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Natalia Celejewska-Wójcik,1 Aleksander Kania,1 Karolina Górka,1 Paweł Nastałek,1 Krzysztof Wójcik,2 Anna Gielicz,3 Lucyna Mastalerz,1 Marek Sanak,3 Krzysztof Sładek1 1Department of Pulmonology, 2nd Department of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland; 2 2nd Department of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, Kraków, Poland; 3Department of Molecular Biology and Clinical Genetics, Faculty of Medicine, Jagiellonian University Medical College, Kraków, PolandCorrespondence: Natalia Celejewska-Wójcik 2nd Department of Internal Medicine, Faculty of Medicine, Jagiellonian University Medical College, ul. Jakubowskiego 2, Krakow, 30-688, PolandTel +48 12 400 30 53Fax +48 12 400 30 67Email natalia.celejewska@gmail.comPurpose: Lipid mediators, particularly eicosanoids, are associated with airway inflammation, especially with the eosinophilic influx. This study aimed to measure lipid mediators and cells in induced sputum, that could possibly reflect the inflammatory process in the bronchial tree of COPD subjects.Patients and Methods: Eighty patients diagnosed with COPD and 37 healthy controls participated in the study. Induced sputum samples were ascertained for differential cell count and induced sputum supernatant concentrations of selected eicosanoids by the means of gas chromatography/mass spectrometry and high-performance liquid chromatography/tandem mass spectrometry.Results: Increased sputum eosinophilia was associated with higher concentrations of selected proinflammatory eicosanoids. In COPD subjects prostaglandin D2 and 11-dehydro-thromboxane B2 correlated negatively with airway obstruction measured by FEV1 and FEV1/FVC values. COPD subjects with disease exacerbations during past 12 months had significantly higher concentrations of prostaglandin D2, 12-oxo-eicosatetraenoic acid and 5-oxo-eicosatetraenoic acid.Conclusion: Stable COPD is often associated with eosinophil influx in the lower airways and elevated concentrations of eicosanoids that is reflected by some disease characteristics.Keywords: chronic obstructive pulmonary disease, eosinophils, eicosanoids

Background Pro- and anti-inflammatory metabolites of arachidonic acid - eicosanoids - participate in skin homeostasis, affecting the growth and differentiation of keratinocytes. Alterations of 12-lipoxygenase ( LOX) and 15- LOX and their metabolites have been described in the epidermis of patients with psoriasis, but systemic production of 12- LOX and 15- LOX eicosanoids has not been studied in the disease. Objectives To ascertain the frequencies of the genetic variants ALOX12 rs1126667 and ALOX15 rs11568070 in cases and controls, and to compare urinary metabolites of 12( S)-hydroxyeicosatetraenoic acid ( HETE) between patients with psoriasis and healthy controls. Methods Patients with psoriasis ( n = 200) were stratified depending on the severity of their dermal lesions. Genotyping was performed using a 5′-nuclease real-time assay. The concentrations of 12( S)- HETE, its metabolites and 15( S)- HETE were determined in urine samples using high-performance liquid chromatography-tandem mass spectrometry. Results Tetranor-12( S)- HETE metabolite excretion was significantly higher in urine of patients with psoriasis, while excretion of 12( S)- HETE was decreased. Neither 12( S)- HETE nor tetranor-12( S)- HETE correlated with the type of disease or severity score. No difference in urinary 15( S)- HETE was found between the study groups. Genotype distribution of the ALOX12 rs1126667 or ALOX15 rs11568070 polymorphisms did not discriminate for the disease or its severity. Conclusions Systemic metabolism of 12( S)- HETE is accelerated in psoriasis because excretion of the tetranor-12( S)- HETE inactivation product is elevated. No correlation with the severity or extent of psoriasis is detectable. We propose that in patients with psoriasis, 12( S)- HETE to tetranor-12( S)- HETE conversion could be at least a marker for this disease, in which inflammation of the skin can induce microsomal beta-oxidation of this eicosanoid. [ABSTRACT FROM AUTHOR]

Background: The high-affinity receptor for immunoglobulin-E (IgE) (Fc ℇRI) plays a major role in the pathogenesis of allergy, but there are only two published studies on its α subunit (Fc ℇRI α) genetic variability in allergic diseases. Aims of the study: Mutational screening in the region of the Fc ℇRIα gene promoter and the first exon with subsequent genetic variability assessment in allergic patients and a random population sample. Methods: Allergic subjects were individuals with asthma or urticaria. Age- and sex-matched controls were randomly selected from a large population sample. Mutational screening was performed using a single-stranded conformational polymorphism and subsequent sequencing. Detected polymorphisms were genotyped by restriction fragment length polymorphism. Total serum IgE was measured in allergic subjects and controls. Skin prick tests, blood eosinophil count and aspirin challenge test were performed only in the subjects. A subgroup of the subjects was further characterized by autologous serum skin test, histamine release test, Phadiatop and IgE antibodies against staphylococcal enterotoxins. Results: Two linked polymorphisms −344 C>T and −95 T>C were found within the Fc ℇRI α gene. The allele −344 T frequency was 0.45 vs 0.37 ( P = 0.33), and the allele −95 C frequency was 0.26 in subjects vs 0.30 in controls ( P = 0.62). Serum IgE was significantly higher in subjects homozygous for the −344T allele (TT genotype) than in those carrying the −344 C allele (CT or CC genotype; P = 0.003), but this association was not detectable in controls. Conclusions: Our findings of genotype-related differences in IgE levels in allergic patients suggest an impact of −344 C>T but not −95 T>C gene polymorphism of Fc ℇRI α on total levels of IgE. The genetic variability in Fc ℇRI α at the −344 nucleotide of its regulatory sequence, though not related to atopy, predicts higher levels of the immunoglobulin. [ABSTRACT FROM AUTHOR]

Background We have reported that in patients with chronic idiopathic urticaria (CIU) who reacted adversely to aspirin, the frequency of the −444C allele of the leukotriene C4 synthase gene ( LTC4S) was higher than in patients who tolerated aspirin well. Objectives To study the pattern of aspirin-induced urticaria (AIU) in two families, with special interest on the polymorphisms of LTC4S (AA, AC, CC) and the glutathione S-transferase M1 and P1 genes ( GSTM1 and GSTP1). Methods Of 74 patients with CIU and a history of aspirin hypersensitivity studied by us, two patients (probands) gave a family history of aspirin intolerance. Oral challenge tests with aspirin were carried out in members of these families. Genomic DNA samples were obtained from peripheral blood to study the polymorphisms of LTC4S, GSTM1 and GSTP1. Results In family 1 the aspirin challenge test confirmed AIU in three of five (60%) individuals, but in family 2 only in two of seven (29%). In both families, the variant genotypes of LTC4S (AC or CC) were present in the parents, but only one of them had CIU. In family 1, with both parents healthy, the three children had AIU; in two it was associated with variant LTC4S genotype. In family 2, urticaria following aspirin ingestion was present only with variant LTC4S genotype. In patients of both families with positive aspirin challenge test, deletion of the GSTM1 gene was present. Conclusions AIU aggregates in families inheriting the LTC4S−444C allele. Segregation of aspirin sensitivity in these families does not follow a clear Mendelian pattern. A common deletion of GSTM1, one of several enzymes involved in conjugation of a wide range of electrophilic substances with glutathione, was present in all individuals ascertained to have AIU. [ABSTRACT FROM AUTHOR]

Background:  Asthma is associated with a prothrombotic state. Plasma factor VIIa-antithrombin complex (FVIIa-AT) concentrations indirectly reflect the interaction of tissue factor (TF) with FVII. Since TF is a key initiator of coagulation in vivo, we hypothesized that FVIIa-AT concentrations are higher in asthma., Methods:  In 159 clinically stable adult asthma patients and 62 controls, we determined FVIIa-AT in plasma and analyzed their relation to circulating inflammatory and prothrombotic markers together with the total plasma potential for fibrinolysis (clot lysis time, CLT) and thrombin generation. We recorded clinical outcomes, including asthma exacerbations, during 3-year follow-up., Results:  Asthma patients were characterized by 38.5% higher FVIIa-AT ( p  < 0.001), related to bronchial obstruction (FEV 1 : r  = -0.397, p  < 0.001), asthma severity ( r  = 0.221, p  = 0.005), and duration ( r  = 0.194, p  = 0.015) compared to controls. FVIIa-AT showed weak positive associations with C-reactive protein ( r  = 0.208, p  = 0.009), fibrinogen ( r  = 0.215, p  = 0.007), and CLT ( r  = 0.303, p  < 0.001) but not with thrombin generation parameters. In the follow-up (data obtained from 151 patients), we documented 151 severe asthma exacerbations in 51 (33.8%) patients, including 33 (21.9%) with ≥2 such events. Exacerbation-prone asthma phenotype was related to 13.1% higher FVIIa-AT ( p  = 0.012), along with asthma severity and control ( p  < 0.003, both). High FVIIa-AT (that is ≥100.1 pmol/L), defined on receiver operating characteristic curves, was linked to exacerbation-prone asthma phenotype (odds ratio 1.85; 95%CI: 1.23-2.80, p  = 0.003) and shorter time to first exacerbation ( p  = 0.023)., Conclusion:  This study is the first to show that FVIIa-AT concentrations are higher in asthma in relation to its severity and may help identify individuals at risk of the exacerbation-prone asthma phenotype., Competing Interests: None declared., (Thieme. All rights reserved.)

Background: Nonsteroidal anti-inflammatory drugs-exacerbated respiratory disease (NSAIDs-ERD) is characterized by altered arachidonic acid (AA) metabolism. Aspirin hypersensitivity is diagnosed using aspirin challenge, while induced sputum is collected to perform cell counts and to identify local biomarkers in induced sputum supernatant (ISS). This study aimed to assess the levels of a newly identified eicosanoid, 15-oxo-eicosatetraenoic acid (15-oxo-ETE), in ISS at baseline and during aspirin-induced bronchospasm in patients with NSAIDs-ERD., Methods: Oral aspirin challenge was performed in 27 patients with NSAIDs-ERD and in 17 patients with aspirin-tolerant asthma (ATA) serving as controls. Sputum was collected before and after aspirin challenge to determine eosinophil, neutrophil, macrophage, and lymphocyte counts as well as the concentration of AA metabolites via 15-lipoxygenase-1 (15-LOX-1) and 5-LOX pathways in ISS. Chromatography-tandem mass spectrometry was used to measure ISS levels of 15-oxo-ETE, 15-hydroxyeicosatetranoic acid (15-HETE), and leukotriene E 4 (LTE 4 )., Results: At baseline, ISS levels of 15-oxo-ETE were higher in NSAIDs-ERD than in ATA (p = 0.04). In contrast, baseline 15-HETE levels in ISS were lower in patients with NSAIDs-ERD (p = 0.03). After aspirin challenge, 15-oxo-ETE levels decreased only in patients with NSAIDs-ERD (p = 0.001) who developed bronchospasm. In both study groups, there was a reduction in sputum macrophage count after aspirin challenge (p = 0.03 and p = 0.02, respectively) irrespective of bronchospasm., Conclusions: Patients with NSAIDs-ERD are characterized by higher baseline 15-oxo-ETE levels in ISS than patients with ATA. Aspirin-induced bronchospasm inhibited the local generation of 15-oxo-ETE., (© 2024 The Author(s). Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)