IL-33/ST2 Axis in Organ Fibrosis

Interleukin 33 (IL-33) is highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 receptor (ST2). IL-33/ST2 axis has long been known to play a pivotal role in immunity and cell homeostasis by promoting wound healing and tissue repair. However, it is also involved in the loss of balance between extensive inflammation and tissue regeneration lead to remodeling, the hallmark of fibrosis. The aim of the current review is to critically evaluate the available evidence regarding the role of the IL-33/ST2 axis in organ fibrosis. The role of the axis in tissue remodeling is better understood considering its crucial role reported in organ development and regeneration. Generally, the IL-33/ST2 signaling pathway has mainly anti-inflammatory/anti-proliferative effects; however, chronic tissue injury is responsible for pro-fibrogenetic responses. Regarding pulmonary fibrosis mature IL-33 enhances pro-fibrogenic type 2 cytokine production in an ST2- and macrophage-dependent manner, while full-length IL-33 is also implicated in the pulmonary fibrotic process in an ST2-independent, Th2-independent fashion. In liver fibrosis, evidence indicate that when acute and massive liver damage occurs, the release of IL-33 might act as an activator of tissue-protective mechanisms, while in cases of chronic injury IL-33 plays the role of a hepatic fibrotic factor. IL-33 signaling has also been involved in the pathogenesis of acute and chronic pancreatitis. Moreover, IL-33 could be used as an early marker for ulcer-associated activated fibroblasts and myofibroblast trans-differentiation; thus one cannot rule out its potential role in inflammatory bowel disease-associated fibrosis. Similarly, the upregulation of the IL-33/ST2 axismay contribute to tubular cell injury and fibrosis via epithelial to mesenchymal transition (EMT) of various cell types in the kidneys. Of note, IL-33 exerts a cardioprotective role via ST2 signaling, while soluble ST2 has been demonstrated as a marker of myocardial fibrosis. Finally, IL-33 is a crucial cytokine in skin pathology responsible for abnormal fibroblast proliferation, leukocyte infiltration and morphologic differentiation of human endothelial cells. Overall, emerging data support a novel contribution of the IL-33/ST2 pathway in tissue fibrosis and highlight the significant role of the Th2 pattern of immune response in the pathophysiology of organ fibrosis

Calprotectin in lung diseases

Calprotectin (CLP) is a heterodimer formed by two S-100 calcium-binding cytosolic proteins, S100A8 and S100A9. It is a multifunctional protein expressed mainly by neutrophils and released extracellularly by activated or damaged cells mediating a broad range of physiological and pathological responses. It has been more than 20 years since the implication of S100A8/A9 in the inflammatory process was shown; however, the evaluation of its role in the pathogenesis of respiratory diseases or its usefulness as a biomarker for the appropriate diagnosis and prognosis of lung diseases have only gained attention in recent years. This review aimed to provide current knowledge regarding the potential role of CLP in the pathophysiology of lung diseases and describe how this knowledge is, up until now, translated into daily clinical practice. CLP is involved in numerous cellular processes in lung health and disease. In addition to its anti-microbial functions, CLP also serves as a molecule with pro- and anti-tumor properties related to cell survival and growth, angiogenesis, DNA damage response, and the remodeling of the extracellular matrix. The findings of this review potentially introduce CLP in daily clinical practice within the spectrum of respiratory diseases

Work place and prevalence of COVID-19 in a rural population in Greece

Introduction: Coronavirus disease-19 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a global pandemic, giving rise to a serious global health threat. Many countries including Greece have seen a two-wave pattern of reported cases, with a first wave in spring and a second in autumn of 2020. Methods: A cross-sectional seroprevalence study was designed to measure the prevalence of IgG antibodies with a quantitative SARS-CoV-2 IgG lab-based serology test, chemiluminescent microparticle immunoassay, against novel coronavirus in rural areas in Greece after the second pandemic wave. The study was conducted on 29 January 2021 in a rural semi-closed area, the municipality of Deskati, prefecture of western Macedonia in Greece after the second pandemic wave. Results: Sixty-nine participants were included in this study. The present study demonstrated a high prevalence of COVID-19 infection (31 of 69 total participants; 45%) and those who were working in the public sector were at higher risk of COVID-19 infection in comparison to their counterparts in private sector (p=0.05364), (relative risk 2.64; 95% confidence interval 1.001-7.086). Conclusion: The study presents data showing a high prevalence of herd immunity for COVID-19 in a semi-closed area in Greece. These findings might help to understand the characteristics of this second wave, the behaviour and danger of SARS-CoV-2 in rural areas in Greece and Europe generally

Repeated Antigen-Based Rapid Diagnostic Testing for Estimating the Coronavirus Disease 2019 Prevalence from the Perspective of the Workers’ Vulnerability before and during the Lockdown

Background: No previous study has investigated the SARS-CoV-2 prevalence and the changes in the proportion of positive results due to lockdown measures from the angle of workers’ vulnerability to coronavirus in Greece. Two community-based programs were implemented to evaluate the SARS-CoV-2 prevalence and investigate if the prevalence changes were significant across various occupations before and one month after lockdown. Methods: Following consent, sociodemographic, clinical, and job-related information were recorded. The VivaDiag™ SARS-CoV-2 Antigen Rapid Test was used. Positive results confirmed by a real-time Reverse Transcriptase Polymerase Chain Reaction for SARS-COV-2. Results: Positive participants were more likely to work in the catering/food sector than negative participants before the lockdown. Lockdown restrictions halved the new cases. No significant differences in the likelihood of being SARS-CoV-2 positive for different job categories were detected during lockdown. The presence of respiratory symptoms was an independent predictor for rapid antigen test positivity; however, one-third of newly diagnosed patients were asymptomatic at both time points. Conclusions: The catering/food sector was the most vulnerable to COVID-19 at the pre-lockdown evaluation. We highlight the crucial role of community-based screening with rapid antigen testing to evaluate the potential modes of community transmission and the impact of infection control strategies

Calprotectin in Lung Diseases

Calprotectin (CLP) is a heterodimer formed by two S-100 calcium-binding cytosolic proteins, S100A8 and S100A9. It is a multifunctional protein expressed mainly by neutrophils and released extracellularly by activated or damaged cells mediating a broad range of physiological and pathological responses. It has been more than 20 years since the implication of S100A8/A9 in the inflammatory process was shown; however, the evaluation of its role in the pathogenesis of respiratory diseases or its usefulness as a biomarker for the appropriate diagnosis and prognosis of lung diseases have only gained attention in recent years. This review aimed to provide current knowledge regarding the potential role of CLP in the pathophysiology of lung diseases and describe how this knowledge is, up until now, translated into daily clinical practice. CLP is involved in numerous cellular processes in lung health and disease. In addition to its anti-microbial functions, CLP also serves as a molecule with pro- and anti-tumor properties related to cell survival and growth, angiogenesis, DNA damage response, and the remodeling of the extracellular matrix. The findings of this review potentially introduce CLP in daily clinical practice within the spectrum of respiratory diseases

Determination of the concentration of HMGB1 and IL-33 along with their respective receptors sRAGE and sST2 in pleural fluids of patients with pleural effusion of various aetiologies

Interleukin 33 (IL-33) is a nuclear cytokine from the IL-1 family which is constitutively highly expressed in barrier sites, acting via the suppression of tumorigenicity 2 (ST2) receptor. On the other hand, high-mobility group box 1 protein (HMGB1) is a chromosomal multifunctional redox sensitive protein. Many actions of HMGB1 are mediated through the receptor for advanced glycation endproducts (RAGE). Both molecules serve various roles in different cellular compartments. Extracellularly, they act as alarmins with multiple roles in immunity and cell homeostasis. Productions of IL-33, HMGB1 and soluble forms of the receptors (sST2 and sRAGE, respectively) have been implicated in several pulmonary diseases. Both axes have been scarcely investigated in pleural diseases. The aims of this thesis were to determine the levels of IL-33 and sST2 as well as ΗΜGB1 and sRAGE in transudative (TrPEs), malignant (MPEs) and parapneumonic (PPEs) pleural effusions (PEs) and investigate the effect of PE fluids with low and high IL-33 or HMGB1 levels on MeT-5A cell adhesion, migration and sphere formation. Further, recombinant IL-33 and HMGB1 were separately used to assess effects on MeT-5A adhesion, migration and sphere formation. IL-33 and sST2 levels were similar among TrPEs, MPEs and PPEs. However, HMGB1 and sRAGE levels were significantly higher and lower, respectively in exudative pleural effusions compared to TrPEs. HMGB1 and sRAGE levels can effectively discriminate transudates from exudates. Remarkably, HMGB1 and sRAGE levels are differentiated between various PEs in an age-dependent manner. A significant positive correlation was found between IL-33 and LDH in TrPEs and between IL-33 and red blood cells (RBCs) in MPEs, while sST2 correlated with lymphocytes in TrPEs. HMGB1 was positively correlated with RBCs and lymphocytes in MPEs. No correlation was found between sRAGE and cellular or specific biochemical characteristics of PEs. Furthermore, we found that in exudates (MPEs and PPEs) high or low levels of IL-33 had significant differential effects on MeT-5A adhesion and migration, while no effect in both cell 33 phenotypes was determined for TrPEs. Further, based on etiology high or low levels of HMGB1 have differential effects on mesothelial cell adhesion, migration and sphere formation. Moreover, significantly decreased MeT-5A cell migration was found when higher concentrations of recombinant IL-33 were used. 50 ng/mL and 100ng/mL of recombinant HMGB1 significantly decreased cell adhesion and sphere size, respectively. These results highlight the emerging role of the IL-33/ST2 and HMGB1/sRAGE axes in pathophysiology of pleural disease. However, further research to improve our understanding of both signaling pathways in pleural homeostasis and disease will be essential to translate aforementioned findings into clinical practice and be able to predict benefits and risks of evolving therapies.Τόσο η ιντερλευκίνη (IL)-33 όσο και η η πρωτεΐνη υψηλής κινητικότητας της ομάδας Β1 (HMGB1) συνιστούν πολυλειτουργικές πρωτεΐνες που εκφράζονται ιδιοσυστατικά στα κύτταρα των ιστικών φραγμών. Σηματοδοτούν μέσω του υποδοχέα καταστολής της ογκογένεσης 2 (ST2) και του υποδοχέα για τα τελικά προϊόντα προχωρημένης μη ενζυματικής γλυκοζυλίωσης (RAGE), αντίστοιχα. Ο ρόλος των δυο πρωτεϊνών διαφοροποιείται ανάλογα με το κυτταρικό διαμέρισμα στο οποίο εδράζονται. Εξωκυτταρίως, δρουν ως DAMPs (μοριακά πρότυπα σχετιζόμενα με καταστροφή) ή αλαρμίνες, διαδραματίζοντας καθοριστικό ρόλο στην κυτταρική ομοιόσταση, ιστική επισκευή και αναδιαμόρφωση. Η ενδοκυττάρια σήμανση παρεμποδίζεται από την παγίδευση των IL-33 και HMGB1 από τις διαλυτές εξωκυττάριες ισομορφές sST2 και sRAGE, αντίστοιχα. Τόσο οι αλαρμίνες IL-33 και HMGB1 όσο και οι διαλυτές ισομορφές των υποδοχέων τους, sST2 και sRAGE αντίστοιχα, εμπλέκονται στην παθοφυσιολογία πολλών νοσημάτων του αναπνευστικού συστήματος. Εντούτοις, ο ρόλος τους στα νοσήματα του υπεζωκότα είναι ελάχιστα μελετημένος. Οι κυριότεροι στόχοι της παρούσας διατριβής ήταν πρώτον ο προσδιορισμός της συγκέντρωσης των IL-33 και HMGB1 καθώς και των διαλυτών υποδοχέων τους σε διιδρωματικές, κακοήθεις και παραπνευμονικές υπεζωκοτικές συλλογές (ΥΣ). Δεύτερον, η διερεύνηση της in vitro επίδρασης των χαμηλών και υψηλών συγκεντρώσεων των IL-33 και HMGB1 από κάθε τύπο ΥΣ, σε τρεις σημαντικούς κυτταρικούς φαινότυπους που εμπλέκονται στην ιστική αναδιαμόρφωση. Συγκεκριμένα μελετήθηκαν η κυτταρική προσκόλληση, κυτταρική μετανάστευση και ικανότητα σχηματισμού σφαιροειδών σε κυτταρική σειρά καλοήθων μεσοθηλιακών κυττάρων MeT-5A. Τέλος, αξιολογήθηκε η επίδραση της χρήσης ανασυνδυασμένων IL-33 και HMGB1 στους τρεις ανωτέρω κυτταρικούς φαινότυπους με χρήση κυτταρικής σειράς MeT-5A. Από την παρούσα μελέτη προέκυψε ότι δεν υπήρχαν σημαντικές διαφορές στη συγκέντρωση των IL-33 και sST2 μεταξύ των διιδρωματικών, κακοήθων και παραπνευμονικών ΥΣ. Αξιοσημείωτα, τα επίπεδα της HMGB1 και sRAGΕ φάνηκε πως μπορούν να διακρίνουν αποτελεσματικά τα διιδρώματα από τα εξιδρώματα με οριακές τιμές (cut-off values) που χαρακτηρίζονται από υψηλή ευαισθησία και ειδικότητα. Επιπρόσθετα, παρατηρήθηκε μια εξαρτώμενη από την ηλικία διαφοροποίηση των επιπέδων HMGB1 και sRAGE στις ΥΣ. Πιθανολογείται ότι η IL-33 συνιστά προϊόν τραυματισμού και δείκτη κυτταρικού στρες των μεσοθηλιακών κυττάρων στις διιδρωματικές ΥΣ, ενώ στις κακοήθεις ΥΣ προϊόν αιμόλυσης. Επίσης, εικάζεται ότι η ΗΜGB1 συνιστά προϊόν των ερυθρών αιμοσφαιρίων και των λεμφοκυττάρων στις κακοήθεις ΥΣ. Όσον αφορά τις in vitro επιδράσεις των χαμηλών και υψηλών συγκεντρώσεων IL-33 και HMGB1 στην κυτταρική προσκόλληση, μετανάστευση και ικανότητα σχηματισμού κυτταρικών σφαιροειδών, τα αποτελέσματα διαφοροποιήθηκαν σημαντικά ανάλογα με το χρόνο της φλεγμονώδους διαδικασίας και τον τύπο της ΥΣ. Τέλος, όσον αφορά τις in vitro επιδράσεις της ανασυνδυασμένης ΙL-33, παρατηρήθηκε ότι η κυτταρική μετανάστευση των καλοήθων μεσοθηλιακών κυττάρων μειώθηκε με δοσοεξαρτώμενο τρόπο (στατιστικά σημαντικά αποτελέσματα για τιμές >1 ng/mL). Η χρήση ανασυνδυασμένης HMGB1 σε συγκέντρωση 50 ng/mL μείωσε σημαντικά την κυτταρική προσκόλληση και σε συγκεντρώσεις ίσες ή μεγαλύτερες των 100 ng/mL μειώσε σημαντικά την περίμετρο κυτταρικών σφαιροειδών. Τα ευρημάτα μας υπογραμμίζουν έναν αναδυόμενο ρόλο των σηματοδοτικών αξόνων IL-33/sST2 και HMGB1/sRAGE στην παθοφυσιολογία των μελετούμενων ΥΣ. Φαίνεται πως είτε αυτόνομα είτε και σε συνδυασμό με άλλα σηματοδοτικά μόρια επιδρούν στους επιδιορθωτικούς μηχανισμούς της τραυματισμένης μεσοθηλιακής στιβάδας όπως στην κυτταρική προσκόλληση, μετανάστευση και ικανότητα σχηματισμού σφαιροειδών. Η σε βάθος κατανόηση του ρόλου των αλαρμινών σε μηχανισμούς ιστικής επιδιόρθωσης μπορεί να βοηθήσει στην ανάπτυξη νέων στοχευμένων θεραπειών τόσο στην οξεία όσο και στη χρόνια νόσο του υπεζωκότα

Cutting-Edge Approaches in Respiratory and Critical Care Medicine

The COVID-19 pandemic has affected health care across the world, with respiratory and critical care medicine being affected the most [...

The Role of Small Airway Disease in Pulmonary Fibrotic Diseases

Small airway disease (SAD) is a pathological condition that affects the bronchioles and non-cartilaginous airways 2 mm or less in diameter. These airways play a crucial role in respiratory function and are often implicated in various pulmonary disorders. Pulmonary fibrotic diseases are characterized by the thickening and scarring of lung tissue, leading to progressive respiratory failure. We aimed to present the link between SAD and fibrotic lung conditions. The evidence suggests that SAD may act as a precursor or exacerbating factor in the progression of fibrotic diseases. Patients with fibrotic conditions often exhibit signs of small airway dysfunction, which can contribute to worsening respiratory symptoms and decreased lung function. Moreover, individuals with advanced SAD are at a heightened risk of developing fibrotic changes in the lung. The interplay between inflammation, environmental factors, and genetic predisposition further complicates this association. The early detection and management of SAD can potentially mitigate the progression of fibrotic diseases, highlighting the need for comprehensive clinical evaluation and research. This review emphasizes the need to understand the evolving connection between SAD and pulmonary fibrosis, urging further detailed research to clarify the causes and potential treatment between the two entities

Estimates of COVID-19 Risk Factors among Social Strata and Predictors for a Vulnerability to the Infection

Coronavirus disease 2019 (COVID-19) has emerged as a potentially severe disease, especially for individuals presenting with certain underlying medical conditions. We analyzed the rates of comorbidities and symptoms to reveal the potential severity of the pandemic in Volos, one of the most air-polluted cities in Greece. Environmental and health-related predictors for SARS-CoV-2 infection were investigated. A web-based questionnaire was disseminated through social media in the first half of March 2021 during a five-month strict lockdown. Sociodemographic data, preexisting medical conditions, frequency of clinical symptoms, and COVID-19 information were recorded. The study population consisted of 2000 responders. Four-fifths of the participants reported comorbidities that could increase vulnerability to severe COVID-19. Respiratory symptoms were reported from the unemployed and from retirees, and cold-related symptoms were reported in the education sector and in undergraduates. Women and younger generations shaped social vulnerability to respiratory infections similar to the elderly. SARS-CoV-2 infection was reported in 3.7% of the study population. Common headache (OR 2; CI 1189–3013; p = 0.007) and prior pneumonia (OR 1.9; CI 1024–2898; p = 0.04) were significant predictors for susceptibility to SARS-CoV-2 infection. The importance of monitoring society through community-based questionnaires is highlighted, for predicting and preventing future widespread transmission of infectious diseases