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

Plichta, Jacek / Kuna, Piotr / Panek, Michał

2023 Volume 14, Page(s) 1207641

Abstract: 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. ...

Abstract	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.
MeSH term(s)	Humans ; Biological Products/therapeutic use ; Administration, Inhalation ; Pulmonary Disease, Chronic Obstructive/drug therapy ; Chronic Disease ; Lung ; Antibodies, Monoclonal/therapeutic use
Chemical Substances	Biological Products ; Antibodies, Monoclonal
Language	English
Publishing date	2023-06-02
Publishing country	Switzerland
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2023.1207641
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Article: Assessment of the effectiveness of the peptide inhibitor homologous to the transforming growth factor β cytokine blocking the TGFβRI/TGFβRII receptor complex-pilot study.

Mateusz, Marynowski / Seweryn, Karbownik Michał / Janusz, Szemraj / Piotr, Kuna / Panek, Michał Gabriel

Clinical and translational allergy

2024 Volume 14, Issue 1, Page(s) e12320

Abstract: Background: A key player in the fibrotic process is the transforming growth factor β (TGF-β) which enhances extracellular matrix production by increasing the transcription of matrix proteins. The cytokine TGF-β first binds to the TGFβRII receptor (dimer) ...

Abstract	Background: A key player in the fibrotic process is the transforming growth factor β (TGF-β) which enhances extracellular matrix production by increasing the transcription of matrix proteins. The cytokine TGF-β first binds to the TGFβRII receptor (dimer), resulting in the recruitment of the TGFβRI receptor (dimer). The complex thus formed leads to the phosphorylation of the kinase domain of TGFβRI, 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-β-Smad signaling pathway. The aim of this study was to design a peptide inhibitor (homologous to the cytokine TGF-β) which, after binding to the TGFβRI/TGFβRII 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 TGFβRI/TGFβRII has allowed us to identify and describe five key regions of the TGF-β-TGFβRI/TGFβRII 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 TGFβRI/TGFβRII, 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 TGFβRI/TGFβRII, 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.
Language	English
Publishing date	2024-01-28
Publishing country	England
Document type	Journal Article
ZDB-ID	2630865-4
ISSN	2045-7022
ISSN	2045-7022
DOI	10.1002/clt2.12320
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Article ; Online: Cytokine TGFβ Gene Polymorphism in Asthma: TGF-Related SNP Analysis Enhances the Prediction of Disease Diagnosis (A Case-Control Study With Multivariable Data-Mining Model Development).

Panek, Michał / Stawiski, Konrad / Kaszkowiak, Marcin / Kuna, Piotr

Frontiers in immunology

2022 Volume 13, Page(s) 746360

Abstract: Introduction: TGF-β and its receptors play a crucial role in asthma pathogenesis and bronchial remodeling in the course of the disease. TGF-β1, TGF-β2, and TGF-β3 isoforms are responsible for chronic inflammation, bronchial hyperreactivity, ... ...

Abstract	Introduction: TGF-β and its receptors play a crucial role in asthma pathogenesis and bronchial remodeling in the course of the disease. TGF-β1, TGF-β2, and TGF-β3 isoforms are responsible for chronic inflammation, bronchial hyperreactivity, myofibroblast activation, fibrosis, bronchial remodeling, and change the expression of approximately 1000 genes in asthma. TGF-β SNPs are associated with the elevated plasma level of TGF-β1, an increased level of total IgE, and an increased risk of remodeling of bronchi. Methods: The analysis of selected TGF-β1, TGF-β2, TGF-β3-related single-nucleotide polymorphisms (SNP) was conducted on 652 DNA samples with an application of the MassARRAY 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-β 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.
MeSH term(s)	Asthma/diagnosis ; Asthma/genetics ; Case-Control Studies ; Cytokines/genetics ; Data Mining ; Humans ; Polymorphism, Single Nucleotide ; Transforming Growth Factor beta1/genetics ; Transforming Growth Factor beta2 ; Transforming Growth Factor beta3/genetics
Chemical Substances	Cytokines ; Transforming Growth Factor beta1 ; Transforming Growth Factor beta2 ; Transforming Growth Factor beta3
Language	English
Publishing date	2022-06-14
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.746360
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Article ; Online: The correlation of the BMP-4 and BMP-7 proteins of the TGFβ-BMP-SMAD pathway in the response to a specific and non-specific trigger in asthma.

Koćwin, Marcelina / Panek, Michał / Jonakowski, Mateusz / Szemraj, Janusz / Kuna, Piotr

Advances in respiratory medicine

2022 Volume 90, Issue 3, Page(s) 211–218

Abstract: 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- ... ...

Abstract	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.
MeSH term(s)	Asthma/metabolism ; Bone Morphogenetic Protein 4/metabolism ; Bone Morphogenetic Protein 7/metabolism ; Bone Morphogenetic Proteins/metabolism ; Humans ; Inflammation ; Smad Proteins/metabolism ; Transforming Growth Factor beta/metabolism
Chemical Substances	BMP4 protein, human ; BMP7 protein, human ; Bone Morphogenetic Protein 4 ; Bone Morphogenetic Protein 7 ; Bone Morphogenetic Proteins ; Smad Proteins ; Transforming Growth Factor beta
Language	English
Publishing date	2022-06-22
Publishing country	Poland
Document type	Journal Article
ZDB-ID	2893877-X
ISSN	2543-6031 ; 2451-4934
ISSN (online)	2543-6031
ISSN	2451-4934
DOI	10.5603/ARM.87955
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Article: Beneficial Influence of Exendin-4 on Specific Organs and Mechanisms Favourable for the Elderly with Concomitant Obstructive Lung Diseases.

Figat, Magdalena / Kardas, Grzegorz / Kuna, Piotr / Panek, Michał G

Brain sciences

2022 Volume 12, Issue 8

Abstract: 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 ... ...

Abstract	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.
Language	English
Publishing date	2022-08-17
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci12081090
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Article ; Online: Biological Therapies of Severe Asthma and Their Possible Effects on Airway Remodeling.

Kardas, Grzegorz / Kuna, Piotr / Panek, Michał

Frontiers in immunology

2020 Volume 11, Page(s) 1134

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Airway Remodeling/drug effects ; Airway Remodeling/immunology ; Anti-Asthmatic Agents/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Asthma/immunology ; Asthma/pathology ; Asthma/therapy ; Biological Therapy/methods ; Biological Therapy/trends ; Humans
Chemical Substances	Anti-Asthmatic Agents ; Antibodies, Monoclonal, Humanized
Language	English
Publishing date	2020-06-18
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2020.01134
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Article ; Online: Comparative analysis of clinical, physiological, temperamental and personality characteristics of elderly subjects and young subjects with asthma.

Panek, Michał G / Karbownik, Michał S / Kuna, Piotr B

PloS one

2020 Volume 15, Issue 11, Page(s) e0241750

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Adaptation, Psychological/classification ; Adult ; Age Distribution ; Aged ; Anxiety/epidemiology ; Anxiety/etiology ; Asthma/psychology ; Female ; Humans ; Male ; Middle Aged ; Personality Inventory ; Stress, Psychological/epidemiology ; Stress, Psychological/etiology ; Young Adult
Language	English
Publishing date	2020-11-06
Publishing country	United States
Document type	Comparative Study ; Journal Article
ISSN	1932-6203
ISSN (online)	1932-6203
DOI	10.1371/journal.pone.0241750
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Article: Primary non-adherence to inhaled medications measured with e-prescription data from Poland.

Kardas, Grzegorz / Panek, Michał / Kuna, Piotr / Kardas, Przemysław

Clinical and translational allergy

2020 Volume 10, Page(s) 39

Abstract: 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 ... ...

Abstract	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.
Keywords	covid19
Language	English
Publishing date	2020-10-07
Publishing country	England
Document type	Journal Article
ZDB-ID	2630865-4
ISSN	2045-7022
ISSN	2045-7022
DOI	10.1186/s13601-020-00346-7
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Article ; Online: Improving the risk-to-benefit ratio of inhaled corticosteroids through delivery and dose: current progress and future directions.

Damiański, Piotr / Kardas, Grzegorz / Panek, Michał / Kuna, Piotr / Kupczyk, Maciej

Expert opinion on drug safety

2021 Volume 21, Issue 4, Page(s) 499–515

Abstract: 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) ...

Abstract	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.
MeSH term(s)	Administration, Inhalation ; Adrenal Cortex Hormones ; Anti-Asthmatic Agents/therapeutic use ; Asthma/drug therapy ; Drug Therapy, Combination ; Humans ; Mometasone Furoate/therapeutic use
Chemical Substances	Adrenal Cortex Hormones ; Anti-Asthmatic Agents ; Mometasone Furoate (04201GDN4R)
Language	English
Publishing date	2021-11-26
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2088728-0
ISSN	1744-764X ; 1474-0338
ISSN (online)	1744-764X
ISSN	1474-0338
DOI	10.1080/14740338.2022.1999926
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Article: Inflammasome signalling pathway in the regulation of inflammation - its involvement in the development and exacerbation of asthma and chronic obstructive pulmonary disease.

Panek, Iga / Liczek, Maciej / Gabryelska, Agata / Rakoczy, Igor / Kuna, Piotr / Panek, Michał

Postepy dermatologii i alergologii

2022 Volume 40, Issue 4, Page(s) 487–495

Abstract: Inflammasomes are multiprotein oligomers, whose main function is the recruitment and activation of caspase-1, which cleaves the precursor forms of interleukin (IL)-1β and IL-18, generating biologically active cytokines. Activation of inflammasome is an ... ...

Abstract	Inflammasomes are multiprotein oligomers, whose main function is the recruitment and activation of caspase-1, which cleaves the precursor forms of interleukin (IL)-1β 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.
Language	English
Publishing date	2022-07-12
Publishing country	Poland
Document type	Journal Article ; Review
ZDB-ID	2596142-1
ISSN	1642-395X
ISSN	1642-395X
DOI	10.5114/ada.2022.118077
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