Inflammasome signalling pathway in the regulation of inflammation - its involvement in the development and exacerbation of asthma and chronic obstructive pulmonary disease.

Inflammasomes are multiprotein oligomers, whose main function is the recruitment and activation of caspase-1, which cleaves the precursor forms of interleukin (IL)-1ß and IL-18, generating biologically active cytokines. Activation of inflammasome is an essential component of the innate immune response, and according to recent reports it is involved in epithelial homeostasis and type 2 T helper cell (Th2) differentiation. In recent years, the contribution of inflammasome dependent signalling pathways to the development of inflammatory diseases became a topic of multiple research studies. Asthma and chronic obstructive pulmonary disease (COPD) are the most prevalent obstructive lung diseases. Recent studies have focused on inflammatory aspects of asthma and COPD development, demonstrating the key role of inflammasome-dependent processes. Factors responsible for activation of inflammasome complex are similar in both asthma and COPD and include bacteria, viruses, cigarette smoke, and particulate matter. Some recent studies have revealed that NLRP3 inflammasome plays a crucial role, particularly in the development of acute exacerbations of COPD (AECOPD). Activation of NLRP3 inflammasome has been linked with neutrophilic severe steroid-resistant asthma. Although most of the studies on inflammasomes in asthma and COPD focused on the NLRP3 inflammasome, there are scarce scientific reports linking other inflammasomes such as AIM2 and NLRP1 with obstructive lung diseases. In this mini review we focus on the role of molecular pathways associated with inflammasome in the most prevalent lung diseases such as asthma and COPD. Furthermore, we will try to answer the question of whether inhibition of inflammasome can occur as a modern therapy in these diseases.

The predictive value of BOAH scale for screening obstructive sleep apnea in patients at a sleep clinic in Scotland.

OBJECTIVES: The study aimed to evaluate the diagnostic value of an original questionnaire for obstructive sleep apnea (OSA), the BOAH scale, and its ability to prioritize patients at high risk for OSA for polysomnography (PSG) examination. METHODS: The analysis included 273 patients referred to the Department of Sleep Medicine of the Royal Infirmary, Edinburgh, Scotland. The BOAH scale is comprised of 5 parameters: BMI (≥ 30 kg/m2 gives 1 point, ≥ 35 kg/m2 2 points), presence of witnessed apneas during sleep (1 point), patient age ≥ 50 years (1 point), and history of hypertension (1 point). Patients were divided into three study groups depending on OSA severity defined by the apnea-hypopnea index (AHI): at least mild (AHI ≥ 5), at least moderate (AHI ≥ 15), and severe (AHI ≥ 30) OSA based on polysomnography examination. RESULTS: In the group of patients with severe OSA, the best BOAH cutoff point was 4 points based upon the Youden index. With 4 points, the area under the receiver operating characteristic (ROC) curve was 0.778 (95% CI 0.721-0.834). Sensitivity and specificity were 57% and 89%, respectively, yielding a positive and negative predictive value of 75% and 78%, respectively, for diagnosis of severe OSAS in a patient sample with a pre-test probability for severe OSA at 37%. CONCLUSIONS: The BOAH scale in this group of Scottish patients performed comparably to other available questionnaires and scales while being shorter and simpler. The findings suggest that the BOAH scale should be considered as a useful instrument in OSA diagnosis and prioritization of high-risk patients for PSG examination.

COEXISTENCE OF PULMONARY FIBROSIS AND PROLIFERATION OF PULMONARY NEUROENDOCRINE CELLS FORMING TUMORLET.

Tumorlet is a disease rarely diagnosed in clinical practice. It is characterized by pulmonary neuroendocrine cell (PNEC) proliferation which invades the bronchiolar basement membrane and forms nodules with a diameter smaller than 5 mm. Case report: 72-year-old female patient was suffered for many years from progressive dyspnea and coughing with evidence of pulmonary fibrosis on high resolution computed tomography (HRCT). As a result of a lung biopsy, based on immunohistochemical tests, a 2 mm cluster of neuroendocrine cells (NEC) was found and it was diagnosed as tumorlet. Due to a long-term, insidious progress of the disease, as well as sex and age of the patient, the case emphasizes that differential diagnosis should include tumorlet as well as diffuse idiopathic neuroendocrine cell hyperplasia (DIPNECH) as a more extensive manifestation of neuroendocrine cell proliferation in the respiratory tract.

Non-necrotizing inflammatory granulomas (n-ngs) in the course of inflammatory bowel disease - immunology and clinical manifestation of intestinal and respiratory N-NGS.

OBJECTIVE: The aim:The article describes and summarizes the immunological pathomechanisms controlling the development of non-necrotizing granulomas in the course of non-specific inflammatory bowel diseases (IBD) in lungs and intestines; it also reviews the possible clinical correlations between the processes in the gastrointestinal and respiratory tracts based on the example of Crohn's disease (CD) and non-specific inflammatory bowel disease (IBC). While the dominant cell subpopulation in ulcerative colitis (UC) is Th2, which produces interleukins IL-4, IL-5, IL-6, IL-10 and IL-13 and Th17 cells; CD characterized by the Th1 cell subpopulation and macrophages predominate, producing IL-23. These are considered to be the key factors crucial for the occurrence of chronic inflammation. Another important causative factor of non-specific inflammatory bowel diseases and granulation is the expression of CD40/CD40L proteins on activated T-cells, i.e. type 2 transmembrane proteins similar to TNF-alpha. However, the interactions between gastrointestinal neuroendocrine peptides/amines (NEPA) and the immune system are believed to have a significant influence on the pathophysiology of non-specific inflammatory bowel diseases and non-necrotizing granulation. The key functions of the immune response of the gastrointestinal tract are managed by the neuroendocrine regulatory system (NES) whose activities govern the production of various hormones including chromogranin/secretogranin, serotonin, vasoactive intestinal polypeptide (VIP), neuropeptide Y (NPY), substance P, somatostatin or ghrelin.

[Pulmonary manifestations of crohn's disease or chronic pharmacotherapy complications? - case report].

Pareneteral manifestations of Crohn's disease (ChLC), apart from the most common skin and joint symptoms include also complications from the respiratory system. In addition chronic pharmacotherapy of ChLC, especially 5-aminosalicylic acid or anti-TNF- α drugs, is associated with possible pulmonologic side effects, sometimes difficult to differentiate. In this study, we describe a patient with ChLC, with a history of pneumocystic pneumonia, who was diagnosed with exfoliative institial pneumonitis as a result of chronic use of mesalazine. This disease is characterized by accumulation of alveolar macrophages in the lumen of the alveoli and intrabepticular septum. The most common etiologic factor is exposure to tobacco smoke. Our patient, non-smoker, was finally diagnosed after lung biopsy and histopathological evaluation. The gradual clinical improvement after mesalazine was an additional factor confirming the etiology of the disease. This side effect of mesalazine is not common but it should be considered in all patient treated with 5-aminosalicylic acid.

Generalized emphysema and chronic obstructive pulmonary disease in a farmer, non-smoker - the more we seek, the more we find.

Although alpha-1 antitrypsin (A1AT) deficiency represents one of the most common genetically conditioned diseases in the population of Caucasian adult individuals, it is rarely diagnosed. Alpha-1 antitrypsin is an important component of the anti-proteolytic protection in the lungs. Individuals affected by the protein deficiency are exposed to a higher risk of developing chronic obstructive pulmonary disease (COPD), emphysema or liver diseases. A CASE REPORT: A 52-year-old farmer, non-smoker, spraying orchards since the age of 15 years, was admitted to the Department with dyspnea at rest and productive cough. He had a medical history of COPD, congestive heart failure, generalized emphysema of ten years' duration On admission the patient's general condition was satisfactory (fair). Physical examination showed symmetric expiratory wheezing over the upper and lower fields of the lungs with loss of vesicular murmur in the lower fields. Spirometry revealed a severe chronic bronchial obstruction, and an arterial blood gas test showed hypoxemia. Laboratory tests demonstrated an increased concentration of inflammatory markers. High resolution computed tomography (HRCT) of the chest showed evidence of generalized emphysema, bronchiectasis and exacerbation of peribronchial inflammatory changes. Intensive anti-inflammatory, bronchodilator treatment and antibiotic therapy were implemented, which resulted in an optimal improvement of the patient's condition. Based on the whole clinical picture A1AT deficiency was suspected. Alpha-1-antitrypsin deficiency, MZ phenotype, with 65 mg/dl concentration was diagnosed. CONCLUSIONS: Diagnostic tests for alpha-1 antitrypsin deficiency should always be considered in patients with emphysema or symptomatic COPD identified at an early age. In the described case the period between occurrence of clinical signs and establishing the diagnosis was ten years, which proves that there is a strong need to spread knowledge on A1AT among medical professionals. Otherwise, most of the patients will lose their chance of modifying their lifestyle or receiving proper treatment that could prevent the progression of changes in the lungs.

Diagnostic challenges in interstitial lung diseases using the example of microscopic usual interstitial pneumonia image in a patient with the clinical hypothesis of idiopathic pulmonary fibrosis - a case report.

Idiopathic pulmonary fibrosis (IPF) is the most common of the idiopathic interstitial pneumonias. The high-resolution tomography (HRCT) is highly recommended among patients with suspected IPF. Usual interstitial pneumonia (UIP) is the histopathological and radiological pattern of IPF. IPF is diagnosed if the appropriate combination of HRCT patterns and histopathological patterns are present. CASE REPORT: The authors present a case of a 49-years-old woman who was hospitalised due to the detection of a focal lesion in the left lung in an X-ray examination. A CT scan of the chest with contrast revealed a solid infiltration of the same area. The histopathology from a transbronchial lung biopsy from this abnormality showed microscopic honeycomb, fibroblast fibrosis, macrophage clusters loaded with hemosiderin and widened bronchioles - an image suggesting Usual Interstitial Pneumonia (UIP). Following that, a HRCT showed considerable differences in the lung image compared to the previous CT examination - no polycyclic lesion in the left lung was detected and the fibrous changes decreased. The patient had substantial formal features of UIP from the histopathological examination from TBLB. Therefore, there was a clinicalradiological discrepancy in the histopathology report. After a multidisciplinary consultation by renowned experts in pulmonology, radiology and histopathology, regardless of the patient's diagnostic path, the primary cause of the disease could not be determined. The analysis of this case strongly suggests that the histopathological examination alone is not sufficient in the diagnosis of IPF.

Type D personality and the degree of control of bronchial asthma.

INTRODUCTION: Poor asthma control is probably associated with both biological and psychological factors. Type D pattern of behavior is characterized by negative emotionality and inhibition in social relationships. It was previously found to be associated with cardiovascular diseases. AIM: To evaluate the correlation between the degree of asthma control and the severity of the components of type D behavior pattern. MATERIAL AND METHODS: The research was conducted on a group of 117 subjects with bronchial asthma. The control group consisted of 32 healthy subjects. The degree of bronchial asthma control was determined using the Asthma Control Test. The D pattern of behavior was measured using the DS-14 questionnaire. RESULTS: The risk of type D behavior pattern, defined as scoring at least 10 points in both scales (Negative Emotionality and Social Inhibition), was higher in subjects with uncontrolled asthma than in healthy individuals (OR = 5.19; 95% CI: 1.74-15.44), those with partial control of asthma (OR = 6.04; 95% CI: 1.87-19.52) and subjects with good control of asthma (OR = 8.46; 95% CI: 3.09-23.16). The severity of depressiveness correlated positively with the number of infections in the past year. Negative emotionality correlated positively with the number of infections and social inhibition. CONCLUSIONS: Type D pattern of behavior may be associated with diagnosis and severity of asthma. Due to its link to poor control of asthma symptoms, a high level of negative emotionality among patients with asthma might be of particular interest to the clinicians.

The role of the TGF-SMAD signalling pathway in the etiopathogenesis of severe asthma.

Asthma is a chronic inflammatory heterogeneous disease of the lower respiratory tract characterised by the occurrence of bronchial hyper-responsiveness and paroxysmal, changeable bronchial obstruction. Transforming growth factor-beta (TGF-b) is one of the cytokines involved in mediating airway inflammation and remodelling. The level of TGF-b1 gene expression correlates with severity of symptoms. Alterations in the main SMAD signal transmission, overexpression of TGF-b genes and changes in the transcriptome cause excessive secretion of TGF-b and its increased expression in target cells, which clinically induces a moderate-severe or severe course of asthma as well as an earlier and faster disease progression. Knowledge of these processes allows clinicians to assess immune responses in patients, which affects adequate disease control and prevention of remodelling.

Temperament and stress coping styles in bronchial asthma patients.

INTRODUCTION: Temperament, defined as the formal characteristics of behavior, is a personality trait which can influence the clinical presentation and course of bronchial asthma. It determines susceptibility to stress as well as stress coping styles. AIM: The aim of the study was to assess whether healthy subjects differ from bronchial asthma patients with regard to temperamental variables and stress coping styles, and whether these factors may also differentiate patients with severe asthma from those with the milder form. The study also assesses whether the results of flow volume curve analysis correlate with temperamental traits and stress coping styles. MATERIAL AND METHODS: The study was conducted in a group of 65 asthma patients and 62 healthy controls. All underwent flow volume curve examination and psychological tests: Formal Characteristics of Behavior - Temperament Inventory (FCB-TI) and Coping in Stress Situations (CISS) questionnaire. RESULTS: Bronchial asthma patients were characterized by a lower level of briskness ("agility") than healthy subjects (13.35 ±4.48 vs. 14.97 ±3.98, p = 0.031). The remaining temperamental traits and stress coping styles did not differ between the groups. Additionally, the forced expiratory volume in 1 s (FEV1) value was found to correlate negatively with the intensity of the emotion-oriented stress coping style, whereas FEV1 and forced vital capacity (FVC) were found to positively correlate with briskness, emotional reactivity and endurance, while a negative correlation was found with activity. CONCLUSIONS: Briskness differentiates healthy subjects from bronchial asthma patients. The values obtained in FEV1 and FVC pulmonary function tests were also found to correlate with some temperamental variables.

Assessment of the effectiveness of the peptide inhibitor homologous to the transforming growth factor ß cytokine blocking the TGFßRI/TGFßRII receptor complex-pilot study.

BACKGROUND: A key player in the fibrotic process is the transforming growth factor ß (TGF-ß) which enhances extracellular matrix production by increasing the transcription of matrix proteins. The cytokine TGF-ß first binds to the TGFßRII receptor (dimer), resulting in the recruitment of the TGFßRI receptor (dimer). The complex thus formed leads to the phosphorylation of the kinase domain of TGFßRI, which in turn results in activation of the Smad pathway. This is therefore a targeted pathway for research into the application of peptide inhibitors in blocking the TGF-ß-Smad signaling pathway. The aim of this study was to design a peptide inhibitor (homologous to the cytokine TGF-ß) which, after binding to the TGFßRI/TGFßRII receptor, would block the cytokine binding and thus prevent the formation of an activating complex. METHODS: Preliminary work on the design and synthesis of inhibitors for TGFßRI/TGFßRII has allowed us to identify and describe five key regions of the TGF-ß-TGFßRI/TGFßRII interface. The following five peptide inhibitors were synthesized for Region 1: 1.1 ALDAAYCFR, 1.2 LDAAYCFRN, 1.3 DAAYCFRNV, 1.4 AAYCFRNVQ, 1.5 AYCFRNVQD. The expression of the SEAP reporter gene, Smad2, Smad3, Smad4, and JNK1 gene was measured using quantitative real-time polymerase chain reaction. RESULTS: For Region 1 peptide inhibitors tested for TGFßRI/TGFßRII, reduced SEAP (reporter gene) expression was observed in cells of the MFB-F11 line, which suggests inhibited the formation of cytokine-receptor complexes. CONCLUSIONS: For IP1_2, 1_3 and 1_5 Region 1 peptides tested for TGFßRI/TGFßRII, reduced cytokine-receptor signal by adding newly designed inhibitors. The study revealed an impact of these peptide inhibitors on the reduction of mRNA expression of Smad2, Smad3, Smad4 and JNK1 genes.

Biologic drugs in the treatment of chronic inflammatory pulmonary diseases: recent developments and future perspectives.

Chronic inflammatory diseases of the lung are some of the leading causes of mortality and significant morbidity worldwide. Despite the tremendous burden these conditions put on global healthcare, treatment options for most of these diseases remain scarce. Inhaled corticosteroids and beta-adrenergic agonists, while effective for symptom control and widely available, are linked to severe and progressive side effects, affecting long-term patient compliance. Biologic drugs, in particular peptide inhibitors and monoclonal antibodies show promise as therapeutics for chronic pulmonary diseases. Peptide inhibitor-based treatments have already been proposed for a range of diseases, including infectious disease, cancers and even Alzheimer disease, while monoclonal antibodies have already been implemented as therapeutics for a range of conditions. Several biologic agents are currently being developed for the treatment of asthma, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis and pulmonary sarcoidosis. This article is a review of the biologics already employed in the treatment of chronic inflammatory pulmonary diseases and recent progress in the development of the most promising of those treatments, with particular focus on randomised clinical trial outcomes.

Functional polymorphism of cyclooxygenase-2 gene (G-765C) in chronic obstructive pulmonary disease patients.

Cyclooxygenase two (COX-2) is an important enzyme metabolizing arachidonic acid. In contrast to constitutive cyclooxygenase one (COX-1), COX-2 is induced by proinflammatory factors. Polymorphism -765 G/C in COX-2-encoding gene promoter is associated with development of Alzheimer's disease, depression, carcinoma of the pancreas in smokers, breast cancer and rheumatoid arthritis. It is interesting whether the -765 G/C polymorphism in COX-2-encoding gene promoter can be associated with COPD, a disease which is inflammatory in character. It is highly probable as the breast and pancreas cancers, whose associations with the analyzed polymorphism have been studied, are smoking-dependent tumors. Additionally, tobacco smoke has been demonstrated to induce COX-2 in the lungs. The study group consisted of 122 COPD patients (48 females, 74 males). The control group consisted of 149 healthy nonsmoking subjects (83 females, 66 males). Polymerase chain reaction/restriction fragment length polymorphism was used for genotyping. A statistically significant difference in genotype distribution was observed as a result of the comparison between healthy subjects and patients with COPD. The distribution of alleles in both groups conformed with Hardy-Weinberg equilibrium. In the group of COPD patients, GG allele was found in 79 subjects, GC in 36, and CC in 7 subjects (F = 0.094, P = 0.296927); in the control group, 73 subjects had GG allele, 68--GC and 8--CC (F = 0.12728, P = 0.120265). The allele frequency revealed differences between those groups, attaining the level of statistical significance (χ(2) = 29.043, df = 2, P = 0.0000. The carriers of -765 G allele are at 1.53-fold higher risk of developing COPD. The presence of GG genotype does not increase significantly the risk of the disease. It is also noteworthy that the carriers of CC or GC genotypes are at significantly lower risk of developing COPD than the group of subjects with GG genotype.

The role of functional single nucleotide polymorphisms of the human glucocorticoid receptor gene NR3C1 in Polish patients with bronchial asthma.

N363S and ER22/23EK polymorphisms observed within glucocorticoid receptor gene (NR3C1) may play an important role in the development of bronchial asthma. NR3C1 gene is associated with an altered sensitivity to GCs. The aim of the research project was to study the correlation between this NR3C1 gene polymorphisms and occurrence of asthma in the population of Polish asthmatics. Peripheral blood was obtained from 207 healthy volunteers and 221 asthma patients. Genotyping was carried out with PCR-RFLP method. In the groups of patients with uncontrolled moderate asthma and uncontrolled severe disease, the genotype distribution for the investigated polymorphisms was as follows: N363S-AA, AG, GG occurring with 0.881/0.073/0.046 frequency and ER22/23EK-GG, GA, AA occurring with 0.963/0.037/0.000 frequency. Chi-square analysis revealed a significantly different (P < 0.05) distribution between cases and controls for the N363S polymorphisms. The N363S polymorphism of NR3C1 gene is significantly associated with bronchial asthma, susceptibility to the development of moderate to severe form of uncontrolled bronchial asthma.

[Intensity of depression in pedagogy students]. / Nasilenie depresyjnosci u studentów kierunku pedagogika.

UNLABELLED: The teacher's profession is regarded to be susceptible to professional burnout. Its early markers include high neuroticism and tendency to depressive reactions. The aim of the study was to assess the depression intensity and the occurrence of mood disorders in the population of full-time and extramural course students of pedagogy aged 19-30, as well as the difference in intensity of the measured constructs between men and women. MATERIAL AND METHODS: The study was carried out on the group of 223 women and 162 men aged 19-30 studying pedagogy at Piotrków Trybunalski Division of Jan Kochanowski Memorial University in Kielce in the years 2008-2011. The control group consisted of 76 women and 88 men studying economics. Students of full-time and extramural courses were included. All the participants were assessed with Beck Depression Inventory. Depression as a syndrome was diagnosed if the score of 10 of more was obtained. RESULTS: Among female students of pedagogy, 21 out of 223 obtained Beck Depression Inventory scores equal to, or above 10; whereas among female students of economics 1 out of 76 obtained such a result. The relative risk of developing depression (understood as Beck Depression Inventory result of 10 or more) was found to be significantly higher among female pedagogues (OR 7.797; CI 1.0306 to 58.9856) than among female economists. Among male pedagogy students, 2 out of 162 obtained 10 points, or more. It means that the risk of depression in female pedagogues was as much as over eight-fold higher than in male pedagogues (OR 8.3168; CI 1.9215 - 35.9979). The risk of depression in men studying pedagogy was not higher than in men studying economics, who obtained the Beck Depression Inventory scores of 10 or more in 1 case out of 88 (OR 1.1; CI 0.0983 to 12.3032). Considering all pedagogues irrespectively of gender versus all economists, the risk of depression in the group of pedagogues is over five-fold higher than among economists (OR 5.1464; CI 1.1991 to 22.0885). In the whole group of women, irrespectively of the study profile, the risk of Beck Depression Inventory result equal to, or exceeding was six-fold higher than among men (OR 6.5391; CI 1.9336 to 22.1144). There was no statistically significant correlation between the Beck Depression Inventory scores obtained in the studied group and the subjects' ages. The mean scores obtained in the particular groups are presented in table. The Beck Depression Inventory scores obtained by women studying pedagogy was found to differ with statistical significance from the scores obtained by male pedagogy students (p = 0.001925), female economics students (p = 0.015781) and female economics students (p = 0.000611). The mean intensity of depression in men studying pedagogy did not differ from the mean intensity of depression in women studying economics (p = 0.94128) and in men studying economics (p = 0.330382). No differences in the mean Beck Depression Inventory scores of female and male students of economics were noted, either (p = 0.444554). The mean intensity of depression in women representing both fields of study was 6.094 +/- 3.13, vs 4.97 +/- 2.45 in men; the difference was statistically significant at the significance level of p = 0.00005. The mean intensity of depression in pedagogy students of both sexes was 5.92 +/- 3.024 vs 4.79 +/- 2.39 in students of economics; the difference was statistically significant at the significance level of p = 0,000026. CONCLUSIONS: Women studying pedagogy demonstrate higher depression intensity than men studying pedagogy, as well as male and female students of economics. Students of pedagogy demonstrate higher depression intensity than students of economics. On the overall, women in the whole studied population have higher depression intensity than men; however, no such gender-related differences were observed among students of economics.

Cytokine TGFß Gene Polymorphism in Asthma: TGF-Related SNP Analysis Enhances the Prediction of Disease Diagnosis (A Case-Control Study With Multivariable Data-Mining Model Development).

Introduction: TGF-ß and its receptors play a crucial role in asthma pathogenesis and bronchial remodeling in the course of the disease. TGF-ß1, TGF-ß2, and TGF-ß3 isoforms are responsible for chronic inflammation, bronchial hyperreactivity, myofibroblast activation, fibrosis, bronchial remodeling, and change the expression of approximately 1000 genes in asthma. TGF-ß SNPs are associated with the elevated plasma level of TGF-ß1, an increased level of total IgE, and an increased risk of remodeling of bronchi. Methods: The analysis of selected TGF-ß1, TGF-ß2, TGF-ß3-related single-nucleotide polymorphisms (SNP) was conducted on 652 DNA samples with an application of the MassARRAY® using the mass spectrometry (MALDI-TOF MS). Dataset was randomly split into training (80%) and validation sets (20%). For both asthma diagnosis and severity prediction, the C5.0 modelling with hyperparameter optimization was conducted on: clinical and SNP data (Clinical+TGF), only clinical (OnlyClinical) and minimum redundancy feature selection set (MRMR). Area under ROC (AUCROC) curves were compared using DeLong's test. Results: Minor allele carriers (MACs) in SNP rs2009112 [OR=1.85 (95%CI:1.11-3.1), p=0.016], rs2796821 [OR=1.72 (95%CI:1.1-2.69), p=0.017] and rs2796822 [OR=1.71 (95%CI:1.07-2.71), p=0.022] demonstrated an increased odds of severe asthma. Clinical+TGF model presented better diagnostic potential than OnlyClinical model in both training (p=0.0009) and validation (AUCROC=0.87 vs. 0.80,p=0.0052). At the same time, the MRMR model was not worse than the Clinical+TGF model (p=0.3607 on the training set, p=0.1590 on the validation set), while it was better in comparison with the Only Clinical model (p=0.0010 on the training set, p=0.0235 on validation set, AUCROC=0.85 vs. 0.87). On validation set Clinical+TGF model allowed for asthma diagnosis prediction with 88.4% sensitivity and 73.8% specificity. Discussion: Derived predictive models suggest the analysis of selected SNPs in TGF-ß genes in combination with clinical factors could predict asthma diagnosis with high sensitivity and specificity, however, the benefit of SNP analysis in severity prediction was not shown.

Beneficial Influence of Exendin-4 on Specific Organs and Mechanisms Favourable for the Elderly with Concomitant Obstructive Lung Diseases.

Exendin-4 (Ex-4), better known in its synthetic form and used clinically as exenatide, currently applied in the treatment of diabetes, induces a beneficial impact on nerve cells, and shows promising effects in obstructive lung diseases. At an advanced age, the development of the neurodegenerative process of brain tissue is masked by numerous concomitant diseases. The initial latent phase of neurodegenerative disease results in occurrence of manifestations at an advanced stage. To protect the brain and to simultaneously ensure proper treatment of common coexisting conditions in late life, such as diabetes, chronic obstructive pulmonary disease, or asthma, a pleiotropic medication should be chosen. Molecular mechanisms of Ex-4 exert neuroprotective effects or lead to secondary neurogenesis. Additionally, Ex-4 plays an important role in anti-inflammatory actions which are necessary both in the case of asthma and Parkinson's disease. Specific receptors in the lungs also reduce the secretion of surfactants, which decreases the risk of exacerbation in chronic obstructive lung disease. In a great number of patients suffering from diabetes, asthma, or chronic lung disease, there is a great potential for both treatment of the main condition and protection against brain neurodegeneration.

The correlation of the BMP-4 and BMP-7 proteins of the TGFß-BMP-SMAD pathway in the response to a specific and non-specific trigger in asthma.

INTRODUCTION: Asthma is characterized by persistent inflammation, airway hypersensitivity and remodelling. Bone Morphogenetic Proteins belong to the Transforming Growth Factor Superfamily and have a similar signalling transduction pathway and common co-mediating protein. However, the BMPs role in the remodelling remains unclear; they appear to be involved in the airway inflammation and fibrogenesis process. MATERIAL AND METHODS: 60 patients with asthma and 48 healthy volunteers were recruited for the study. Blood samples were collected before, 1 hour, 24 and 48 hours after the allergen or the methacholine challenge test. Evaluation of BMP-4 and BMP-7 serum concentration and expression was performed using ELISA and real time PCR methods, respectively. RESULTS: Statistically significant differences in BMP-7 concentration between healthy controls and asthmatics before the chal-lenge were noted. We found two statistically significant correlations: between the basal BMP-4 concentration and the FEV1(L) raw value and FEV1/FVC(%) index. We did not observe significant changes in the gene expression of BMP-4 and BMP-7 in different time points. CONCLUSIONS: Observed differences in BMP-7 concentration between asthmatic and healthy groups and correlations between BMP-4 concentration and some lung function test values may indicate the role of the BMPs in the etiopathogenesis of asthma. The unique characteristic of our study is the evaluation of BMPs serum levels, not in the bronchial epithelium.

Improving the risk-to-benefit ratio of inhaled corticosteroids through delivery and dose: current progress and future directions.

INTRODUCTION: Inhaled corticosteroids (ICS) are known to increase the risk of systemic and local adverse effects, especially with high doses and long-term use. Hence, considerable resources are invested to improve pharmacokinetic/pharmacodynamic (PK/PD) properties of ICS, effective delivery systems and novel combination therapies to enhance the risk-to-benefit ratio of ICS. AREAS COVERED: There is an unmet need for new solutions to achieve optimal clinical outcomes with minimal dose of ICS. This paper gives an overview of novel treatment strategies regarding the safety of ICS therapy on the basis of the three most recent molecules introduced to our everyday clinical practice - ciclesonide, mometasone furoate, and fluticasone furoate. Advances in aerosol devices and new areas of inhalation therapy are also discussed. EXPERT OPINION: Current progress in improving the risk-to-benefit ratio of ICS through dose and delivery probably established pathways for further developments. This applies both to the improvement of the PK/PD properties of ICS molecules but also includes technical aspects that lead to simplified applicability of the device with simultaneous optimal drug deposition in the lungs. Indubitably, the future of medicine lies not only in the development of new molecules but also in technology and digital revolution.

Monoclonal antibodies in the management of asthma: Dead ends, current status and future perspectives.

Patients with moderate-to-severe asthma may now be treated using a variety of monoclonal antibodies that target key inflammatory cytokines involved in disease pathogenesis. Existing clinical data on anti-IgE, anti-IL-5 and other immunological pathways indicate these therapies to offer reduced exacerbation rates, improved lung function, greater asthma control and better quality of life. However, as several patients still do not achieve satisfactory clinical response with the antibodies available, many more biologics, aiming different immunological pathways, are under evaluation. This review summarizes recent data on existing and potential monoclonal antibodies in asthma. Recent advances have resulted in the registration of a new antibody targeting TSLP (tezepelumab), with others being under development. Some of the researched monoclonal antibodies (e.g. anti-IL-13 tralokinumab and lebrikizumab or anti-IL-17A secukinumab) have shown optimistic results in preliminary research; however, these have been discontinued in asthma clinical research. In addition, as available monoclonal antibody treatments have shown little benefit among patients with T2-low asthma, research continues in this area, with several antibodies in development. This article summarizes the available pre-clinical and clinical data on new and emerging drugs for treating severe asthma, discusses discontinued treatments and outlines future directions in this area.