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.

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.

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.

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.

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.

New insights into the regulation of TGF-ß/Smad and MPK signaling pathway gene expressions by nasal allergen and methacholine challenge test in asthma.

Background: Asthma is a heterogeneous chronic inflammatory disease of the bronchi, the course of which is significantly influenced by extrinsic factors (specific and non-specific). Methods: The aim of this study was to evaluate the effect of these factors represented by nasal allergen challenge (specific factors) and methacholine challenge test (non-specific) on changes in mRNA expression of genes encoding the TGF-ß (TGF-ß1 and TGF-ß3)‒Smad (mitogen-activated protein kinase 1/3 [MPK1/3], Smad1/3/6/7) signaling pathway in asthmatic patients. Results: Seventy-five subjects were included in the study, of whom 27 were applied an intranasal allergen provocation and 48 a methacholine provocation. There were 9 men and 18 women in the intranasal provocation group, and 17 men and 31 women in the methacholine test group. We found that both examined the types of challenges contributed to changes in the relative expression of genes of the TGF-ß (TGF-ß1 and TGF-ß3)‒Smad (MPK1/3, Smad1/3/6/7) signaling pathway in asthmatic patients. A decrease was noted for MAPK1, MAPK3, Smad3, Smad6, and Smad7 genes and an increase of up to 2.5 times for TGF-ß1 gene. Conclusions: Our experiment allows us to conclude that the change in the mRNA expression of the TGF-ß1-MPK1/3 and Smad3/6/7 genes occurs after an intranasal allergen and bronchial methacholine challenge.

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.

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.

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.

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.

Comparative analysis of clinical, physiological, temperamental and personality characteristics of elderly subjects and young subjects with asthma.

BACKGROUND: Asthma is a heterogeneous disease of a complex etiology in which genetic, environmental and personality variables are important factors determining the development of complicated strategies related to coping with stress and temperament traits. Our thesis is that coping styles in asthmatic patients are modified by the environment (chronic inflammation and stress) which affects individual temperament traits in the course of time. Thus, patient age is one of factors which determine the clinical image of asthma and its natural history. AIM: The aim of the study was to evaluate the variables describing stress coping styles and temperament in young (18 to 35 years old) and elderly asthmatics (aged ≥60 years). MATERIAL AND METHODS: A total of 200 patients, 104 elderly and 96 young asthmatics were enrolled in the study. Apart from medical examination, the following tests were performed in all subjects: the Formal Characteristics of Behavior- Temperament Inventory (FCB-TI), Coping Inventory for Stressful Situations (CISS), Beck Depression Inventory, State-Trait Anxiety Inventory, and Borg Rating of Perceived Exertion (RPE) Scale. RESULTS: Elderly patients with asthma exhibited higher intensity of anxiety as a trait, a higher level of depression and experienced dyspnea, as well as higher levels of stress coping strategies such as Avoidance-Oriented Coping (AOC), Distraction Seeking (DS) and Social Diversion (SD) compared to young asthmatics. In elderly patients, Perseverance and Sensory Sensitivity traits have been observed to decline with the duration and development of asthma at later life stages as opposed to young asthmatics, in whom these temperament characteristics are elevated. CONCLUSIONS: Asthma is a heterogeneous disease of a complex etiopathogenesis that has a complex interplay with mental health. The present study confirms a relationship between age and stress coping strategies as well as temperament traits.

Primary non-adherence to inhaled medications measured with e-prescription data from Poland.

BACKGROUND: Treatment adherence greatly influences the clinical outcomes in various fields of medicine, including management of asthma and COPD. With the recent implementation of a nationwide e-Health solutions in Poland, new and unique opportunities for studying primary non-adherence in asthma and COPD emerged. The aim was to study primary non-adherence to inhaled medications available in Poland indicated in asthma and/or COPD and analyse the impact of patients' demographics and inhalers' characteristics (dry powder inhalers (DPIs) vs metered dose inhalers (MDIs) and presence of a dosage counter) on primary non-adherence. METHODS: A retrospective analysis of all e-prescriptions issued in Poland in 2018 (n = 119,880) from the national e-prescription pilot framework. RESULTS: Primary non-adherence for inhalable medications reached 15.3%. It significantly differed among age groups-the lowest (10.8%) was in 75 + years-old patients, highest (18%) in 65-74 years-old patients. No gender differences in primary non-adherence were found. The highest non-adherence was observed for ICS + LABA combinations (18.86%). A significant difference was found between MDI and DPI inhalers and between inhalers with/without a dosage counter. CONCLUSIONS: Out of e-prescriptions for inhaled medications issued in 2018 in Poland, 15.3% were not redeemed. The degree of primary non-adherence was influenced by age, but not gender. Significant differences between MDIs and DPIs and between inhalers with/without a dosage counter were observed.

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.

Biological Therapies of Severe Asthma and Their Possible Effects on Airway Remodeling.

Asthma is a chronic and heterogenic respiratory tract disorder with a high global prevalence. The underlying chronic inflammatory process and airway remodeling (AR) contribute to the symptomatology of the disease. The most severely ill asthma patients may now be treated using a variety of monoclonal antibodies aiming key inflammatory cytokines involved in asthma pathogenesis. Although clinical data shows much beneficial effects of biological therapies in terms of reduction of exacerbation rates, improvement of lung functions, asthma control and patients' quality of life, little is known on the effects of these monoclonal antibodies on AR-a key clinical trait of long-term asthma management. In this review, the authors summarize the data on the proven effects of monoclonal antibodies in asthma on AR. To date, in terms of reversing AR, the mostly studied was omalizumab. However, some studies also addressed this clinical issue in context of other severe asthma biological therapies (mepolizumab, benralizumab, tralokinumab). Still, data on effects of particular biological therapies on AR in severe asthma are incomplete and require further studies. According to the American Thoracic Society research recommendations, future research shall focus on AR in asthma and improve drugs targeting AR, including the available and future monoclonal antibodies.

Primary Non-Adherence to Antihistamines-Conclusions From E-Prescription Pilot Data in Poland.

BACKGROUND: In allergic conditions such as allergic rhinitis and urticaria, orally administered H1-antihistamines belong to first-line therapy and therefore, are widely prescribed. Due to the frequent, and often chronic, course of allergic diseases, adherence is of great importance. In 2018 a novel, nationwide e-prescription system was piloted in Poland, which allowed to analyze primary non-adherence to orally administered H1 antihistamines. OBJECTIVES: To assess the primary non-adherence to orally administered H1-antihistamines in Poland, defined as not redeeming the drug issued on a particular e-prescription within its validity period. METHODS: The study was based on all e-prescriptions issued in Poland in 2018, issued for 119.880 drugs. The analysis included nine major orally administered H1 antihistamines available in Poland. RESULTS: Out of 2280 analyzed e-prescriptions on orally administered antihistamines, 1803 (79.1%) of them were redeemed. Therefore, the level of primary non-adherence reached 21%. Among women it reached 19.9%, but it was not significantly lower than among men (23.4%, p=0.064). The highest non-adherence (31.3%) was observed in the age group 19-39, whilst the highest adherence rate (84.6%) was observed in those 75 years or older. The most frequently prescribed second-generation antihistamine was bilastine-596 e-prescriptions with 23.7% primary non-adherence. CONCLUSIONS: More than 1 out of 5 e-prescriptions on orally administered H1-antihistamines were not redeemed in Poland in 2018. Age, but not gender, significantly influenced the degree of primary non-adherence to these drugs. To authors knowledge, this is the first real-life study on primary non-adherence to H1-antihistamines in Poland and one of the very few on this subject worldwide.

Role of Platelet-Derived Growth Factor (PDGF) in Asthma as an Immunoregulatory Factor Mediating Airway Remodeling and Possible Pharmacological Target.

Asthma is a chronic and heterogenic disease of the respiratory system, one of the most common lung diseases worldwide. The underlying pathologies, which are chronic inflammatory process and airway remodeling (AR), are mediated by numerous cells and cytokines. Particularly interesting in this field is the platelet-derived growth factor (PDGF), one of the members of the human growth factor family. In this article, the authors analyze the available data on the role of PDGF in asthma in experimental models and in human research. PDGF is expressed in airway by various cells contributing to asthma pathogenesis-mast cells, eosinophils, and airway epithelial cells. Research confirms the thesis that this factor is also secreted by these cells in the course of asthma. The main effects of PDGF on bronchi are the proliferation of airway smooth muscle (ASM) cells, migration of ASM cells into the epithelium and enhanced collagen synthesis by lung fibroblasts. The importance of AR in asthma is well recognized and new therapies should also aim to manage it, possibly targeting PDGFRs. Further studies on new and already existing drugs, mediating the PDGF signaling and related to asthma are necessary. Several promising drugs from the tyrosine kinase inhibitors group, including nilotinib, imatinib masitinib, and sunitinib, are currently being clinically tested and other molecules are likely to emerge in this field.

[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.