LTB4 and LTD4 inhibited calcium deposition. Inhibitors of LT synthesis and BLT1/2 antagonists were effective to recover the mineralized nodules formation. The kinetics of Alox5 showed an increase in expression during cellular differentiation period in WT OBL. In addition, expression of OCN, MMPs 2 and 9 and RANKL were increased in 5- LO KO cells in almost all evaluated periods. In general, the stimulation with LTs, their inhibitors and antagonists decreased the expression of Sp7, Col1a1, Opg and MMP- 9. But it increased the RANKL expression in KO cells. The second messengers signaling was also evaluated. 5-LO KO cells showed lower concentration levels of intracellular calcium (Ca2+ i) when compared to WT cells. In the 14-day period, the LTD4 treatment inhibited the Ca2+i independent of the murine lineage, relative to the control. cAMP levels were lower in OBL 5-LO KO, in all treated or control groups. LTD4 decreased the concentration of cAMP, but not LTB4, in KO cells. The study also quantified the production of LTB4 and other eicosanoids in osteoblasts showing their ability to synthesize those metabolites. The proteomic analysis revealed 89 downregulated proteins in OBL KO, out of a total of 154, most of them related to cytoskeleton and energy metabolism. Also 59 identified proteins were unique in OBL 5-LO KO and 06 exclusively expressed in WT cells, revealing the intrinsic differences of each strain. The osteoclastogenic profile of WT vs. 5-LO KO showed significant differences in phenotypic analysis, TRAP and in the gene expression of cells derived from the monocyte-macrophage-lineage. After M-CSF and RANKL stimulation, WT cells showed multinucleated giant osteoclasts. However, 5-LO KO cells presented a population of cells with variable shapes and sizes, and a lower maturation stage. In addition, exogenous LTs did not modulate TRAP activity. The conditioned medium from OBL WT and 5-LO KO delayed the formation process of osteoclasts. Gene expression analysis in osteoclasts showed decreased expression of Alox 5, Il-1b, Il-6 and TNFα in 5-LO KO cells. BLT1/2, CysLt1 and the osteoclast differentiation markers Acp5, Ctsk and Nfact1 showed no differences between the strains. In addition, LTB4 decreased the expression of Alox5, and IL-1b was increased in WT osteoclasts. Thus, the results demonstrate that the LTs are able to modulate the bone metabolism, and the absence of the 5-LO gene is related to the greater osteogenic profile.(AU)

Relação entre os efeitos de glicocorticoides e leucotrienos sobre a granulopoiese em medula óssea de camundongos normais e alérgicos / Relationship between the effects of glucocorticoids and leukotrienes on granulopoiesis in bone marrow of normal and allergic mice

A produção de eosinófilos (eosinopoiese) na medula óssea (MO) murina é aumentada in vitro por glicocorticoides (GC) e por cisteinil-leucotrienos (CisLT), produtos da 5-lipoxigenase (5-LO), na presença do fator de crescimento para eosinófilos, Interleucina(IL)-5. A eosinofilia da MO, induzida in vivo por sensibilização e provocação alérgica (S/P), é bloqueada pelo RU486, antagonista do receptor de GC, e pela dietilcarbamazina (DEC), inibidora da 5- LO. O efeito da DEC sobre a eosinopoiese requer tanto a 5-LO como a NO sintase indutível (iNOS), necessária à indução de apoptose via CD95. A Prostaglandina(PG)E2, ativadora da via iNOS/CD95, suprime a eosinopoiese, induzindo apoptose em eosinófilos imaturos em cultura; em contrapartida, o ácido retinóico all-trans (ATRA) induz a apoptose de eosinófilos por outro mecanismo, independente de iNOS. Os GC e os CisLT protegem eosinófilos imaturos da apoptose induzida tanto pela PGE2 como pelo ATRA. Nesta trabalho evidenciamos que a eosinopoiese é regulada por GC e CisLT, os quais, atuando sobre receptores distintos, funcionam de forma integrada em animais S/P, induzindo numa primeira fase a eosinofilia da MO in vivo, mas atenuando numa segunda fase as respostas da MO à reexposição aos CisLT ex vivo. Os alvos de GC e CisLT na regulação da eosinopoiese foram melhor caracterizados, assim como os mecanismos de articulação funcional in vivo entre essas vias. Por outro lado, GC e produtos da 5-LO também têm efeitos sobre a produção de neutrófilos em cultura de MO (neutropoiese). Esta é estimulada por GC, na presença do fator estimulante de colônias GM (GM-CSF). Apesar de um efeito antagônico sobre a eosinopoiese, o ATRA, assim como os GCs, na presença de GM-CSF, estimula a neutropoiese. Finalmente, o Leucotrieno (LT)B4 estimula a hematopoiese, tanto na presença como na ausência de GM-CSF, por um mecanismos sensível à deficiência de 5-LO.

Research advances in gene polymorphisms in biological pathways of drugs for asthma / 中国当代儿科杂志

The studies on gene polymorphisms in biological pathways of the drugs for the treatment of asthma refer to the studies in which pharmacogenetic methods, such as genome-wide association studies, candidate gene studies, genome sequencing, admixture mapping analysis, and linkage disequilibrium, are used to identify, determine, and repeatedly validate the effect of one or more single nucleotide polymorphisms on the efficacy of drugs. This can provide therapeutic strategies with optimal benefits, least side effects, and lowest costs to patients with asthma, and thus realize individualized medicine. The common drugs for asthma are β2 receptor agonists, glucocorticoids, and leukotriene modifiers. This article reviews the research achievements in polymorphisms in biological pathways of the common drugs for asthma, hoping to provide guidance for pharmacogenetic studies on asthma in future and realize individualized medicine for patients with asthma soon.

Eicosanoid Mediators in the Airway Inflammation of Asthmatic Patients: What is New?

Lipid mediators contribute to inflammation providing both pro-inflammatory signals and terminating the inflammatory process by activation of macrophages. Among the most significant biologically lipid mediators, these are produced by free-radical or enzymatic oxygenation of arachidonic acid named "eicosanoids". There were some novel eicosanoids identified within the last decade, and many of them are measurable in clinical samples by affordable chromatography-mass spectrometry equipment or sensitive immunoassays. In this review, we present some recent advances in understanding of the signaling by eicosanoid mediators during asthmatic airway inflammation. Eicosanoid profiling in the exhaled breath condensate, induced sputum, or their metabolites measurements in urine is complementary to the cellular phenotyping of asthmatic inflammation. Special attention is paid to aspirin-exacerbated respiratory disease, a phenotype of asthma manifested by the most profound changes in the profile of eicosanoids produced. A hallmark of this type of asthma with hypersensitivity to non-steroid anti-inflammatory drugs (NSAIDs) is to increase biosynthesis of cysteinyl leukotrienes on the systemic level. It depends on transcellular biosynthesis of leukotriene C₄ by platelets that adhere to granulocytes releasing leukotriene A₄. However, other abnormalities are also reported in this type of asthma as a resistance to anti-inflammatory activity of prostaglandin E₂ or a robust eosinophil interferon-γ response resulting in cysteinyl leukotrienes production. A novel mechanism is also discussed in which an isoprostane structurally related to prostaglandin E₂ is released into exhaled breath condensate during a provoked asthmatic attack. However, it is concluded that any single eicosanoid or even their complex profile can hardly provide a thorough explanation for the mechanism of asthmatic inflammation.

A Double-Blind, Randomized, Crossover Study to Compare the Effectiveness of Montelukast on Atopic Dermatitis in Korean Children

PURPOSE: Some studies report a role of leukotrienes in the pathogenesis of atopic dermatitis and suggest a rationale for the use of leukotriene receptor antagonist (LTRA) in the treatment of atopic dermatitis. This study aimed to evaluate the treatment effectiveness of montelukast in children with atopic dermatitis. METHODS: Fifty-four children between the ages of 2 and 6 years with moderate to severe atopic dermatitis were enrolled. Group A received montelukast for 8 weeks, followed by a crossover to 8 weeks of placebo after a 2-week washout period. Group B reversed the administration according to a randomized, double-blind, placebo-controlled, crossover design. The SCORing atopic dermatitis (SCORAD) index, urinary leukotriene E4 (LTE4), and eosinophil-derived neurotoxin (EDN) were assessed at every visit. RESULTS: Forty-three patients (21 males) completed the study. Although the SCORAD index was decreased in both groups, there was no statistically significant difference between montelukast and placebo (-3.0±11.2 vs -5.7±11.3, P=0.43). The level of urinary LTE4 was decreased after taking montelukast when compared to placebo, but there was no statistically significant difference (-65.9±556.2 vs 87.7±618.3, P=0.26). The changes in urinary EDN after taking montelukast and placebo had no significant difference (37.0±1,008.6 vs -195.8±916.7, P=0.10). When analyzing SCORAD indices, urinary LTE4, and EDN, we could not prove the effectiveness of montelukast in the atopic, non-atopic or high ECP (ECP ≥15 µg/L) subgroups. CONCLUSIONS: There was no statistically significant difference in clinical improvement or biomarkers between montelukast and placebo treatment. Therefore, conventional treatments with skin care and infection control might be more important strategies in the treatment of atopic dermatitis.

Mast cells generate cysteinyl leukotrienes and interferon- as well as evince impaired IgE-dependent degranulation upon TLR7 engagement.

Mast cells are numerous at anatomical sites close to external environment, virtually at the portals of infection. A few data indicated that these cells express cytoplasmic Toll-like receptors (TLRs) recognizing virus-derived molecules. Accordingly, mast cells could participate in anti-viral defense or/and in viral-related diseases. However, data concerning the influence of viruses on mast cell activity are limited. Thus, the aim of our study was to determine mast cell response to TLR7 ligand, i.e. resiquimod (R848), a synthetic mimic of viral ssRNA. Since mast cells play a central role in allergic reactions the effect of TLR7 agonist was also investigated on FcεRI-dependent mast cell response. Experiments were carried out in vitro on freshly isolated fully mature rat peritoneal mast cells. Mast cells exhibit constitutive TLR7 molecule expression and its up-regulation after the agonist challenge. TLR7-mediated mast cell stimulation resulted in cysteinyl leukotriene (cysLT) and interferon (IFN)-β synthesis, whereas no histamine and CXCL8 secretion was stated. Moreover, mast cell priming with TLR7 ligand caused the reduction in anti-IgE-induced histamine release. The results suggest that ssRNA viruses could directly activate mast cells to alter their phenotype and to release of potent proinflammatory mediators or indirectly modulate IgE-dependent allergic processes.

Cysteinyl Leukotrienes and Their Receptors; Emerging Concepts

Cysteinyl leukotrienes (cys-LTs) are potent mediators of inflammation derived from arachidonic acid through the 5-lipoxygenase/leukotriene C4 synthase pathway. The derivation of their chemical structures and identification of their pharmacologic properties predated the cloning of their classical receptors and the development of drugs that modify their synthesis and actions. Recent studies have revealed unanticipated insights into the regulation of cys-LT synthesis, the function of the cys-LTs in innate and adaptive immunity and human disease, and the identification of a new receptor for the cys-LTs. This review highlights these studies and summarizes their potential pathobiologic and therapeutic implications.

Association between genetic variants of the leukotriene biosynthesis pathway and the risk of stroke: a case-control study in the Chinese Han population / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Leukotrienes are arachidonic acid derivatives long known for their inflammatory properties. Leukotriene-based inflammation has been demonstrated to play a crucial role in atherosclerosis, a major risk factor for several human diseases. Recently, human genetic studies from us and others suggest that single nucleotide polymorphisms (SNPs) in leukotriene pathway genes influence the risk of atherosclerotic diseases such as stroke. This study aimed to assess the role of additional leukotriene pathway genes as a stroke risk factor within the Chinese Han population.</p><p><b>METHODS</b>We sequenced the promoter, exonic, and intronic regions of leukotriene A4 hydrolase (LTA4H) and arachidonate 5-lipoxygenase (ALOX5), and then genotyped five SNPs in LTA4H and four SNPs in ALOX5 among 691 cases with stroke and 732 controls from the Chinese population.</p><p><b>RESULTS</b>We detected a significant association between an intronic SNP in LTA4H (rs6538697) and stroke in our subjects (adjusted odds ratio, recessive model, 1.75; P = 0.022); and the SNP rs2029253 in ALOX5 was associated with a decreased risk of stroke (adjusted odds ratio, 0.76; 95% confidence interval, 0.59 - 0.97).</p><p><b>CONCLUSION</b>Genetic variants in LTA4H and ALOX5 may modulate the risk of stroke in the Chinese Han population.</p>

Inhaled corticosteroids and leukotriene modifiers as mono-therapy for mild persistent asthma

Several guidelines have endorsed inhaled corticosteroids [ICs] as superior for mild per-Mild persistent asthma; sistent asthma. The use of Leukotriene modifiers has been showing an effective potential based on Leukotriene modifiers; reports in past years. In this study the efficacy of a single daily dose of 200 microg of inhaled fluticasone Inhaled corticosteroids propionate was compared with that of the recommended dose of 10 mg of oral montelukast. Comparative data were based on the measurement of specific biomarkers including IgE, eosinophil count, interleukin 4 [IL-4] and fractional exhaled nitric oxide [FENO] as airway inflammation predictors and routine investigations were determined including the pulmonary function tests and X-ray imaging. After week 16, the levels of FENO, IgE, Forced expiratory volume in one second [FEVj] and eosinophilia count percentage were recognized to be of lower significance in asthmatic patients treated with ICS in comparison to those under treatment of leukotriene modifiers. Also, the results revealed a significant positive correlation between FENO level and eosinophil count [r = 0.272, p = 0.047]. The clinical effectiveness of a low dose of fluticasone propionate was superior clinically as a first-line of choice in patients with persistent asthma to that of mentulokast

Identificação e purificação de prostaglandinas e leucotrienos produzidos por Paracoccidioides brasiliensis / Identification and purification of prostaglandins and leukotrienes produced by Paracoccidioides brasiliensis

A paracoccidioidomicose (PCM) é uma micose sistêmica causada pelo fungo Paracoccidioides brasiliensis. O estabelecimento da paracoccidioidomicose-infecção ou paracoccidioidomicose-doença depende das interações parasita-hospedeiro que podem resultar em uma resposta imune mais ou menos eficaz por parte deste último. Embora vários dos mecanismos decorrentes dessa interação já estejam descritos, estudos sobre a participação de outros fatores potenciais podem ampliar sobremaneira o nosso entendimento sobre a imunopatogênese da PCM. Nesse sentido, os eicosanóides como as prostaglandinas (PGs) e leucotrienos (LTs) devem ser avaliados. Em trabalhos anteriores detectamos que o fungo induz a produção de PGs e LTs por monócitos humanos que, de uma forma autócrina, suprimem ou aumentam respectivamente, as atividades antifúngicas dessas células. No entanto, os estudos têm mostrado que além de induzir a produção de eicosanóides, os próprios fungos podem produzir esses mediadores, revelando um mecanismo de virulência que tem potencialmente grandes implicações para o entendimento dos mecanismos das infecções fúngicas. Baseados nesses estudos detectamos que o P. brasiliensis produz tanto PGs como LTs, usando fontes endógenas e exógenas de ácido araquidônico, e que ambos são importantes para a manutenção da viabilidade do fungo. Adicionalmente, os resultados sugeriram que o fungo utiliza as vias metabólicas da ciclooxigenase (COX) para a produção de PGs e da lipoxigenase (5-LO) para LTs. No presente trabalho, aprofundamos esses estudos objetivando avaliar se o fungo produz outras classes de eicosanóides, além da PGE2 e LTB4, se as PGs e LTs liberados pelo P. brasiliensis podem ser considerados como PGE2 e LTB4 autênticos, isto é semelhantes aos detectados para os mamíferos, assim como estabelecer de uma forma definitiva se a COX e a 5-LO são as vias metabólicas utilizadas para essa produção...

Paracoccidioidomycosis (PCM) is a systemic mycosis caused by the dimorphic fungus Paracoccidioides brasiliensis. The establishment of paracoccidioidomycosis-infection or the evolution to paracoccidioidomycosis-disease in its more or less severe forms, primarily depends on complex host-parasite interaction, in which immune response mechanisms play an essential role. While many of these mechanisms have been elucidated, studies on the participation of other potential factors can greatly expand our understanding of PCM immunopathogenesis. Accordingly, eicosanoids such as prostaglandins (PGs) and leukotrienes (LTs) should be evaluated. In previous studies we found that the fungus induces the production of prostaglandins and leukotrienes by human monocytes that in an autocrine way suppress and increase, respectively, the antifungal activities of these cells. However, studies have shown that in addition to inducing the production of eicosanoids, fungi themselves can produce these mediators, showing a mechanism for virulence that has potentially important implications for understanding the mechanisms of fungal pathogenicity. Based on these studies, we found that P. brasiliensis produces both PGs and LTs, using exogenous and endogenous sources of arachidonic acid and that both are important for fungus viability. Additionally, the results suggested that the fungus uses cyclooxygenase (COX) and lipoxygenase (5-LO) metabolic pathways for PGs and LTs production, respectively. Here, we profound these studies evaluating whether PGs and LTs released by P. brasiliensis can be considered as authentic LTB4 and PGE2, i.e. similar to those detected for mammals. We also asked whether the fungus, in addition to PGE2 and LTB4, produces other classes of eicosanoids. Finally, we intended to definitively determine whether COX and 5-LO are the metabolic pathways used for this production...

Treatment of Allergic Rhinitis / 대한내과학회지

Allergic rhinitis (AR) is defined as chronic inflammatory reactions to common allergens in the nasal mucosa with at least two AR symptoms including rhinorrhea, nasal congestion, sneezing, nasal/ocular pruritus, and postnasal drainage. AR is a common health problem, and it affects around 10-25% of general population. Its prevalence is increasing according to the environmental changes. AR and asthma frequently coexist in the same patient, therefore we should consider it and check for asthma to diagnose AR. Antihistamines and nasal corticosteroids are recommended as the 1st line treatment of AR. Decongestants may be effective for nasal congestion, and leukotrienes are helpful to improve both nasal and bronchial inflammations in patients with AR and asthma. Allergen specific immunotherapy is useful in IgE mediated AR and can prevent the progression to asthma and new sensitizations. Appropriate AR treatment including medications and immunotherapy can improve symptoms and reduce medications. Finally improvement of quality of life can be achieved.

Treatment of Allergic Rhinitis / 대한내과학회지

Allergic rhinitis (AR) is defined as chronic inflammatory reactions to common allergens in the nasal mucosa with at least two AR symptoms including rhinorrhea, nasal congestion, sneezing, nasal/ocular pruritus, and postnasal drainage. AR is a common health problem, and it affects around 10-25% of general population. Its prevalence is increasing according to the environmental changes. AR and asthma frequently coexist in the same patient, therefore we should consider it and check for asthma to diagnose AR. Antihistamines and nasal corticosteroids are recommended as the 1st line treatment of AR. Decongestants may be effective for nasal congestion, and leukotrienes are helpful to improve both nasal and bronchial inflammations in patients with AR and asthma. Allergen specific immunotherapy is useful in IgE mediated AR and can prevent the progression to asthma and new sensitizations. Appropriate AR treatment including medications and immunotherapy can improve symptoms and reduce medications. Finally improvement of quality of life can be achieved.