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Background: Montelukast (MTK), a potent antagonist of cysteinyl leukotriene receptor 1, has shown therapeutic promise for the treatment of neuropsychiatric disorders. Delirium, a common complication in critically ill patients, lacks effective treatment. This study aims to explore the impact of pre-intensive care unit (ICU) MTK use on in-hospital delirium incidence and, subsequent, prognosis in critically ill patients. Methods: A retrospective cohort study (n = 6344) was conducted using the MIMIC-IV database. After propensity score matching, logistic/Cox regression, E-value sensitivity analysis, and causal mediation analysis were performed to assess associations between pre-ICU MTK exposure and delirium and prognosis in critically ill patients. Results: Pre-ICU MTK use was significantly associated with reduced in-hospital delirium (OR: 0.705; 95% CI 0.497–0.999; p = 0.049) and 90-day mortality (OR: 0.554; 95% CI 0.366–0.840; p = 0.005). The association was more significant in patients without myocardial infarction (OR: 0.856; 95% CI 0.383–0.896; p = 0.014) and could be increased by extending the duration of use. Causal mediation analysis showed that the reduction in delirium partially mediated the association between MTK and 90-day mortality (ACME: −0.053; 95% CI −0.0142 to 0.0002; p = 0.020). Conclusions: In critically ill patients, MTK has shown promising therapeutic benefits by reducing the incidence of delirium and 90-day mortality. This study highlights the potential of MTK, beyond its traditional use in respiratory disease, and may contribute to the development of novel therapeutic strategies for delirium. [ABSTRACT FROM AUTHOR]

Introduction: COVID-19 is associated with a cascade of inflammatory responses potentially lead to devastating outcomes. Objectives: The current study aims to investigate the efficacy of montelukast, a leukotriene receptor antagonist (LTRA), on laboratory parameters in COVID-19 infection. Patients and Methods: The current randomized clinical trial (RCT) conducted on 67 patients with moderate-to-severe COVID-19 pneumonia in 2020-2021. All patients received treatments according to the national guidelines, while the case group additionally applied 10 mg montelukast for 14 days. The clinical disease improvement and laboratory data (complete blood cells count and differentiation, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), D-dimer, blood urea nitrogen (BUN), creatinine (Cr), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH) were assessed within two weeks after the infection and compared between the groups. Results: Baseline assessed parameters did not differ between the groups (P>0.05). A significant decrease in pulse rate, also in normal ranges, was notified in the montelukast-treated group compared with the baseline (P=0.001) and with controls (P=0.033); however, other vital signs were not statistically different (P>0.05). CRP (P

Innate lymphoid cells (ILC) promote lung inflammation in asthma through cytokine production. RNA-binding proteins (RBPs) are critical post-transcriptional regulators, although less is known about RBPs in ILC biology. Here, we demonstrate that RNA-binding motif 3 (RBM3) is highly expressed in lung ILCs and is further induced by alarmins TSLP and IL-33. Rbm3-/- and Rbm3-/-Rag2-/- mice exposed to asthma-associated Alternaria allergen develop enhanced eosinophilic lung inflammation and ILC activation. IL-33 stimulation studies in vivo and in vitro show that RBM3 suppressed lung ILC responses. Further, Rbm3-/- ILCs from bone marrow chimeric mice display increased ILC cytokine production suggesting an ILC-intrinsic suppressive function of RBM3. RNA-sequencing of Rbm3-/- lung ILCs demonstrates increased expression of type 2/17 cytokines and cysteinyl leukotriene 1 receptor (CysLT1R). Finally, Rbm3-/-Cyslt1r-/- mice show dependence on CysLT1R for accumulation of ST2+IL-17+ ILCs. Thus, RBM3 intrinsically regulates lung ILCs during allergen-induced type 2 inflammation that is partially dependent on CysLT1R.

Objective:Triple negative breast cancer (TNBC) has high relapse rates due to dysregulated inflammatory signaling pathways and significant changes in the tumor microenvironment, probably influencing the failure of several therapies. The Cysteinyl Leukotriene Receptor 1 (CYSLTR1), a leukotriene modulator of inflammation, has been shown to play an important role in cancer pathogenesis and survival but few studies have been reported on its role in breast cancer.Materials and Methods:The present work was conducted using publicly available platforms that have omics data to assess the clinical potential of CYSLTR1 expression and its prognostic validation in large cohorts of samples from breast cancer patients. Web platforms containing clinical information, RNA-seq and protein data were selected to perform in silico analyses of the potential marker CYLSTR1. Added together, the platforms included modules for correlation, expression, prognosis, drug interactions, and construction of gene networks.Results:Kaplan–Meier curves revealed that reduced levels of CYSLTR1 corresponded to an unfavorable outcome for overall survival (p

Uveal melanoma (UM) is a currently untreatable form of melanoma with a 50% mortality rate. Characterization of the essential signaling pathways driving this cancer is critical to develop target therapies. Activating mutations in the Gαq signaling pathway at the level of GNAQ, GNA11, or rarely CYSLTR2 or PLCβ4 are considered alterations driving proliferation in UM and several other neoplastic disorders. Here, we systematically examined the oncogenic signaling output of various mutations recurrently identified in human tumors. We demonstrate that CYSLTR2 → GNAQ/11 → PLCβ act in a linear signaling cascade that, via protein kinase C (PKC), activates in parallel the MAP-kinase and FAK/Yes-associated protein pathways. Using genetic ablation and pharmacological inhibition, we show that the PKC/RasGRP3/MAPK signaling branch is the essential component that drives the proliferation of UM. Only inhibition of the MAPK branch but not the FAK branch synergizes with inhibition of the proximal cascade, providing a blueprint for combination therapy. All oncogenic signaling could be extinguished by the novel GNAQ/11 inhibitor YM-254890, in all UM cells with driver mutation in the Gαq subunit or the upstream receptor. Our findings highlight the GNAQ/11 → PLCβ → PKC → MAPK pathway as the central signaling axis to be suppressed pharmacologically to treat for neoplastic disorders with Gαq pathway mutations.

Background: Pregnancy is a physiological state in which the female body undergoes a series of changes and adaptations to provide the best possible conditions for the growth and development of the forming baby. The internal adaptations that take place lead to the production of inflammation, which is necessary for the initial and final stages of pregnancy (embryo implantation and induction of labor). Gestational diabetes mellitus is considered to be the most common pathology during this period. However, many more serious health complications can arise, which include pre-eclampsia, fetal stunting, and preterm labor. The purpose of this study was to analyze the impact of the levels of individual eicosanoids on the course of normal pregnancy and the possibility of pathologies including gestational diabetes and pre-eclampsia. Methods: Sixty-nine pregnant women who were overweight or obese before and during pregnancy were studied. Eicosanoids were extracted as appropriate and then determined using liquid chromatography. The levels of eicosanoids studied in pregnant women differed not only according to the week of pregnancy but also in relation to individual anthropometric and biochemical parameters. Results: There was a significant correlation between being overweight and having a high BMI before pregnancy—as well as biochemical parameters of lipid and carbohydrate profiles—and the occurrence of pathological conditions in pregnancy. Conclusions: Eicosanoids are involved in the pathology of pregnancy associated with the occurrence of gestational diabetes and pre-eclampsia. Salicylic acid may find use in the treatment of pregnant women exposed to both phenomena, as well as in overweight and obese women found before pregnancy. Diets rich in natural salicylates, methods of administration, and pharmacotherapy and dosage need further study. Some of the mediators (lipoxin, prostaglandin and leucotrien) may be new diagnostic markers in pregnancy pathology and intervention pathways in the future. [ABSTRACT FROM AUTHOR]

Abstract Background Breast cancer survivors face long-term sequelae compared to the general population, suggesting altered metabolic profiles after breast cancer. We used metabolomics approaches to investigate the metabolic differences between breast cancer patients and women in the general population, aiming to elaborate metabolic changes among breast cancer patients and identify potential targets for clinical interventions to mitigate long-term sequelae. Methods Serum samples were retrieved from 125 breast cancer cases recruited from the Chicago Multiethnic Epidemiologic Breast Cancer Cohort (ChiMEC), and 125 healthy controls selected from Chicago Multiethnic Prevention and Surveillance Study (COMPASS). We used liquid chromatography-high resolution mass spectrometry to obtain untargeted metabolic profiles and partial least squares discriminant analysis (PLS-DA) combined with fold change to select metabolic features associated with breast cancer. Pathway analyses were conducted using Mummichog to identify differentially enriched metabolic pathways among cancer patients. As potential confounders we included age, marital status, tobacco smoking, alcohol drinking, type 2 diabetes, and area deprivation index in our model. Random effects of residence for intercept was also included in the model. We further conducted subgroup analysis by treatment timing (chemotherapy/radiotherapy/surgery), lymph node status, and cancer stages. Results The entire study participants were African American. The average ages were 57.1 for cases and 58.0 for controls. We extracted 15,829 features in total, among which 507 features were eventually selected by our criteria. Pathway enrichment analysis of these 507 features identified three differentially enriched metabolic pathways related to prostaglandin, leukotriene, and glycerophospholipid. The three pathways demonstrated inconsistent patterns. Metabolic features in the prostaglandin and leukotriene pathways exhibited increased abundances among cancer patients. In contrast, metabolic intensity in the glycerolphospholipid pathway was deregulated among cancer patients. Subgroup analysis yielded consistent results. However, changes in these pathways were strengthened when only using cases with positive lymph nodes, and attenuated when only using cases with stage I disease. Conclusion Breast cancer in African American women is associated with increase in serum metabolites involved in prostaglandin and leukotriene pathways, but with decrease in serum metabolites in glycerolphospholipid pathway. Positive lymph nodes and advanced cancer stage may strengthen changes in these pathways.

Purpose: Arthrofibrosis is a common inflammatory complication of joint trauma and surgery. 5lipoxygenase (5-LO) is a key enzyme involved in inflammation. Inhibition of 5-LO has been shown to reduce inflammation in heart and lung models but has not been examined in a joint contracture model. Methods: Twenty-six rats underwent joint contracture. Six rats served as non-surgical controls. A 5-LO inhibitor, caffeic acid (CA), suspended in 10% ethanol was orally administered to 14 rats and ethanol without CA to the remaining 12 rats daily for 21 days. Leukotriene B4 (LTB4) levels were measured, both systemically and locally. 5-LO levels in the posterior capsule were quantified by measuring the ratio of the length of the posterior capsule demonstrating 5-LO immunostaining to the total length of the capsule. Results: Joint contracture was successfully achieved in all rats who underwent manipulation. Levels of 5- LO measured in the posterior capsule were significantly increased in the animals who underwent surgery (56%/44–64) compared to the non-surgical control animals (7%/4–9). LTB4 levels were found to be significantly lower in the non-surgical control animals (107.79 ± 34.08 pg/ml) compared to all surgical animals (157.6 ± 55.3 pg/ml). Conclusion: Surgical intervention resulted in increased 5-LO activity of the synovial surface of the posterior capsule and increased LTB4 levels in the patellar tendon—fat pad. Oral administration of the 5LO inhibitor, CA, was ineffective at reducing systemic and local LTB4 levels and preventing knee joint contracture. Inhibiting 5-LO activity may still be effective in preventing arthrofibrosis and warrants further investigation. [ABSTRACT FROM AUTHOR]

Allergic inflammation of the airways such as allergic asthma is a major health problem with growing incidence world-wide. One cardinal feature in severe type 2-dominated airway inflammation is the release of lipid mediators of the eicosanoid family that can either promote or dampen allergic inflammation. Macrophages are key producers of prostaglandins and leukotrienes which play diverse roles in allergic airway inflammation and thus require tight control. Using RNA- and ATAC-sequencing, liquid chromatography coupled to mass spectrometry (LC-MS/MS), enzyme immunoassays (EIA), gene expression analysis and in vivo models, we show that the aryl hydrocarbon receptor (AhR) contributes to this control via transcriptional regulation of lipid mediator synthesis enzymes in bone marrow-derived as well as in primary alveolar macrophages. In the absence or inhibition of AhR activity, multiple genes of both the prostaglandin and the leukotriene pathway were downregulated, resulting in lower synthesis of prostanoids, such as prostaglandin E2 (PGE2), and cysteinyl leukotrienes, e.g., Leukotriene C4 (LTC4). These AhR-dependent genes include PTGS1 encoding for the enzyme cyclooxygenase 1 (COX1) and ALOX5 encoding for the arachidonate 5-lipoxygenase (5-LO) both of which major upstream regulators of the prostanoid and leukotriene pathway, respectively. This regulation is independent of the activation stimulus and partially also detectable in unstimulated macrophages suggesting an important role of basal AhR activity for eicosanoid production in steady state macrophages. Lastly, we demonstrate that AhR deficiency in hematopoietic but not epithelial cells aggravates house dust mite induced allergic airway inflammation. These results suggest an essential role for AhR-dependent eicosanoid regulation in macrophages during homeostasis and inflammation. [ABSTRACT FROM AUTHOR]

Objective: Triple negative breast cancer (TNBC) has high relapse rates due to dysregulated inflammatory signaling pathways and significant changes in the tumor microenvironment, probably influencing the failure of several therapies. The Cysteinyl Leukotriene Receptor 1 (CYSLTR1), a leukotriene modulator of inflammation, has been shown to play an important role in cancer pathogenesis and survival but few studies have been reported on its role in breast cancer. Materials and Methods: The present work was conducted using publicly available platforms that have omics data to assess the clinical potential of CYSLTR1 expression and its prognostic validation in large cohorts of samples from breast cancer patients. Web platforms containing clinical information, RNA-seq and protein data were selected to perform in silico analyses of the potential marker CYLSTR1. Added together, the platforms included modules for correlation, expression, prognosis, drug interactions, and construction of gene networks. Results: Kaplan–Meier curves revealed that reduced levels of CYSLTR1 corresponded to an unfavorable outcome for overall survival (p<0.005) as well as relapse-free survival (p<0.001) in the basal subtype. Additionally, CYSLTR1 was downregulated in breast tumor samples compared to adjacent healthy tissue (p<0.01) and the basal subtype exhibited the lowest expression of CYSLTR1 relative to the other subtypes (p<0.0001). Furthermore, gene networking analysis showed strong associations of CYSLTR1 with two protein-coding genes (P2RY10 and XCR1) when tested on a TNBC dataset. Conclusion: Our data highlighted the relevance of CYSLTR1 since it may play an important role in TNBC therapy. However, further in vitro and in vivo studies should be directed towards validating our findings in an effort to improve our understanding of TNBC pathology. [ABSTRACT FROM AUTHOR]

Background: Montelukast (MTK), a potent antagonist of cysteinyl leukotriene receptor 1, has shown therapeutic promise for the treatment of neuropsychiatric disorders. Delirium, a common complication in critically ill patients, lacks effective treatment. This study aims to explore the impact of pre-intensive care unit (ICU) MTK use on in-hospital delirium incidence and, subsequent, prognosis in critically ill patients. Methods: A retrospective cohort study (n = 6344) was conducted using the MIMIC-IV database. After propensity score matching, logistic/Cox regression, E-value sensitivity analysis, and causal mediation analysis were performed to assess associations between pre-ICU MTK exposure and delirium and prognosis in critically ill patients. Results: Pre-ICU MTK use was significantly associated with reduced in-hospital delirium (OR: 0.705; 95% CI 0.497–0.999; p = 0.049) and 90-day mortality (OR: 0.554; 95% CI 0.366–0.840; p = 0.005). The association was more significant in patients without myocardial infarction (OR: 0.856; 95% CI 0.383–0.896; p = 0.014) and could be increased by extending the duration of use. Causal mediation analysis showed that the reduction in delirium partially mediated the association between MTK and 90-day mortality (ACME: −0.053; 95% CI −0.0142 to 0.0002; p = 0.020). Conclusions: In critically ill patients, MTK has shown promising therapeutic benefits by reducing the incidence of delirium and 90-day mortality. This study highlights the potential of MTK, beyond its traditional use in respiratory disease, and may contribute to the development of novel therapeutic strategies for delirium.

Allergic inflammation of the airways such as allergic asthma is a major health problem with growing incidence world-wide. One cardinal feature in severe type 2-dominated airway inflammation is the release of lipid mediators of the eicosanoid family that can either promote or dampen allergic inflammation. Macrophages are key producers of prostaglandins and leukotrienes which play diverse roles in allergic airway inflammation and thus require tight control. Using RNA- and ATAC-sequencing, liquid chromatography coupled to mass spectrometry (LC-MS/MS), enzyme immunoassays (EIA), gene expression analysis and in vivo models, we show that the aryl hydrocarbon receptor (AhR) contributes to this control via transcriptional regulation of lipid mediator synthesis enzymes in bone marrow-derived as well as in primary alveolar macrophages. In the absence or inhibition of AhR activity, multiple genes of both the prostaglandin and the leukotriene pathway were downregulated, resulting in lower synthesis of prostanoids, such as prostaglandin E2 (PGE2), and cysteinyl leukotrienes, e.g., Leukotriene C4 (LTC4). These AhR-dependent genes include PTGS1 encoding for the enzyme cyclooxygenase 1 (COX1) and ALOX5 encoding for the arachidonate 5-lipoxygenase (5-LO) both of which major upstream regulators of the prostanoid and leukotriene pathway, respectively. This regulation is independent of the activation stimulus and partially also detectable in unstimulated macrophages suggesting an important role of basal AhR activity for eicosanoid production in steady state macrophages. Lastly, we demonstrate that AhR deficiency in hematopoietic but not epithelial cells aggravates house dust mite induced allergic airway inflammation. These results suggest an essential role for AhR-dependent eicosanoid regulation in macrophages during homeostasis and inflammation.

Simple Summary: Glioblastoma multiforme is a brain tumor with a very unfavorable prognosis, where the vast majority of patients do not survive a year after diagnosis. One line of research that may help in designing more successful therapeutic approaches is the synthesis and metabolism of arachidonic acid, which is then converted into a large number of different lipid mediators, including prostaglandins and leukotrienes (by cyclooxygenases and lipoxygenases, respectively). In this paper, we discuss the synthesis of arachidonic acid in glioblastoma multiforme tumors as well as the significance of lipid mediators synthesized from arachidonic acid, which can increase the proliferation of glioblastoma multiforme cancer cells, cause angiogenesis, inhibit the anti-tumor response of the immune system, and be responsible for resistance to treatment. Glioblastoma multiforme (GBM) is one of the most aggressive gliomas. New and more effective therapeutic approaches are being sought based on studies of the various mechanisms of GBM tumorigenesis, including the synthesis and metabolism of arachidonic acid (ARA), an omega-6 polyunsaturated fatty acid (PUFA). PubMed, GEPIA, and the transcriptomics analysis carried out by Seifert et al. were used in writing this paper. In this paper, we discuss in detail the biosynthesis of this acid in GBM tumors, with a special focus on certain enzymes: fatty acid desaturase (FADS)1, FADS2, and elongation of long-chain fatty acids family member 5 (ELOVL5). We also discuss ARA metabolism, particularly its release from cell membrane phospholipids by phospholipase A2 (cPLA2, iPLA2, and sPLA2) and its processing by cyclooxygenases (COX-1 and COX-2), lipoxygenases (5-LOX, 12-LOX, 15-LOX-1, and 15-LOX-2), and cytochrome P450. Next, we discuss the significance of lipid mediators synthesized from ARA in GBM cancer processes, including prostaglandins (PGE2, PGD2, and 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2)), thromboxane A2 (TxA2), oxo-eicosatetraenoic acids, leukotrienes (LTB4, LTC4, LTD4, and LTE4), lipoxins, and many others. These lipid mediators can increase the proliferation of GBM cancer cells, cause angiogenesis, inhibit the anti-tumor response of the immune system, and be responsible for resistance to treatment. [ABSTRACT FROM AUTHOR]

Abstract Background Leukotriene B4 (LTB4) is a potent lipid mediator that stimulate the immune response. Because dental pulp inflammation and dentin repair are intrinsically related responses, the aim of this research was to investigate the potential of LTB4 in inducing differentiation of dental pulp stem cells. Methods Microspheres (MS) loaded with LTB4 were prepared using an oil emulsion solvent extraction evaporation process and sterility, characterization, efficiency of LTB4 encapsulation and in vitro LTB4 release assay were investigated. Mouse dental pulp stem cells (OD-21) were stimulated with soluble LTB4 or MS loaded with LTB4 (0.01 and 0.1 μM). Cytotoxicity and cell viability was determined by lactate dehydrogenase and methylthiazol tetrazolium assays. Gene expression were measured by quantitative reverse transcription polymerase chain reaction after 3, 6, 24, 48 and 72 h. Mineralized nodule formation was assessed after 28 days of OD-21 cell stimulation with LTB4 in mineralized media or not. Groups were compared using one-way ANOVA test followed by Dunnett’s post-test (α = 0.05). Results Treatment with LTB4 or MS loaded with LTB4 (0.01 and 0.1 µm-μM) were not cytotoxic to OD-21 cells. Treatment with LTB4 modulated the expression of the Ibsp (integrin binding sialoprotein) and Runx2 (runt-related transcription factor 2) genes differently depending on the experimental period analyzed. Interestingly LTB4 loaded in microspheres (0.1 μM) allowed long term dental pulp cell differentiation and biomineralization. Conclusion LTB4, soluble or loaded in MS, were not cytotoxic and modulated the expression of the Ibsp and Runx2 genes in cultured OD-21 cells. When LTB4 was incorporated into MS, odontoblast differentiation and mineralization was induced in long term culture.

Abstract Purpose Arthrofibrosis is a common inflammatory complication of joint trauma and surgery. 5lipoxygenase (5‐LO) is a key enzyme involved in inflammation. Inhibition of 5‐LO has been shown to reduce inflammation in heart and lung models but has not been examined in a joint contracture model. Methods Twenty‐six rats underwent joint contracture. Six rats served as non‐surgical controls. A 5‐LO inhibitor, caffeic acid (CA), suspended in 10% ethanol was orally administered to 14 rats and ethanol without CA to the remaining 12 rats daily for 21 days. Leukotriene B4 (LTB4) levels were measured, both systemically and locally. 5‐LO levels in the posterior capsule were quantified by measuring the ratio of the length of the posterior capsule demonstrating 5‐LO immunostaining to the total length of the capsule. Results Joint contracture was successfully achieved in all rats who underwent manipulation. Levels of 5‐ LO measured in the posterior capsule were significantly increased in the animals who underwent surgery (56%/44–64) compared to the non‐surgical control animals (7%/4–9). LTB4 levels were found to be significantly lower in the non‐surgical control animals (107.79 ± 34.08 pg/ml) compared to all surgical animals (157.6 ± 55.3 pg/ml). Conclusion Surgical intervention resulted in increased 5‐LO activity of the synovial surface of the posterior capsule and increased LTB4 levels in the patellar tendon—fat pad. Oral administration of the 5LO inhibitor, CA, was ineffective at reducing systemic and local LTB4 levels and preventing knee joint contracture. Inhibiting 5‐LO activity may still be effective in preventing arthrofibrosis and warrants further investigation.

BackgroundCritical examination of the quality and validity of available allergic rhinitis (AR) literature is necessary to improve understanding and to appropriately translate this knowledge to clinical care of the AR patient. To evaluate the existing AR literature, international multidisciplinary experts with an interest in AR have produced the International Consensus statement on Allergy and Rhinology: Allergic Rhinitis (ICAR:AR).MethodsUsing previously described methodology, specific topics were developed relating to AR. Each topic was assigned a literature review, evidence-based review (EBR), or evidence-based review with recommendations (EBRR) format as dictated by available evidence and purpose within the ICAR:AR document. Following iterative reviews of each topic, the ICAR:AR document was synthesized and reviewed by all authors for consensus.ResultsThe ICAR:AR document addresses over 100 individual topics related to AR, including diagnosis, pathophysiology, epidemiology, disease burden, risk factors for the development of AR, allergy testing modalities, treatment, and other conditions/comorbidities associated with AR.ConclusionThis critical review of the AR literature has identified several strengths; providers can be confident that treatment decisions are supported by rigorous studies. However, there are also substantial gaps in the AR literature. These knowledge gaps should be viewed as opportunities for improvement, as often the things that we teach and the medicine that we practice are not based on the best quality evidence. This document aims to highlight the strengths and weaknesses of the AR literature to identify areas for future AR research and improved understanding.

The 5th Scientific Conference of the International Pemphigus and Pemphigoid Foundation (IPPF), "Pemphigus and Pemphigoid: A New Era of Clinical and Translational Science" was held in Orlando, Florida, on May 15-16, 2018. Scientific sessions covered recent, ongoing, and future clinical trials in pemphigus and bullous pemphigoid, disease activity and quality of life instruments, and the IPPF Natural History Study. Furthermore, the meeting provided an opportunity to hear firsthand from patients, investigators, and industry about their experience enrolling for clinical trials.

Acute coronary syndrome (ACS) is a set of signs and symptoms caused by a reduction of coronary blood flow with subsequent myocardial ischemia. ACS is associated with activation of the leukotriene (LT) pathway with subsequent releases of various LTs, including LTB4, LTC4, and LTD4, which cause inflammatory changes and induction of immunothrombosis. LTs through cysteine leukotriene (CysLT) induce activation of platelets and clotting factors with succeeding coronary thrombosis. CysLT receptor (CysLTR) antagonists such as montelukast (MK) may reduce the risk of the development of ACS and associated complications through suppression of the activation of platelet and clotting factors. Thus, this critical review aimed to elucidate the possible protective role of MK in the management of ACS. The LT pathway is implicated in the pathogenesis of atherosclerosis, cardiac hypertrophy, and heart failure. Inhibition of the LT pathway and CysL1TR by MK might be effective in preventing cardiovascular complications. MK could be an effective novel therapy in the management of ACS through inhibition of pro-inflammatory CysLT1R and modulation of inflammatory signaling pathways. MK can attenuate thrombotic events by inhibiting platelet activation and clotting factors that are activated during the development of ACS. In conclusion, MK could be an effective agent in reducing the severity of ACS and associated complications. Experimental, preclinical, and clinical studies are recommended to confirm the potential therapeutic of MK in the management of ACS. [ABSTRACT FROM AUTHOR]

Background: This paper discusses the role of inflammation in the pathogenesis of nondipping blood pressure and its role in the pathogenesis of obstructive sleep apnea syndrome. The aim of the study was to assess the impact of free fatty acids (FAs) and their inflammatory metabolites on the nondipping phenomenon and the risk of sleep apnea in stroke patients. Methods: Sixty-four ischemic stroke patients were included in the prospective study. Group I consisted of 33 patients with a preserved physiological dipping effect (DIP), while group II included 31 patients with the nondipping phenomenon (NDIP). All subjects had FA gas chromatography and inflammatory metabolite measurements performed with the use of liquid chromatography, their 24 h blood pressure was recorded, and they were assessed with the Epworth sleepiness scale (ESS). Results: In the nondipping group a higher level of C16:0 palmitic acid was observed, while lower levels were observed in regard to C20:0 arachidic acid, C22:0 behenic acid and C24:1 nervonic acid. A decreased leukotriene B4 level was recorded in the nondipping group. None of the FAs and derivatives correlated with the ESS scale in the group of patients after stroke. Correlations were observed after dividing into the DIP and NDIP groups. In the DIP group, a higher score of ESS was correlated with numerous FAs and derivatives. Inflammation of a lower degree and a higher level of anti-inflammatory mediators from EPA and DHA acids favored the occurrence of the DIP. A high level of C18: 3n6 gamma linoleic acid indicating advanced inflammation, intensified the NDIP effect. Conclusions: We demonstrated potential novel associations between the FA levels and eicosanoids in the pathogenesis of the nondipping phenomenon. There are common connections between fatty acids, their metabolites, inflammation, obstructive sleep apnea syndrome and nondipping in stroke patients. [ABSTRACT FROM AUTHOR]

Acute inflammation caused by bacterial infections is an essential biological defence mechanism of the host in order to neutralize and clear the invaders and to return to homeostasis. Despite its protective function, inflammation may become persistent and uncontrolled, resulting in chronic diseases and tissue destruction as consequence of the unresolved inflammatory process. Therefore, spatiotemporal induction of endogenous inflammation resolution programs that govern bacterial clearance as well as tissue repair and regeneration, are of major importance in order to enable tissues to restore functions. Lipid mediators that are de‐novo biosynthesized from polyunsaturated fatty acids (PUFAs) mainly by lipoxygenases and cyclooxygenases, critically regulate the initiation, the maintenance but also the resolution of infectious inflammation and tissue regeneration. The discovery of specialized pro‐resolving mediators (SPMs) generated from omega‐3 PUFAs stimulated intensive research in inflammation resolution, especially in infectious inflammation elicited by bacteria. SPMs are immunoresolvents that actively terminate inflammation by limiting neutrophil influx, stimulating phagocytosis, bacterial killing and clearance as well as efferocytosis of apoptotic neutrophils and cellular debris by macrophages. Moreover, SPMs prevent collateral tissue damage, promote tissue repair and regeneration and lower antibiotic requirement. Here, we review the biosynthesis of SPMs in bacterial infections and cover specific mechanisms of SPMs that govern the resolution of bacteria‐initiated inflammation. [ABSTRACT FROM AUTHOR]

Asthma is a complex disease that is promoted by dysregulated immunity and the presence of many cytokine and lipid mediators. Despite this, there is a paucity of data demonstrating the combined effects of multiple mediators in asthma pathogenesis. Group 2 innate lymphoid cells (ILC2s) have recently been shown to play important roles in the initiation of allergic inflammation; however, it is unclear whether lipid mediators, such as cysteinyl leukotrienes (CysLTs), which are present in asthma, could further amplify the effects of IL-33 on ILC2 activation and lung inflammation. In this article, we show that airway challenges with the parent CysLT, leukotriene C4 (LTC4), given in combination with low-dose IL-33 to naive wild-type mice, led to synergistic increases in airway Th2 cytokines, eosinophilia, and peribronchial inflammation compared with IL-33 alone. Further, the numbers of proliferating and cytokine-producing lung ILC2s were increased after challenge with both LTC4 and IL-33. Levels of CysLT1R, CysLT2R, and candidate leukotriene E4 receptor P2Y12 mRNAs were increased in ILC2s. The synergistic effect of LTC4 with IL-33 was completely dependent upon CysLT1R, because CysLT1R-/- mice, but not CysLT2R-/- mice, had abrogated responses. Further, CysLTs directly potentiated IL-5 and IL-13 production from purified ILC2s stimulated with IL-33 and resulted in NFAT1 nuclear translocation. Finally, CysLT1R-/- mice had reduced lung eosinophils and ILC2 responses after exposure to the fungal allergen Alternaria alternata Thus, CysLT1R promotes LTC4- and Alternaria-induced ILC2 activation and lung inflammation. These findings suggest that multiple pathways likely exist in asthma to activate ILC2s and propagate inflammatory responses.

Abstract Purpose To evaluate the safety and preliminary efficacy of topical rVA576, a dual inhibitor of complement component 5 (C5) and leukotriene B4 (LTB4), in patients with recalcitrant atopic keratoconjunctivitis (AKC) in the open label phase 1 TRACKER clinical trial. Methods Three patients diagnosed with moderate or severe AKC who had been on maximal topical treatment (antihistamines and ciclosporin) for at least three months prior to entry, and showed persistent symptoms and signs of inflammation, were recruited into the trial. Patients received rVA576 eye drops twice a day for 8 weeks. Patients were seen at baseline and weeks 1, 2, 4, 6 and 8. Safety data was recorded and a composite sum score of symptoms and signs was obtained. This score comprised symptoms such as itching, mucous discharge and photophobia, and conjunctival and corneal signs such as hyperemia, tarsal papillae, punctate keratitis and corneal neovascularization, all rated individually from 0 to 3 for a maximum score of 33. Results Two of the three patients completed the initial open label phase of the trial. The third patient was unable to attend appointments and terminated the study early at day 14. Topical rVA576 was well tolerated with no serious adverse events reported. There was an average improvement in overall clinical score of 53%, composed of an improvement in symptoms of 65% [63.64–66.67%] and signs of 40% [40–40.12%] by day 56. Conclusions In this open label phase 1 TRACKER trial, rVA576 eye drops were well tolerated and showed a response across signs and symptoms of active inflammation. This study is exploratory but supports topical rVA576 safety and shows promising efficacy for recalcitrant AKC. A phase 2 randomised control trial is currently underway.

Simple Summary: Aspirin and related drugs with anti-inflammatory effects have lung cancer prevention effects in laboratory studies and through their use in populations at risk for lung cancer. We studied aspirin plus zileuton compared to two placebo pills for 3 months in smokers. We studied genes associated with lung cancer, smoking, and lung disease. We used nasal swabs to collect nasal cells that were smoke exposed to look for changes in these genes. We found that most of the gene panels in the nasal cells related to smoking and lung cancer lung disease did not change in a favorable way, but we did see a favorable change in a gene panel representing abnormal squamous cells that may progress to lung cancer. We think this finding is of interest and can be studied further using deep lung biopsies to understand if this drug effect occurs where squamous cell lung cancer actually starts. The chemopreventive effect of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on lung cancer risk is supported by epidemiologic and preclinical studies. Zileuton, a 5-lipoxygenase inhibitor, has additive activity with NSAIDs against tobacco carcinogenesis in preclinical models. We hypothesized that cyclooxygenase plus 5-lipoxygenase inhibition would be more effective than a placebo in modulating the nasal epithelium gene signatures of tobacco exposure and lung cancer. We conducted a randomized, double-blinded study of low-dose aspirin plus zileuton vs. double placebo in current smokers to compare the modulating effects on nasal gene expression and arachidonic acid metabolism. In total, 63 participants took aspirin 81 mg daily plus zileuton (Zyflo CR) 600 mg BID or the placebo for 12 weeks. Nasal brushes from the baseline, end-of-intervention, and one-week post intervention were profiled via microarray. Aspirin plus zilueton had minimal effects on the modulation of the nasal or bronchial gene expression signatures of smoking, lung cancer, and COPD but favorably modulated a bronchial gene expression signature of squamous dysplasia. Aspirin plus zileuton suppressed urinary leukotriene but not prostaglandin E2, suggesting shunting through the cyclooxygenase pathway when combined with 5-lipoxygenase inhibition. Continued investigation of leukotriene inhibitors is needed to confirm these findings, understand the long-term effects on the airway epithelium, and identify the safest, optimally dosed agents. [ABSTRACT FROM AUTHOR]

Formation of specialized pro-resolving lipid mediators (SPMs) such as lipoxins or resolvins usually involves arachidonic acid 5-lipoxygenase (5-LO, ALOX5) and different types of arachidonic acid 12- and 15-lipoxygenating paralogues (15-LO1, ALOX15; 15-LO2, ALOX15B; 12-LO, ALOX12). Typically, SPMs are thought to be formed via consecutive steps of oxidation of polyenoic fatty acids such as arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. One hallmark of SPM formation is that reported levels of these lipid mediators are much lower than typical pro-inflammatory mediators including the monohydroxylated fatty acid derivatives (e.g., 5-HETE), leukotrienes or certain cyclooxygenase-derived prostaglandins. Thus, reliable detection and quantification of these metabolites is challenging. This paper is aimed at critically evaluating i) the proposed biosynthetic pathways of SPM formation, ii) the current knowledge on SPM receptors and their signaling cascades and iii) the analytical methods used to quantify these pro-resolving mediators in the context of their instability and their low concentrations. Based on current literature it can be concluded that i) there is at most, a low biosynthetic capacity for SPMs in human leukocytes. ii) The identity and the signaling of the proposed G-protein-coupled SPM receptors have not been supported by studies in knock-out mice and remain to be validated. iii) In humans, SPM levels were neither related to dietary supplementation with their ω-3 polyunsaturated fatty acid precursors nor were they formed during the resolution phase of an evoked inflammatory response. iv) The reported low SPM levels cannot be reliably quantified by means of the most commonly reported methodology. Overall, these questions regarding formation, signaling and occurrence of SPMs challenge their role as endogenous mediators of the resolution of inflammation. [ABSTRACT FROM AUTHOR]

Background: Leukotriene B4 (LTB4) is a potent lipid mediator that stimulate the immune response. Because dental pulp inflammation and dentin repair are intrinsically related responses, the aim of this research was to investigate the potential of LTB4 in inducing differentiation of dental pulp stem cells. Methods: Microspheres (MS) loaded with LTB4 were prepared using an oil emulsion solvent extraction evaporation process and sterility, characterization, efficiency of LTB4 encapsulation and in vitro LTB4 release assay were investigated. Mouse dental pulp stem cells (OD-21) were stimulated with soluble LTB4 or MS loaded with LTB4 (0.01 and 0.1 μM). Cytotoxicity and cell viability was determined by lactate dehydrogenase and methylthiazol tetrazolium assays. Gene expression were measured by quantitative reverse transcription polymerase chain reaction after 3, 6, 24, 48 and 72 h. Mineralized nodule formation was assessed after 28 days of OD-21 cell stimulation with LTB4 in mineralized media or not. Groups were compared using one-way ANOVA test followed by Dunnett's post-test (α = 0.05). Results: Treatment with LTB4 or MS loaded with LTB4 (0.01 and 0.1 µm-μM) were not cytotoxic to OD-21 cells. Treatment with LTB4 modulated the expression of the Ibsp (integrin binding sialoprotein) and Runx2 (runt-related transcription factor 2) genes differently depending on the experimental period analyzed. Interestingly LTB4 loaded in microspheres (0.1 μM) allowed long term dental pulp cell differentiation and biomineralization. Conclusion: LTB4, soluble or loaded in MS, were not cytotoxic and modulated the expression of the Ibsp and Runx2 genes in cultured OD-21 cells. When LTB4 was incorporated into MS, odontoblast differentiation and mineralization was induced in long term culture. [ABSTRACT FROM AUTHOR]

Abstract A significant role in the pathogenesis of rhinosinusitis is played by an inflammatory reaction in the maxillary sinuses of the nasal cavity. Leukotrienes are the most powerful mediators of inflammation, especially at the early stages. The effect of combined dry extract BNO 1016 could be useful for the inhibition of the inflammation in rhinosinusitis. Thus, it appears reasonable to study the anti-inflammatory activity of the combined dry extract BNO 1016. Materials and methods The tested drug is the combined dry extract BNO 1016 produced by “Bionorica SE”. The reference drug is Ibuprofen. Leukotriene inflammation was induced by subplantar injection of zymozan into the right hind paw of male and female Wistar rats. Volumes of the resulting edema were measured and levels of anti-inflammatory activity together with mean effective dose (ED50) were calculated. Results The highest anti-inflammatory activity was observed at a dose level of 500 mg/kg of BNO 1016 during all time-points of the experiment and reached 65.2% 2 h after induction of inflammation. The anti-inflammatory activity of BNO 1016 at 500 mg/kg was credibly higher than that of Ibuprofen at all time-points of the experiment. Based on the data obtained from this leukotriene-dependent inflammation experiment the mean effective dose (ED50) for anti-inflammatory activity of dry combined extract BNO 1016 was calculated with help of Probit analysis. Conclusion The combined dry extract BNO 1016 shows a high level of anti-inflammatory activity in leukotriene-dependent inflammation which is very promising for the improvement of the treatment of patients. However, additional preclinical and clinical research on this drug should be carried out.

Formation of specialized pro-resolving lipid mediators (SPMs) such as lipoxins or resolvins usually involves arachidonic acid 5-lipoxygenase (5-LO, ALOX5) and different types of arachidonic acid 12- and 15-lipoxygenating paralogues (15-LO1, ALOX15; 15-LO2, ALOX15B; 12-LO, ALOX12). Typically, SPMs are thought to be formed via consecutive steps of oxidation of polyenoic fatty acids such as arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid. One hallmark of SPM formation is that reported levels of these lipid mediators are much lower than typical pro-inflammatory mediators including the monohydroxylated fatty acid derivatives (e.g., 5-HETE), leukotrienes or certain cyclooxygenase-derived prostaglandins. Thus, reliable detection and quantification of these metabolites is challenging. This paper is aimed at critically evaluating i) the proposed biosynthetic pathways of SPM formation, ii) the current knowledge on SPM receptors and their signaling cascades and iii) the analytical methods used to quantify these pro-resolving mediators in the context of their instability and their low concentrations. Based on current literature it can be concluded that i) there is at most, a low biosynthetic capacity for SPMs in human leukocytes. ii) The identity and the signaling of the proposed G-protein-coupled SPM receptors have not been supported by studies in knock-out mice and remain to be validated. iii) In humans, SPM levels were neither related to dietary supplementation with their ω-3 polyunsaturated fatty acid precursors nor were they formed during the resolution phase of an evoked inflammatory response. iv) The reported low SPM levels cannot be reliably quantified by means of the most commonly reported methodology. Overall, these questions regarding formation, signaling and occurrence of SPMs challenge their role as endogenous mediators of the resolution of inflammation.

This study aimed to evaluate the levels of eicosanoids derived from arachidonic acid (ARA) in the lungs of asthmatic rats supplemented with fish oil. The present data gives insight into the action of fish oil in asthma, related to its inability to modify the contractile capacity of tracheal smooth muscle reported previously in a model of asthma in rats. Male Wistar rats were supplemented daily with 1 g of fish oil/kg of body weight for 21 days. They were exposed to ovalbumin (OVA) after previous sensitization with OVA to induce asthma. Pulmonary levels of five eicosanoids were measured using immunoassay kits: PGE2, TXB2, LTB4, LXA4, and 8-iso PGF2α. In asthmatic rats, supplementation with fish oil resulted in lower concentrations of lung eicosanoids produced by cyclooxygenase-2 and 15-lipoxygenase: PGE2, TXB2, and LXA4, respectively. Fish oil supplementation also decreased the non-enzymatically produced eicosanoid 8-iso PGF2α. Fish oil supplementation did not affect LTB4, a metabolite of 5-lipoxygenase. The limited efficacy of fish oil supplementation in asthmatic rats is associated with a lack of action in reducing the levels of LTB4 in the lungs. Thus, fish oil differentially modulates the concentrations of eicosanoids derived from ARA via specific pathways in an animal model of asthma.

BackgroundExercise-induced bronchoconstriction (EIB) is a prototypical feature of indirect airway hyperresponsiveness. Mast cells are implicated in EIB, but the characteristics, regulation, and function of mast cells in patients with EIB are poorly understood.ObjectivesWe sought to examine mast cell infiltration of the airway epithelium in patients with EIB and the regulation of mast cell phenotype and function by epithelially derived cytokines.MethodsEndobronchial biopsy specimens, epithelial brushings, and induced sputum were obtained from asthmatic patients with and without EIB and healthy control subjects. Mast cell proteases were quantified by using quantitative PCR, and mast cell density was quantified by using design-based stereology. Airway epithelial responses to wounding and osmotic stress were assessed in primary airway epithelial cells and ex vivo murine lung tissue. Mast cell granule development and function were examined in cord blood-derived mast cells.ResultsTryptase and carboxypeptidase A3 expression in epithelial brushings and epithelial mast cell density were selectively increased in the asthma group with EIB. An in vitro scratch wound initiated the release of thymic stromal lymphopoietin, which was greater in epithelial cells derived from asthmatic patients. Osmotic stress induced the release of IL-33 from explanted murine lungs, which was increased in allergen-treated mice. Thymic stromal lymphopoietin combined with IL-33 increased tryptase and carboxypeptidase A3 immunostaining in mast cell precursors and selectively increased cysteinyl leukotriene formation by mast cells in a manner that was independent of in vitro sensitization.ConclusionsMast cell infiltration of the epithelium is a critical determinant of indirect airway hyperresponsiveness, and the airway epithelium might serve as an important regulator of the development and function of this mast cell population.

Background: This paper discusses the role of inflammation in the pathogenesis of nondipping blood pressure and its role in the pathogenesis of obstructive sleep apnea syndrome. The aim of the study was to assess the impact of free fatty acids (FAs) and their inflammatory metabolites on the nondipping phenomenon and the risk of sleep apnea in stroke patients. Methods: Sixty-four ischemic stroke patients were included in the prospective study. Group I consisted of 33 patients with a preserved physiological dipping effect (DIP), while group II included 31 patients with the nondipping phenomenon (NDIP). All subjects had FA gas chromatography and inflammatory metabolite measurements performed with the use of liquid chromatography, their 24 h blood pressure was recorded, and they were assessed with the Epworth sleepiness scale (ESS). Results: In the nondipping group a higher level of C16:0 palmitic acid was observed, while lower levels were observed in regard to C20:0 arachidic acid, C22:0 behenic acid and C24:1 nervonic acid. A decreased leukotriene B4 level was recorded in the nondipping group. None of the FAs and derivatives correlated with the ESS scale in the group of patients after stroke. Correlations were observed after dividing into the DIP and NDIP groups. In the DIP group, a higher score of ESS was correlated with numerous FAs and derivatives. Inflammation of a lower degree and a higher level of anti-inflammatory mediators from EPA and DHA acids favored the occurrence of the DIP. A high level of C18: 3n6 gamma linoleic acid indicating advanced inflammation, intensified the NDIP effect. Conclusions: We demonstrated potential novel associations between the FA levels and eicosanoids in the pathogenesis of the nondipping phenomenon. There are common connections between fatty acids, their metabolites, inflammation, obstructive sleep apnea syndrome and nondipping in stroke patients.

Acute coronary syndrome (ACS) is a set of signs and symptoms caused by a reduction of coronary blood flow with subsequent myocardial ischemia. ACS is associated with activation of the leukotriene (LT) pathway with subsequent releases of various LTs, including LTB4, LTC4, and LTD4, which cause inflammatory changes and induction of immunothrombosis. LTs through cysteine leukotriene (CysLT) induce activation of platelets and clotting factors with succeeding coronary thrombosis. CysLT receptor (CysLTR) antagonists such as montelukast (MK) may reduce the risk of the development of ACS and associated complications through suppression of the activation of platelet and clotting factors. Thus, this critical review aimed to elucidate the possible protective role of MK in the management of ACS. The LT pathway is implicated in the pathogenesis of atherosclerosis, cardiac hypertrophy, and heart failure. Inhibition of the LT pathway and CysL1TR by MK might be effective in preventing cardiovascular complications. MK could be an effective novel therapy in the management of ACS through inhibition of pro-inflammatory CysLT1R and modulation of inflammatory signaling pathways. MK can attenuate thrombotic events by inhibiting platelet activation and clotting factors that are activated during the development of ACS. In conclusion, MK could be an effective agent in reducing the severity of ACS and associated complications. Experimental, preclinical, and clinical studies are recommended to confirm the potential therapeutic of MK in the management of ACS.

MicroRNAs (miRNAs) are small, non-coding RNAs that regulate posttranscription by binding to 3′-untranslated regions of target mRNAs. Recent functional studies have elucidated mechanisms that miRNAs regulate leukotriene synthesis by perturbing arachidonic acid metabolism. Both microarrays and high-throughput sequencing revealed distinct differential expression of miRNAs in children with respiratory syncytial virus (RSV) infection compared with healthy controls. Abnormal miRNA expression may contribute to higher leukotriene levels, which is associated with airway hyperreactivity. Targeting miRNAs may benefit to restore the homeostasis of inflammatory reaction and provide new strategies to alleviate airway hyperreactivity induced by RSV. In this article, we provide an overview of the current knowledge about miRNAs modulating leukotrienes through regulation of arachidonic acid metabolism with a special focus on miRNAs aberrantly expressed in children with RSV infection.

Purpose: To evaluate the safety and preliminary efficacy of topical rVA576, a dual inhibitor of complement component 5 (C5) and leukotriene B4 (LTB4), in patients with recalcitrant atopic keratoconjunctivitis (AKC) in the open label phase 1 TRACKER clinical trial.Methods: Three patients diagnosed with moderate or severe AKC who had been on maximal topical treatment (antihistamines and ciclosporin) for at least three months prior to entry, and showed persistent symptoms and signs of inflammation, were recruited into the trial. Patients received rVA576 eye drops twice a day for 8 weeks. Patients were seen at baseline and weeks 1, 2, 4, 6 and 8. Safety data was recorded and a composite sum score of symptoms and signs was obtained. This score comprised symptoms such as itching, mucous discharge and photophobia, and conjunctival and corneal signs such as hyperemia, tarsal papillae, punctate keratitis and corneal neovascularization, all rated individually from 0 to 3 for a maximum score of 33.Results: Two of the three patients completed the initial open label phase of the trial. The third patient was unable to attend appointments and terminated the study early at day 14. Topical rVA576 was well tolerated with no serious adverse events reported. There was an average improvement in overall clinical score of 53%, composed of an improvement in symptoms of 65% [63.64-66.67%] and signs of 40% [40-40.12%] by day 56.Conclusions: In this open label phase 1 TRACKER trial, rVA576 eye drops were well tolerated and showed a response across signs and symptoms of active inflammation. This study is exploratory but supports topical rVA576 safety and shows promising efficacy for recalcitrant AKC. A phase 2 randomised control trial is currently underway. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the use of the leukotriene modifiers (LTMs), zafirlukast and montelukast, in children with asthma managed by an inner city pediatric pulmonary practice. A retrospective chart review was done of children 6 years of age with persistent asthma seen at Connecticut Children's Medical Center and prescribed LTM drugs. Eighty-three children whose asthma control was adequately assessed both before and after addition of a LTM to his/her treatment regimen was included in the study. There were statistically significant improvements in several parameters of asthma control following initiation of LTM use, including provider assessment score (p = 0.0005), number of hospitalizations and unscheduled visits (clinic or emergency department; p < 0.0001), use of oral corticosteroids (p = 0.0015), spirometry severity score (p = 0.0015), and spirometry test results (FEV1, FEV1/FVC, FEF, FEF25-75%; p < 0.005 for all). These results suggest that montelukast and zafirlukast help to improve asthma control in young patients with persistent asthma.

Rheumatoid arthritis, asthma, allergic rhinitis and many other disorders related to an aberrant immune response have a higher incidence and severity in women than in men. Emerging evidences from scientific studies indicate that the activity of the immune system is superior in females and that androgens may act as “immunosuppressive” molecules with inhibitory effects on inflammatory reactions. Among the multiple factors that contribute to the inflammatory response, lipid mediators (LM), produced from polyunsaturated fatty acids, represent a class of bioactive small molecules with pivotal roles in the onset, maintenance and resolution of inflammation. LM encompass pro-inflammatory eicosanoids and specialized pro-resolving mediators (SPM) that coexist in a tightly regulated balance necessary for the return to homeostasis. Innate immune cells including neutrophils, monocytes and macrophages possess high capacities to generate distinct LM. In the last decades it became more and more evident that sex represents an important variable in the regulation of inflammation where sex hormones play crucial roles. Recent findings showed that the biosynthesis of inflammation-related LM is sex-biased and that androgens impact LM formation with consequences not only for pathophysiology but also for pharmacotherapy. Here, we review the modulation of the inflammatory response by sex and androgens with a specific focus on LM pathways. In particular, we highlight the impact of androgens on the biosynthetic pathway of inflammation-related eicosanoids in innate immune cells.

High eosinophil (EOS) counts are a key feature of eosinophilic asthma. EOS notably affect asthmatic response by generating several lipid mediators. Mice have been utilized in hopes of defining new pharmacological targets to treat asthma. However, many pinpointed targets in mice did not translate into clinics, underscoring that key differences exist between the two species. In this study, we compared the ability of human (h) and mouse (m) EOS to biosynthesize key bioactive lipids derived from arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). hEOS were isolated from the blood of healthy subjects and mild asthmatics, while mEOSs were differentiated from the bone marrow. EOSs were treated with fatty acids and lipid mediator biosynthesis assessed by LC-MS/MS. We found that hEOS biosynthesized leukotriene (LT) C4 and LTB4 in a 5:1 ratio while mEOS almost exclusively biosynthesized LTB4. The biosynthesis of the 15-lipoxygenase (LO) metabolites 15-HETE and 12-HETE also differed, with a 15-HETE:12-HETE ratio of 6.3 for hEOS and 0.727 for mEOS. EOS biosynthesized some specialized pro-resolving mediators, and the levels from mEOS were 9-times higher than those of hEOS. In contrast, hEOS produced important amounts of the endocannabinoid 2-arachidonoyl-glycerol (2-AG) and its congeners from EPA and DHA, a biosynthetic pathway that was up to ~100-fold less prominent in mEOS. Our data show that hEOS and mEOS biosynthesize the same lipid mediators but in different amounts. Compared to asthmatics, mouse models likely have an amplified involvement of LTB4 and specialized pro-resolving mediators and a diminished impact of the endocannabinoid 2-arachidonoyl-glycerol and its congeners.

Abstract Background Aspirin-exacerbated respiratory disease (AERD) is a distinct eosinophilic phenotype of severe asthma with accompanying chronic rhinosinusitis, nasal polyposis, and hypersensitivity to aspirin. Urinary 3-bromotyrosine (uBrTyr) is a noninvasive marker of eosinophil-catalyzed protein oxidation. The lack of in vitro diagnostic test makes the diagnosis of AERD difficult. We aimed to determine uBrTyr levels in patients with AERD (n = 240) and aspirin-tolerant asthma (ATA) (n = 226) and to assess whether its addition to urinary leukotriene E4 (uLTE4) levels and blood eosinophilia can improve the prediction of AERD diagnosis. Methods Clinical data, spirometry and blood eosinophilis were evaluated. UBrTyr and uLTE4 levels were measured in urine by HPLC and ELISA, respectively. Results Both groups of asthmatics (AERD, n = 240; ATA, n = 226) had significantly higher uBrTyr, uLTE4 levels, and blood eosinophils than healthy controls (HC) (n = 71) (p 0.101 ng/mg Cr), uLTE4 levels (> 800 pg/mg Cr) and blood eosinophils (> 300 cells/ul) were 7 times more likely to have AERD.. However, uBrTyr did not increase the benefit for predicting AERD when uLTE4 and blood eosinophils were already taken into account (p = 0.57). Conclusion UBrTyr levels are elevated both in AERD and ATA as compared to HC, but they could not differentiate between these asthma phenotypes suggesting a similar eosinophilic activation. The addition of uBrTyr to elevated uLTE4 levels and blood eosinophils did not statistically enhance the prediction of AERD diagnosis.

Abstract Background The herbal medicinal product Bronchipret® TP film-coated tablets contains a fixed combination of thyme and primula dry extracts (BRO) and has long and successfully been used for the treatment of acute bronchitis. However, the underlying pharmacological mechanisms of action have not been determined so far. We report a tiered approach applying in vivo and in vitro studies to investigate the pharmacodynamic activity and underlying mechanisms of action, and to identify possible active ingredients contributing to the product’s pharmacodynamic activity. Results In an LPS-induced rat model of bronchoalveolitis oral administration of BRO effectively ameliorated the influx of leukocytes into the lung. This was accompanied by reduced levels of leukotriene (LT) B4, cysteinyl-LTs (cysLT), and prostaglandin (PG) E2. We also found that BRO potently reduced the production of LTB4 in vitro in rat whole blood stimulated with the Ca2+-ionophore A23187 whereas the effect on PGE2 was much less pronounced. The transferability of these findings to human cells was assessed by measuring the effects of BRO on A23187-stimulated human monocytes and neutrophils. BRO and thyme extract were potent inhibitors of LTB4 and cysLT production. We further investigated the effects of BRO, thyme extract as well as single compounds of thyme extract on enzymatic activity of 5-lipoxygenase (5-LO). 5-LO activity was potently reduced by BRO and thyme extract. Of the single ingredients, thymoquinone and rosmarinic acid showed most potent inhibitory activity against 5-LO, with lower potency for thymol and carvacrol. Conclusion BRO attenuates inflammation-induced leukotriene formation in vivo and affects leukotriene biosynthesis in vitro via 5-LO inhibition. This inhibitory activity appears to be primarily related to the thyme extract component. However, none of the single ingredients tested seems to fully account for the activity of thyme extract alone. Rather, the interaction of different compounds seems to be required for its overall inhibitory effect on leukotriene production.

Massive neutrophil infiltration is an early key event in infectious inflammation, accompanied by chemotactic leukotriene (LT)B4 generation. LTB4 biosynthesis is mediated by 5-lipoxygenase (5-LOX), but which pathogenic factors cause 5-LOX activation during bacterial infections is elusive. Here, we reveal staphylococcal exotoxins as 5-LOX activators. Conditioned medium of wild-type Staphylococcus aureus but not of exotoxin-deficient strains induced 5-LOX activation in transfected HEK293 cells. Two different staphylococcal exotoxins mimicked the effects of S. aureus-conditioned medium: (1) the pore-forming toxin α-hemolysin and (2) amphipathic α-helical phenol-soluble modulin (PSM) peptides. Interestingly, in human neutrophils, 5-LOX activation was exclusively evoked by PSMs, which was prevented by the selective FPR2/ALX receptor antagonist WRW4. 5-LOX activation by PSMs was confirmed in vivo as LT formation in infected paws of mice was impaired in response to PSM-deficient S. aureus. Conclusively, exotoxins from S. aureus are potent pathogenic factors that activate 5-LOX and induce LT formation in neutrophils. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis, asthma, allergic rhinitis and many other disorders related to an aberrant immune response have a higher incidence and severity in women than in men. Emerging evidences from scientific studies indicate that the activity of the immune system is superior in females and that androgens may act as "immunosuppressive" molecules with inhibitory effects on inflammatory reactions. Among the multiple factors that contribute to the inflammatory response, lipid mediators (LM), produced from polyunsaturated fatty acids, represent a class of bioactive small molecules with pivotal roles in the onset, maintenance and resolution of inflammation. LM encompass pro-inflammatory eicosanoids and specialized pro-resolving mediators (SPM) that coexist in a tightly regulated balance necessary for the return to homeostasis. Innate immune cells including neutrophils, monocytes and macrophages possess high capacities to generate distinct LM. In the last decades it became more and more evident that sex represents an important variable in the regulation of inflammation where sex hormones play crucial roles. Recent findings showed that the biosynthesis of inflammation-related LM is sex-biased and that androgens impact LM formation with consequences not only for pathophysiology but also for pharmacotherapy. Here, we review the modulation of the inflammatory response by sex and androgens with a specific focus on LM pathways. In particular, we highlight the impact of androgens on the biosynthetic pathway of inflammation-related eicosanoids in innate immune cells. [ABSTRACT FROM AUTHOR]

A significant role in the pathogenesis of rhinosinusitis is played by an inflammatory reaction in the maxillary sinuses of the nasal cavity. Leukotrienes are the most powerful mediators of inflammation, especially at the early stages. The effect of combined dry extract BNO 1016 could be useful for the inhibition of the inflammation in rhinosinusitis. Thus, it appears reasonable to study the anti-inflammatory activity of the combined dry extract BNO 1016. Materials and methods: The tested drug is the combined dry extract BNO 1016 produced by "Bionorica SE". The reference drug is Ibuprofen. Leukotriene inflammation was induced by subplantar injection of zymozan into the right hind paw of male and female Wistar rats. Volumes of the resulting edema were measured and levels of anti-inflammatory activity together with mean effective dose (ED50) were calculated. Results: The highest anti-inflammatory activity was observed at a dose level of 500 mg/kg of BNO 1016 during all time-points of the experiment and reached 65.2% 2 h after induction of inflammation. The anti-inflammatory activity of BNO 1016 at 500 mg/kg was credibly higher than that of Ibuprofen at all time-points of the experiment. Based on the data obtained from this leukotriene-dependent inflammation experiment the mean effective dose (ED50) for anti-inflammatory activity of dry combined extract BNO 1016 was calculated with help of Probit analysis. Conclusion: The combined dry extract BNO 1016 shows a high level of anti-inflammatory activity in leukotriene-dependent inflammation which is very promising for the improvement of the treatment of patients. However, additional preclinical and clinical research on this drug should be carried out. [ABSTRACT FROM AUTHOR]

Eicosanoids have been implicated in a vast number of devastating inflammatory conditions, including arthritis, atherosclerosis, pain, and cancer. Currently, over a hundred different eicosanoids have been identified, with many having potent bioactive signaling capacity. These lipid metabolites are synthesized de novo by at least 50 unique enzymes, many of which have been cloned and characterized. Due to the extensive characterization of eicosanoid biosynthetic pathways, this field provides a unique framework for integrating genomics, proteomics, and metabolomics toward the investigation of disease pathology. To facilitate a concerted systems biology approach, this review outlines the proteins implicated in eicosanoid biosynthesis and signaling in human, mouse, and rat. Applications of the extensive genomic and lipidomic research to date illustrate the questions in eicosanoid signaling that could be uniquely addressed by a thorough analysis of the entire eicosanoid proteome.

Background. For many women, the monthly suffering induced by menstrual “cramps” is severe enough to profoundly disrupt their quality of life. In the case of primary dysmenorrhea, a condition related to premenstrual syndrome (PMS), intense uterine contractions are thought to trigger moderate to intense pain despite the absence of an underlying infection or other medically-identifiable disease states. The associated uterine hyper-contractility is reminiscent of labor, and associated pain is likely to be mediated by the release of prostaglandins, leukotrienes and the infiltration of leukocytes that normally accompany the breakdown of the endometrial lining. Standardized extracts of Vitex agnus-castus berries (VAC extracts of chaste tree, or chaste berries) are clinically effective in treating the symptoms of PMS, yet the mechanisms of how the chemically complex mixture acts are largely unknown. Methods. Using an in vivo dysmenorrhea model rats were treated with 10 mg/kg estradiol-benzoate i.p. once daily for 12 days and with 2.1, 10.3 or 20.7 mg/kg VAC dry extract p.o. once daily for 7 days prior to induction of convulsions. Uterine contractions where induced with 2 IU/kg oxytocin i.p., followed by monitoring of abdominal convulsions and signs of pain on the last day of the experiment. Moreover, in vitro methods were applied that are described in the methods section. Results. Here, we show that the VAC herbal dry extract BNO 1095 (commercially available as Cyclodynon®) targets the uterine myometrial tissue and inflammatory signaling molecules of associated migratory/inflammatory cells. Specifically, BNO 1095 dose-dependently inhibited oxytocin-induced uterine contractions in a rat dysmenorrhea model in vivo and drug-induced contractions in isolated human and rat uterine tissue in vitro. Furthermore, BNO 1095 showed a promising anti-inflammatory capacity by potently inhibiting 5-lipoxygenase activity and leukotriene production and by reducing the production of reactive oxygen species and inflammatory cytokines in vitro. Conclusion. These results provide evidence that BNO 1095 effectively treats menstruation-related complaints including primary dysmenorrhea.