Upregulation of Notch Signaling and Cell-Differentiation Inhibitory Transcription Factors in Stable Chronic Obstructive Pulmonary Disease Patients.

Notch signaling is involved in the prevention of cell differentiation and cell fate in various organs, including the lungs. We aimed to determine the transcriptomic and protein expression of Notch receptors, their ligands, and related transcription factors in stable COPD. The expression and localization of Notch receptors, their ligands, and related transcription factors were measured in bronchial biopsies of individuals with stable mild/moderate (MCOPD) (n = 18) or severe/very severe (SCOPD) (n = 16) COPD, control smokers (CSs) (n = 13), and control nonsmokers (CNSs) (n = 11), and in the lung parenchyma of those with MCOPD (n = 13), CSs (n = 10), and CNSs (n = 10) using immunohistochemistry, ELISA tests, and transcriptome analyses. In the bronchial biopsies, Notch4 and HES7 significantly increased in the lamina propria of those with SCOPD compared to those with MCOPD, CSs, and CNSs. In the peripheral lung bronchiolar epithelium, Notch1 significantly increased in those with MCOPD and CSs compared to CNSs. ELISA tests of lung parenchyma homogenates showed significantly increased Notch2 in those with MCOPD compared to CSs and CNSs. Transcriptomic data in lung parenchyma showed increased DLL4 and HES1 mRNA levels in those with MCOPD and CSs compared to CNSs. These data show the increased expression of the Notch pathway in the lungs of those with stable COPD. These alterations may play a role in impairing the regenerative-reparative responses of diseased bronchioles and lung parenchyma.

Bone Morphogenic Proteins and Their Antagonists in the Lower Airways of Stable COPD Patients.

BACKGROUND: Bone morphogenic proteins (BMPs) and their antagonists are involved in the tissue development and homeostasis of various organs. OBJECTIVE: To determine transcriptomic and protein expression of BMPs and their antagonists in stable COPD. METHODS: We measured the expression and localization of BMPs and some relevant antagonists in bronchial biopsies of stable mild/moderate COPD (MCOPD) (n = 18), severe/very severe COPD (SCOPD) (n = 16), control smokers (CS) (n = 13), and control non-smokers (CNS) (n = 11), and in lung parenchyma of MCOPD (n = 9), CS (n = 11), and CNS (n = 9) using immunohistochemistry and transcriptome analysis, in vitro after the stimulation of the 16HBE cells. RESULTS: In bronchial biopsies, BMP4 antagonists CRIM1 and chordin were increased in the bronchial epithelium and lamina propria of COPD patients. BMP4 expression was decreased in the bronchial epithelium of SCOPD and MCOPD compared to CNS. Lung transcriptomic data showed non-significant changes between groups. CRIM1 and chordin were significantly decreased in the alveolar macrophages and alveolar septa in COPD patients. External 16HBE treatment with BMP4 protein reduced the bronchial epithelial cell proliferation. CONCLUSIONS: These data show an imbalance between BMP proteins and their antagonists in the lungs of stable COPD. This imbalance may play a role in the remodeling of the airways, altering the regenerative-reparative responses of the diseased bronchioles and lung parenchyma.

Cardiovascular Risk Associated with Alpha-1 Antitrypsin Deficiency (AATD) Genotypes: A Meta-Analysis with Meta-Regressions.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) can result in severe liver and respiratory disorders. The uninhibited elastase activity on the elastic tissue of arterial walls suggests that AATD may also impact vascular health. Thus, we performed a meta-analysis of the studies evaluating cardiovascular risk in individuals with AATD and non-AATD controls. METHODS: A systematic literature search was conducted in the main scientific databases according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Differences between cases and controls were expressed as odds ratios (OR) with 95% confidence intervals (95%CI). The protocol was registered on PROSPERO under the identification number CRD42023429756. RESULTS: The analysis of eight studies showed that, with a prevented fraction of disease of 15.0% and a corresponding OR of 0.779 (95%CI: 0.665-0.912; p = 0.002), a total of 24,428 individuals with AATD exhibited a significantly lower risk of ischemic heart disease compared to 534,654 non-AATD controls. Accordingly, given a prevented fraction of disease of 19.5%, a lower risk of acute myocardial infarction was documented when analyzing four studies on 21,741 cases and 513,733 controls (OR: 0.774; 95%CI: 0.599-0.999; p = 0.049). Sensitivity and subgroup analyses substantially confirmed results. Meta-regression models suggested that these findings were not influenced by AATD genotypes or prevalence of chronic obstructive pulmonary disease (COPD) among cases and controls, while higher differences in the prevalence of male sex (Z-score: 3.40; p < 0.001), hypertension (Z-score: 2.31; p = 0.021), and diabetes (Z-score: 4.25; p < 0.001) were associated with a lower effect size. CONCLUSIONS: Individuals with AATD may exhibit a reduced risk of ischemic heart disease, even in the presence of mild deficiency of the serine protease inhibitor. Although caution is warranted due to the observational nature of the data, future pharmacological and rehabilitation strategies should also take this controversial relationship into account.

Pulmonary rehabilitation and endothelial function in patients with chronic obstructive pulmonary disease: A prospective cohort study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with subclinical atherosclerosis and endothelial dysfunction, thereby leading to increased cardiovascular risk. In the present study, we evaluated the changes in endothelium-dependent flow-mediated dilation (FMD) in a cohort of severe COPD patients undergoing pulmonary rehabilitation. METHODS: Consecutive COPD patients referred to our Pulmonary Rehabilitation Unit were screened for inclusion. All study procedures were performed at hospital admission and discharge. RESULTS: Of 78 patients screened for eligibility, a total of 40 participants (67.5% males, median age 72.5 years) were included. After pulmonary rehabilitation, a significant improvement in functional parameters, exercise capacity, and measures of disability and quality of life were documented. FMD changed from 3.25% (IQR: 2.31-4.26) to 4.95% (IQR: 3.57-6.02), corresponding to a 52.3% increase of its median value (P < 0.001). Significantly lower changes in FMD were documented in COPD patients with hypercholesterolemia as compared to those without (+0.33% ± 1.61 vs. +1.62% ± 1.59, P = 0.037). Changes in FMD (ΔFMD) were positively associated with changes in forced expiratory volume in 1 s (FEV1), when expressed both as absolute values (ΔFEV1) (r = 0.503, P = 0.002) and as percentages of predicted values (ΔFEV1%) (r = 0.608; P < 0.001). In multiple linear regressions, after adjusting for major cardiovascular risk factors, ΔFEV1 (ß=0.342; P = 0.049) and ΔFEV1% (ß=0.480; P = 0.015) were both confirmed as independent predictors of ΔFMD. CONCLUSIONS: Results of our study suggest that endothelial function may improve in COPD after pulmonary rehabilitation. The potential beneficial effect in terms of cardiovascular risk prevention should be evaluated in ad hoc designed studies.

Bacterial load and related innate immune response in the bronchi of rapid decliners with chronic obstructive pulmonary disease.

BACKGROUND: Characterization of COPD patients with rapid lung functional decline is of interest for prognostic and therapeutic reasons. We recently reported an impaired humoral immune response in rapid decliners. OBJECTIVE: To determine the microbiota associated to markers of innate immune host response in COPD patients with rapid lung functional decline. METHODS: In COPD patients monitored for at least 3 years (mean ± SD: 5.8 ± 3 years) for lung functional decline, the microbiota and related markers of immune response was measured in bronchial biopsies of patients with different lung functional decline (rate of FEV1% lung functional decline: no decline FEV1%, ≤20 ml/year n = 21, slow decline FEV1%, >20 ≤ 70 ml/year, n = 14 and rapid decline FEV1%, >70 ml/year, n = 15) using qPCR for microbiota and immunohistochemistry for cell-receptors and inflammatory markers. MAIN RESULTS: Pseudomonas aeruginosa and Streptococcus pneumoniae were increased in rapid decliners vs slow decliners, S. pneumoniae was also increased compared to non decliners. In all patients, S. pneumoniae (copies/ml) positively correlated with pack-years consumption, lung function decline, TLR4, NOD1, NOD2 scored in bronchial epithelium and NOD1/mm2 in lamina propria. CONCLUSION: These data show an imbalance of microbiota components in rapid decliners which is associated to the expression of the related cell-receptors in all COPD patients. These findings may help in the prognostic stratification and treatment of patients.

The Role of High-Flow Nasal Cannula Oxygen Therapy in Exercise Testing and Pulmonary Rehabilitation: A Review of the Current Literature.

High-flow nasal cannula (HFNC) has recently emerged as a crucial therapeutic strategy for hypoxemic patients both in acute and chronic settings. Indeed, HFNC therapy is able to deliver higher fractions of inspired oxygen (FiO2) with a heated and humidified gas flow ranging from 20 up to 60 L per minute, in a more comfortable way for the patient in comparison with Conventional Oxygen Therapy (COT). In fact, the flow keeps the epithelium of the airways adequately moisturized, thus positively affecting the mucus clearance. Finally, the flow is able to wash out the carbon dioxide in the dead space of the airways; this is also enhanced by a modest positive end-expiratory pressure (PEEP) effect. Recent evidence has shown applications of HFNC in exercise training and chronic settings with promising results. In this narrative review, we explored how HFNC might contribute to enhancing outcomes of exercise training and pulmonary rehabilitation among patients dealing with chronic obstructive pulmonary disease, interstitial lung diseases, and lung cancer.

Is It All about Endothelial Dysfunction? Focusing on the Alteration in Endothelial Integrity as a Key Determinant of Different Pathological Mechanisms.

The endothelium is composed of a monolayer of endothelial cells (ECs) covering the inner side of arterial, venous and lymphatic vessels [...].

Decreased humoral immune response in the bronchi of rapid decliners with chronic obstructive pulmonary disease.

BACKGROUND: Identification of COPD patients with a rapid decline in FEV1 is of particular interest for prognostic and therapeutic reasons. OBJECTIVE: To determine the expression of markers of inflammation in COPD patients with rapid functional decline in comparison to slow or no decliners. METHODS: In COPD patients monitored for at least 3 years (mean ± SD: 5.8 ± 3 years) for lung functional decline, the expression and localization of inflammatory markers was measured in bronchial biopsies of patients with no lung functional decline (FEV1% + 30 ± 43 ml/year, n = 21), slow (FEV1% ml/year, - 40 ± 19, n = 14) and rapid decline (FEV1% ml/year, - 112 ± 53, n = 15) using immunohistochemistry. ELISA test was used for polymeric immunoglobulin receptor (pIgR) quantitation "in vitro". RESULTS: The expression of secretory IgA was significantly reduced in bronchial epithelium (p = 0.011) and plasma cell numbers was significantly reduced in the bronchial lamina propria (p = 0.017) of rapid decliners compared to no decliners. Bronchial inflammatory cell infiltration, CD4, CD8, CD68, CD20, NK, neutrophils, eosinophils, mast cells, pIgR, was not changed in epithelium and lamina propria of rapid decliners compared to other groups. Plasma cells/mm2 correlated positively with scored total IgA in lamina propria of all patients. "In vitro" stimulation of 16HBE cells with LPS (10 µg/ml) and IL-8 (10 ng/ml) induced a significant increase while H2O2 (100 µM) significantly decreased pIgR epithelial expression. CONCLUSION: These data show an impaired humoral immune response in rapid decliners with COPD, marked by reduced epithelial secretory IgA and plasma cell numbers in the bronchial lamina propria. These findings may help in the prognostic stratification and treatment of COPD.

Bronchodilator Response as a Possible Predictor of Lung Function Improvement After Pulmonary Rehabilitation in Post-COVID-19 Patients

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Mechanisms and Clinical Implications of Endothelial Dysfunction in Arterial Hypertension.

The endothelium is composed of a monolayer of endothelial cells, lining the interior surface of blood and lymphatic vessels. Endothelial cells display important homeostatic functions, since they are able to respond to humoral and hemodynamic stimuli. Thus, endothelial dysfunction has been proposed as a key and early pathogenic mechanism in many clinical conditions. Given the relevant repercussions on cardiovascular risk, the complex interplay between endothelial dysfunction and systemic arterial hypertension has been a matter of study in recent years. Numerous articles have been published on this issue, all of which contribute to providing an interesting insight into the molecular mechanisms of endothelial dysfunction in arterial hypertension and its role as a biomarker of inflammation, oxidative stress, and vascular disease. The prognostic and therapeutic implications of endothelial dysfunction have also been analyzed in this clinical setting, with interesting new findings and potential applications in clinical practice and future research. The aim of this review is to summarize the pathophysiology of the relationship between endothelial dysfunction and systemic arterial hypertension, with a focus on the personalized pharmacological and rehabilitation strategies targeting endothelial dysfunction while treating hypertension and cardiovascular comorbidities.

Endothelial Dysfunction in COVID-19: A Unifying Mechanism and a Potential Therapeutic Target.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) generated a worldwide emergency, until the declaration of the pandemic in March 2020. SARS-CoV-2 could be responsible for coronavirus disease 2019 (COVID-19), which goes from a flu-like illness to a potentially fatal condition that needs intensive care. Furthermore, the persistence of functional disability and long-term cardiovascular sequelae in COVID-19 survivors suggests that convalescent patients may suffer from post-acute COVID-19 syndrome, requiring long-term care and personalized rehabilitation. However, the pathophysiology of acute and post-acute manifestations of COVID-19 is still under study, as a better comprehension of these mechanisms would ensure more effective personalized therapies. To date, mounting evidence suggests a crucial endothelial contribution to the clinical manifestations of COVID-19, as endothelial cells appear to be a direct or indirect preferential target of the virus. Thus, the dysregulation of many of the homeostatic pathways of the endothelium has emerged as a hallmark of severity in COVID-19. The aim of this review is to summarize the pathophysiology of endothelial dysfunction in COVID-19, with a focus on personalized pharmacological and rehabilitation strategies targeting endothelial dysfunction as an attractive therapeutic option in this clinical setting.

Cardiopulmonary Exercise Performance and Endothelial Function in Convalescent COVID-19 Patients.

BACKGROUND: Endothelial dysfunction has been proposed as the common pathogenic background of most manifestations of coronavirus disease 2019 (COVID-19). Among these, some authors also reported an impaired exercise response during cardiopulmonary exercise testing (CPET). We aimed to explore the potential association between endothelial dysfunction and the reduced CPET performance in COVID-19 survivors. METHODS: 36 consecutive COVID-19 survivors underwent symptom-limited incremental CPET and assessment of endothelium-dependent flow-mediate dilation (FMD) according to standardized protocols. RESULTS: A significantly higher FMD was documented in patients with a preserved, as compared to those with a reduced, exercise capacity (4.11% ± 2.08 vs. 2.54% ± 1.85, p = 0.048), confirmed in a multivariate analysis (ß = 0.899, p = 0.038). In the overall study population, FMD values showed a significant Pearson's correlation with two primary CPET parameters, namely ventilation/carbon dioxide production (VE/VCO2) slope (r = -0.371, p = 0.026) and end-tidal carbon dioxide tension (PETCO2) at peak (r = 0.439, p = 0.007). In multiple linear regressions, FMD was the only independent predictor of VE/VCO2 slope (ß = -1.308, p = 0.029) and peak PETCO2 values (ß = 0.779, p = 0.021). Accordingly, when stratifying our study population based on their ventilatory efficiency, patients with a ventilatory class III-IV (VE/VCO2 slope ≥ 36) exhibited significantly lower FMD values as compared to those with a ventilatory class I-II. CONCLUSIONS: The alteration of endothelial barrier properties in systemic and pulmonary circulation may represent a key pathogenic mechanism of the reduced CPET performance in COVID-19 survivors. Personalized pharmacological and rehabilitation strategies targeting endothelial function may represent an attractive therapeutic option.

Bacterial and viral infections and related inflammatory responses in chronic obstructive pulmonary disease.

In chronic obstructive pulmonary disease (COPD) patients, bacterial and viral infections play a relevant role in worsening lung function and, therefore, favour disease progression. The inflammatory response to lung infections may become a specific indication of the bacterial and viral infections. We here review data on the bacterial-viral infections and related airways and lung parenchyma inflammation in stable and exacerbated COPD, focussing our attention on the prevalent molecular pathways in these different clinical conditions. The roles of macrophages, autophagy and NETosis are also briefly discussed in the context of lung infections in COPD. Controlling their combined response may restore a balanced lung homeostasis, reducing the risk of lung function decline. KEY MESSAGE Bacteria and viruses can influence the responses of the innate and adaptive immune system in the lung of chronic obstructive pulmonary disease (COPD) patients. The relationship between viruses and bacterial colonization, and the consequences of the imbalance of these components can modulate the inflammatory state of the COPD lung. The complex actions involving immune trigger cells, which activate innate and cell-mediated inflammatory responses, could be responsible for the clinical consequences of irreversible airflow limitation, lung remodelling and emphysema in COPD patients.

A case scenario study on adherence to COPD GOLD recommendations by general practitioners in a rural area of southern Italy: The "progetto PADRE".

The aim of the present study was to evaluate in a sample of 200 patients diagnosed with COPD and selected from the physician database of 15 general practices from Valle Telesina (Benevento, Italy) if the diagnostic-therapeutic algorithm adopted by GPs operating in a non-urban district in Southern Italy adhered to GOLD 2018 recommendations for COPD. Each patient underwent a specialist visit by an experienced chest physician that collected anamnesis, assessed mMRC and CAT scores, and performed a spirometry. In case of diagnostic doubt, a second visit was performed at the Pulmonary Rehabilitation Unit of the Istituti Clinici Scientifici Maugeri IRCCS in Telese Terme where other diagnostic tests were performed. Our results showed that GPs participating in the study often diagnosed and empirically treated COPD without a confirmative spirometry or even despite a spirometry that was not diagnostic of obstructive lung disease. Furthermore, real-life implementation of GOLD strategy, as regards patients' ABCD categorization, was poor and many patients belonging to groups A and B (39% and 48%, respectively) were over-treated and 19% of those belonging to group D were under-treated. The discrepancy between guidelines and daily clinical practice present also in this study supports the opinion of many that those who develop guidelines for the management of COPD must seriously try to understand if and why the guidelines might not reflect real life and therefore how it could be improved.

Bacterial-viral load and the immune response in stable and exacerbated COPD: significance and therapeutic prospects.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and an abnormal inflammatory response of the lung. Bacteria and viruses are a major cause of COPD exacerbations and may contribute to COPD progression by perpetuating the inflammatory response in the airways. Bacterial variety diminishes with increasing COPD severity. Respiratory viruses can colonize the lower respiratory tract in stable COPD, altering the respiratory microbiome and facilitating secondary bacterial infections. In this review, we present the most updated information about the role of bacteria and viruses in stable and exacerbated COPD. In our opinion, to optimize therapeutic strategies, the dynamic events involving bacterial-viral infections and related immune response in COPD phenotypes need to be better clarified. Our paper would address these points that we consider of great importance for the clinical management of COPD.

Hsp10 nuclear localization and changes in lung cells response to cigarette smoke suggest novel roles for this chaperonin.

Heat-shock protein (Hsp)10 is the co-chaperone for Hsp60 inside mitochondria, but it also resides outside the organelle. Variations in its levels and intracellular distribution have been documented in pathological conditions, e.g. cancer and chronic obstructive pulmonary disease (COPD). Here, we show that Hsp10 in COPD undergoes changes at the molecular and subcellular levels in bronchial cells from human specimens and derived cell lines, intact or subjected to stress induced by cigarette smoke extract (CSE). Noteworthy findings are: (i) Hsp10 occurred in nuclei of epithelial and lamina propria cells of bronchial mucosa from non-smokers and smokers; (ii) human bronchial epithelial (16HBE) and lung fibroblast (HFL-1) cells, in vitro, showed Hsp10 in the nucleus, before and after CSE exposure; (iii) CSE stimulation did not increase the levels of Hsp10 but did elicit qualitative changes as indicated by molecular weight and isoelectric point shifts; and (iv) Hsp10 nuclear levels increased after CSE stimulation in HFL-1, indicating cytosol to nucleus migration, and although Hsp10 did not bind DNA, it bound a DNA-associated protein.

High-resolution computed tomography quantitation of emphysema is correlated with selected lung function values in stable COPD.

BACKGROUND: The literature shows conflicting results when high-resolution computed tomography (HRCT) scores of emphysema were correlated with different indices of airflow obstruction. OBJECTIVES: We correlated HRCT scores of emphysema with different indices of airflow obstruction. METHODS: We performed HRCT of the chest in 59 patients, all smokers or ex-smokers, with stable chronic obstructive pulmonary disease of different severity [GOLD stages I-IV; mean age ± SD 67.8 ± 7.3 years; pack/years 51.0 ± 34.6; percent predicted forced expiratory volume in 1 s (FEV(1)% predicted) 52.3 ± 17.6; post-bronchodilator FEV(1)% predicted 56.5 ± 19.1; FEV(1)/forced vital capacity (FVC) ratio 50.8 ± 10.2; post-bronchodilator FEV(1)/FVC ratio 51.6 ± 11.0; percent diffusion lung capacity for carbon monoxide (DLCO%) 59.2 ± 21.1; DLCO/percent alveolar volume (VA%) 54.5 ± 18.2; percent residual volume 163.0 ± 35.6; percent total lung capacity (TLC%) 113.2 ± 15; residual volume/TLC 1.44 ± 0.2]. All patients were in stable phase. RESULTS: The mean ± SD visual emphysema score in all patients was 25.6 ± 25.4%. There was a weak but significant correlation between the percentage of pulmonary emphysema and numbers of pack/years (R = +0.31, p = 0.024). The percentage of emphysema was inversely correlated with the FEV(1)/FVC ratio before and after bronchodilator use (R = -0.44, p = 0.002, and R = -0.39, p = 0.005), DLCO% (R = -0.64, p = 0.0003) and DLCO/VA% (R = -0.68, p < 0.0001). A weak positive correlation was also found with TLC% (R = +0.28, p = 0.048). When patients with documented emphysema were considered separately, the best significant correlation observed was between DLCO/VA% and HRCT scan score (p = 0.007). CONCLUSIONS: These data suggest that in patients with stable chronic obstructive pulmonary disease of varying severity, the presence of pulmonary emphysema is best represented by the impaired gas exchange capability of the respiratory system.

Convergent sets of data from in vivo and in vitro methods point to an active role of Hsp60 in chronic obstructive pulmonary disease pathogenesis.

BACKGROUND: It is increasingly clear that some heat shock proteins (Hsps) play a role in inflammation. Here, we report results showing participation of Hsp60 in the pathogenesis of chronic obstructive pulmonary diseases (COPD), as indicated by data from both in vivo and in vitro analyses. METHODS AND RESULTS: Bronchial biopsies from patients with stable COPD, smoker controls with normal lung function, and non-smoker controls were studied. We quantified by immunohistochemistry levels of Hsp10, Hsp27, Hsp40, Hsp60, Hsp70, Hsp90, and HSF-1, along with levels of inflammatory markers. Hsp10, Hsp40, and Hsp60 were increased during progression of disease. We found also a positive correlation between the number of neutrophils and Hsp60 levels. Double-immunostaining showed that Hsp60-positive neutrophils were significantly increased in COPD patients. We then investigated in vitro the effect on Hsp60 expression in bronchial epithelial cells (16HBE) caused by oxidative stress, a hallmark of COPD mucosa, which we induced with H2O2. This stressor determined increased levels of Hsp60 through a gene up-regulation mechanism involving NFkB-p65. Release of Hsp60 in the extracellular medium by the bronchial epithelial cells was also increased after H2O2 treatment in the absence of cell death. CONCLUSIONS: This is the first report clearly pointing to participation of Hsps, particularly Hsp60, in COPD pathogenesis. Hsp60 induction by NFkB-p65 and its release by epithelial cells after oxidative stress can have a role in maintaining inflammation, e.g., by stimulating neutrophils activity. The data open new scenarios that might help in designing efficacious anti-inflammatory therapies centered on Hsp60 and applicable to COPD.