Arsenic exposure and pulmonary function decline: Potential mediating role of TRAIL in chronic obstructive pulmonary disease patients.

BACKGROUND: Environmental arsenic (As) exposure is strongly related to the progression of chronic obstructive pulmonary disease (COPD). Pulmonary epithelial cells apoptosis is implicated in the pathophysiological mechanisms of COPD. However, the role of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), one biomarker of apoptosis, remains unclear in As-mediated pulmonary function alternations in COPD patients. METHODS: This study included 239 COPD patients. The serum level of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) was measured by enzyme-linked immunosorbent assay (ELISA). The blood As level was determined through inductively coupled plasma mass spectrometry (ICP-MS). RESULTS: Blood As levels exhibited a negative and dose-dependent correlation with pulmonary function. Per unit elevation of blood arsenic concentrations was related to reductions of 0.339 L in FEV1, 0.311 L in FVC, 1.171% in FEV1/FVC%, and 7.999% in FEV1% in COPD subjects. Additionally, a positive dose-response correlation of blood As with serum TRAIL was found in COPD subjects. Additionally, the level of serum TRAIL was negatively linked to lung function. Elevated TRAIL significantly mediated As-induced decreases of 11.05%, 13.35%, and 31.78% in FVC, FEV1, and FEV1%, respectively among the COPD patients. CONCLUSION: Blood As level is positively correlated with pulmonary function decline and serum TRAIL increase in individuals with COPD. Our findings suggest that elevated TRAIL levels may serve as a mediating mechanism through which As contributes to declining lung function in COPD patients.

Alterations in the molecular control of mitochondrial turnover in COPD lung and airway epithelial cells.

Abnormal mitochondria have been observed in bronchial- and alveolar epithelial cells of patients with chronic obstructive pulmonary disease (COPD). However, it is unknown if alterations in the molecular pathways regulating mitochondrial turnover (mitochondrial biogenesis vs mitophagy) are involved. Therefore, in this study, the abundance of key molecules controlling mitochondrial turnover were assessed in peripheral lung tissue from non-COPD patients (n = 6) and COPD patients (n = 11; GOLDII n = 4/11; GOLDIV n = 7/11) and in both undifferentiated and differentiated human primary bronchial epithelial cells (PBEC) from non-COPD patients and COPD patients (n = 4-7 patients/group). We observed significantly decreased transcript levels of key molecules controlling mitochondrial biogenesis (PPARGC1B, PPRC1, PPARD) in peripheral lung tissue from severe COPD patients. Interestingly, mRNA levels of the transcription factor TFAM (mitochondrial biogenesis) and BNIP3L (mitophagy) were increased in these patients. In general, these alterations were not recapitulated in undifferentiated and differentiated PBECs with the exception of decreased PPARGC1B expression in both PBEC models. Although these findings provide valuable insight in these pathways in bronchial epithelial cells and peripheral lung tissue of COPD patients, whether or not these alterations contribute to COPD pathogenesis, underlie changes in mitochondrial function or may represent compensatory mechanisms remains to be established.

Lianhua Qingke Preserves Mucociliary Clearance in Rat with Acute Exacerbation of Chronic Obstructive Pulmonary Disease by Maintaining Ciliated Cells Proportion and Protecting Structural Integrity and Beat Function of Cilia.

Purpose: Acute Exacerbation of Chronic Obstructive Pulmonary Disease (AECOPD) is a sudden worsening of symptoms in patients with Chronic Obstructive Pulmonary Disease (COPD), such as cough, increased sputum volume, and sputum purulence. COPD and AECOPD are characterized by damage to cilia and increased mucus secretion. Mucociliary clearance (MCC) functions as part of the primary innate system of the lung to remove harmful particles and pathogens together with airway mucus and is therefore crucial for patients with COPD. Methods: AECOPD was induced by cigarette smoke exposure (80 cigarettes/day, 5 days/week for 12 weeks) and lipopolysaccharide (LPS) instillation (200 µg, on days 1, 14, and 84). Rats administered Lianhua Qingke (LHQK) (0.367, 0.732, and 1.465 g/kg/d) or Eucalyptol, Limonene, and Pinene Enteric Soft Capsules (ELP, 0.3 g/kg/d) intragastrically. Pulmonary pathology, Muc5ac+ goblet cell and ß-tubulin IV+ ciliated cells, and mRNA levels of forkhead box J1 (Foxj1) and multiciliate differentiation and DNA synthesis associated cell cycle protein (MCIDAS) were assessed by hematoxylin and eosin staining, immunofluorescence staining, and RT-qPCR, respectively. Ciliary morphology and ultrastructure were examined through scanning electron microscopy and transmission electron microscopy. Ciliary beat frequency (CBF) was recorded using a high-speed camera. Results: Compared to the model group, LHQK treatment groups showed a reduction in inflammatory cell infiltration, significantly reduced goblet cell and increased ciliated cell proportion. LHQK significantly upregulated mRNA levels of MCIDAS and Foxj1, indicating promoted ciliated cell differentiation. LHQK protected ciliary structure and maintained ciliary function via increasing the ciliary length and density, reducing ciliary ultrastructure damage, and ameliorating random ciliary oscillations, consequently enhancing CBF. Conclusion: LHQK enhances the MCC capability of ciliated cells in rat with AECOPD by preserving the structural integrity and beating function of cilia, indicating its therapeutic potential on promoting sputum expulsion in patients with AECOPD.

The role of extracellular vesicles in COPD and potential clinical value.

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung disease and a major health burden worldwide. Extracellular vesicles (EVs) are nanosized vesicles which possess a lipid bilayer structure that are secreted by various cells. They contain a variety of bioactive substances, which can regulate various physiological and pathological processes and are closely related to the development of diseases. Recently, EVs have emerged as a novel tool for intercellular crosstalk, which plays an essential role in COPD development. This paper reviews the role of EVs in the development of COPD and their potential clinical value, in order to provide a reference for further research on COPD.

Chronic aryl hydrocarbon receptor activity impairs muscle mitochondrial function with tobacco smoking.

BACKGROUND: Accumulating evidence has demonstrated that chronic tobacco smoking directly contributes to skeletal muscle dysfunction independent of its pathological impact to the cardiorespiratory systems. The mechanisms underlying tobacco smoke toxicity in skeletal muscle are not fully resolved. In this study, the role of the aryl hydrocarbon receptor (AHR), a transcription factor known to be activated with tobacco smoke, was investigated. METHODS: AHR related gene (mRNA) expression was quantified in skeletal muscle from adult controls and patients with chronic obstructive pulmonary disease (COPD), as well as mice with and without cigarette smoke exposure. Utilizing both skeletal muscle-specific AHR knockout mice exposed to chronic repeated (5 days per week for 16 weeks) cigarette smoke and skeletal muscle-specific expression of a constitutively active mutant AHR in healthy mice, a battery of assessments interrogating muscle size, contractile function, mitochondrial energetics, and RNA sequencing were employed. RESULTS: Skeletal muscle from COPD patients (N = 79, age = 67.0 ± 8.4 years) had higher levels of AHR (P = 0.0451) and CYP1B1 (P < 0.0001) compared to healthy adult controls (N = 16, age = 66.5 ± 6.5 years). Mice exposed to cigarette smoke displayed higher expression of Ahr (P = 0.008), Cyp1b1 (P < 0.0001), and Cyp1a1 (P < 0.0001) in skeletal muscle compared to air controls. Cigarette smoke exposure was found to impair skeletal muscle mitochondrial oxidative phosphorylation by ~50% in littermate controls (Treatment effect, P < 0.001), which was attenuated by deletion of the AHR in muscle in male (P = 0.001), but not female, mice (P = 0.37), indicating there are sex-dependent pathological effects of smoking-induced AHR activation in skeletal muscle. Viral mediated expression of a constitutively active mutant AHR in the muscle of healthy mice recapitulated the effects of cigarette smoking by decreasing muscle mitochondrial oxidative phosphorylation by ~40% (P = 0.003). CONCLUSIONS: These findings provide evidence linking chronic AHR activation secondary to cigarette smoke exposure to skeletal muscle bioenergetic deficits in male, but not female, mice. AHR activation is a likely contributor to the decline in muscle oxidative capacity observed in smokers and AHR antagonism may provide a therapeutic avenue aimed to improve muscle function in COPD.

Monocyte-derived alveolar macrophages are key drivers of smoke-induced lung inflammation and tissue remodeling.

Smoking is a leading risk factor of chronic obstructive pulmonary disease (COPD), that is characterized by chronic lung inflammation, tissue remodeling and emphysema. Although inflammation is critical to COPD pathogenesis, the cellular and molecular basis underlying smoking-induced lung inflammation and pathology remains unclear. Using murine smoke models and single-cell RNA-sequencing, we show that smoking establishes a self-amplifying inflammatory loop characterized by an influx of molecularly heterogeneous neutrophil subsets and excessive recruitment of monocyte-derived alveolar macrophages (MoAM). In contrast to tissue-resident AM, MoAM are absent in homeostasis and characterized by a pro-inflammatory gene signature. Moreover, MoAM represent 46% of AM in emphysematous mice and express markers causally linked to emphysema. We also demonstrate the presence of pro-inflammatory and tissue remodeling associated MoAM orthologs in humans that are significantly increased in emphysematous COPD patients. Inhibition of the IRAK4 kinase depletes a rare inflammatory neutrophil subset, diminishes MoAM recruitment, and alleviates inflammation in the lung of cigarette smoke-exposed mice. This study extends our understanding of the molecular signaling circuits and cellular dynamics in smoking-induced lung inflammation and pathology, highlights the functional consequence of monocyte and neutrophil recruitment, identifies MoAM as key drivers of the inflammatory process, and supports their contribution to pathological tissue remodeling.

miR­186­5p regulates the inflammatory response of chronic obstructive pulmonary disorder by targeting HIF­1α.

Chronic obstructive pulmonary disorder (COPD) is a chronic respiratory disease that is a major cause of morbidity and mortality worldwide. Previous studies have shown that miR­186­5p expression is significantly increased in COPD and is involved in multiple physiological and pathological processes. However, the role of miRNA­186­5p in the inflammatory response of COPD remains unclear. In this study, an in vitro model of COPD was established using lipopolysaccharide (LPS)­induced human bronchial epithelial cells (BEAS­2B). CCK­8 assays, flow cytometry, and a Muse cell analyzer were used to determine cell viability, cell cycle distribution, and apoptosis, respectively. The production of TNF­α and IL­6 were measured by ELISA. Reverse­transcription­quantitative PCR and western blotting were used to analyze mRNA and protein expression levels. The targeting relation between miR­186­5p and HIF­1α was discovered using dual­luciferase reporter assays. The results showed that transfection of miR­186­5p inhibitor inhibited cell proliferation and promoted cell apoptosis in the LPS­induced BEAS­2B cells. Inhibition of miR­186­5p markedly increased the levels of TNF­α and IL­6. miR­186­5p directly targeted and negatively regulated HIF­1α expression. In addition, inhibition of miR­186­5p increased the expression of the NF­κB pathway protein p­p65. In conclusion, it was found that inhibiting miR­186­5p may improve inflammation of COPD through HIF­1α in LPS­induced BEAS­2B cells, possibly by regulating NF­κB signaling. These findings provide a novel potential avenue for the clinical management of COPD. Future research is required to determine the mechanism of the interaction between miR­186­5p and HIF­1α in COPD.

Human Umbilical Cord Mesenchymal Stem Cells Improve Lung Function in Chronic Obstructive Pulmonary Disease Rat Model Through Regulating Lung Microbiota.

BACKGROUND: The use of human umbilical cord mesenchymal stem cells (UC-MSCs) has shown promise in improving the pathophysiological characteristics of rats with chronic obstructive pulmonary disease (COPD). However, more research is needed to understand the exact mechanism behind their therapeutic effects and their impact on lung microbiota. METHODS: To investigate this, rats were randomly assigned to one of 3 groups: Control, COPD + vehicle, and COPD + UC-MSCs group. Lung function changes after UC-MSCs therapy were evaluated weekly for 6 weeks. Additionally, lactate dehydrogenase (LDH), TNF (tumor necrosis factor)-α, IL (interleukin)-6, and IL-1ß level in bronchoalveolar lavage fluid (BALF) were analyzed. Arterial blood gas and weight were recorded. Hematoxylin and eosin (HE) staining was used to examine lung pathology, while changes in the lung microbiota were evaluated through 16S rRNA sequencing. RESULTS: The administration of UC-MSCs in rats led to a progressive amelioration of COPD, as demonstrated by enhanced lung function and reduced inflammatory response. UC-MSCs treatment significantly altered the structure and diversity of the lung microbiota, effectively preventing microbiota dysbiosis. This was achieved by increasing the abundance of Bacteroidetes and reducing the levels of Proteobacteria. Additionally, treatment with UC-MSCs reduced the activation of pathways associated with COPD, including microbial metabolism, ABC transporters, and Quorum sensing. The group of UC-MSCs showed increased metabolic pathways, such as amino acid biosynthesis, purine metabolism, starch and sucrose metabolism, and biosynthesis of secondary metabolites, compared to the COPD group. CONCLUSIONS: The use of UC-MSCs was found to reduce inflammation and improve lung function in rats with COPD. The mechanism may be related to the lung microbiota, as UC-MSCs improved the communities of lung microbiota and regulated dysregulated metabolic pathways.

miR-146a regulates emphysema formation and abnormal inflammation in the lungs of two mouse models.

miR-146a, a microRNA (miRNA) that regulates inflammatory responses, plays an important role in many inflammatory diseases. Although an in vitro study had suggested that miR-146a is involved in abnormal inflammatory response, being a critical factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), in vivo evidence of its pathogenic role in COPD remains limited. Eight-week-old male B6(FVB)-Mir146tm1.1Bal/J [miR-146a knockout (KO)] and C57BL/6J mice were intratracheally administered elastase and evaluated after 28 days or exposed to cigarette smoke (CS) and evaluated after 5 mo. miR-146a expression was significantly increased in C57BL/6J mouse lungs due to elastase administration (P = 0.027) or CS exposure (P = 0.019) compared with that in the control group. Compared with C57BL/6J mice, elastase-administered miR-146a-KO mice had lower average computed tomography (CT) values (P = 0.017) and increased lung volume-to-weight ratio (P = 0.016), mean linear intercept (P < 0.001), and destructive index (P < 0.001). Moreover, total cell (P = 0.006), macrophage (P = 0.001), neutrophil (P = 0.026), chemokine (C-X-C motif) ligand 2/macrophage inflammatory protein-2 [P = 0.045; in bronchoalveolar lavage fluid (BALF)], cyclooxygenase-2, and matrix metalloproteinase-2 levels were all increased (in the lungs). Following long-term CS exposure, miR-146a-KO mice showed a greater degree of emphysema formation in their lungs and inflammatory response in the BALF and lungs than C57BL/6J mice. Collectively, miR-146a protected against emphysema formation and the associated abnormal inflammatory response in two murine models.NEW & NOTEWORTHY This study demonstrates that miR-146a expression is upregulated in mouse lungs because of elastase- and CS-induced emphysema and that the inflammatory response by elastase or CS is enhanced in the lungs of miR-146a-KO mice than in those of control mice, resulting in the promotion of emphysema. This is the first study to evaluate the protective role of miR-146a in emphysema formation and the associated abnormal inflammatory response in different in vivo models.

Loss of p73 Expression Contributes to Chronic Obstructive Pulmonary Disease.

Rationale: Multiciliated cell (MCC) loss and/or dysfunction is common in the small airways of patients with chronic obstructive pulmonary disease (COPD), but it is unclear if this contributes to COPD lung pathology. Objectives: To determine if loss of p73 causes a COPD-like phenotype in mice and explore whether smoking or COPD impact p73 expression. Methods: p73floxE7-E9 mice were crossed with Shh-Cre mice to generate mice lacking MCCs in the airway epithelium. The resulting p73Δairway mice were analyzed using electron microscopy, flow cytometry, morphometry, forced oscillation technique, and single-cell RNA sequencing. Furthermore, the effects of cigarette smoke on p73 transcript and protein expression were examined using in vitro and in vivo models and in studies including airway epithelium from smokers and patients with COPD. Measurements and Main Results: Loss of functional p73 in the respiratory epithelium resulted in a near-complete absence of MCCs in p73Δairway mice. In adulthood, these mice spontaneously developed neutrophilic inflammation and emphysema-like lung remodeling and had progressive loss of secretory cells. Exposure of normal airway epithelium cells to cigarette smoke rapidly and durably suppressed p73 expression in vitro and in vivo. Furthermore, tumor protein 73 mRNA expression was reduced in the airways of current smokers (n = 82) compared with former smokers (n = 69), and p73-expressing MCCs were reduced in the small airways of patients with COPD (n = 11) compared with control subjects without COPD (n = 12). Conclusions: Loss of functional p73 in murine airway epithelium results in the absence of MCCs and promotes COPD-like lung pathology. In smokers and patients with COPD, loss of p73 may contribute to MCC loss or dysfunction.

Exploring the role of neutrophils in infectious and noninfectious pulmonary disorders.

With the change in global environment, respiratory disorders are becoming more threatening to the health of people all over the world. These diseases are closely linked to performance of immune system. Within the innate arm of immune system, Neutrophils are an important moiety to serve as an immune defense barrier. They are one of the first cells recruited to the site of infection and plays a critical role in pathogenesis of various pulmonary diseases. It is established that the migration and activation of neutrophils can lead to inflammation either directly or indirectly and this inflammation caused is very crucial for the clearance of pathogens and resolution of infection. However, the immunopathological mechanisms involved to carry out the same is very complex and not well understood. Despite there being studies concentrating on the role of neutrophils in multiple respiratory diseases, there is still a long way to go in order to completely understand the complexity of the participation of neutrophils and mechanisms involved in the development of these respiratory diseases. In the present article, we have reviewed the literature to comprehensively provide an insight in the current development and advancements about the role of neutrophils in infectious respiratory disorders including viral respiratory disorders such as Coronavirus disease (COVID-19) and bacterial pulmonary disorders with a focused review on pulmonary tuberculosis as well as in noninfectious disorders like Chronic obstructive pulmonary disease (COPD) and asthma. Also, future directions into research and therapeutic targets have been discussed for further exploration.

Respiratory illnesses are becoming more prevalent and a substantial source of sickness and mortality worldwide as a result of the changes in the global environment. Although diagnostic and therapeutic approaches for respiratory disorders have improved over the years, a thorough and in-depth approach is still required to understand the underlying immuno-pathophysiological mechanisms. Neutrophils are a crucial part of innate immune system which functions as a first line defense against various pulmonary infections. They are known to be involved in resistance against invading pulmonary pathogens and also play an important role in repairing of damaged lung tissue by removing debris. However, emerging evidences suggest that neutrophils may also be involved in promoting and aggravating the unabating inflammation in several pulmonary disorders by release of various proteases, forming neutrophil extracellular traps or by attracting and activating other immune cells at the site of inflammation. In this article, we have discussed diverse roles and responses of neutrophils and their use in potential future research and therapeutic approaches in infectious pulmonary disorders like Tuberculosis and COVID-19 and noninfectious pulmonary disorders like Chronic obstructive pulmonary disease (COPD) and asthma.

Small airway fibroblasts from patients with chronic obstructive pulmonary disease exhibit cellular senescence.

Small airway disease (SAD) is a key early-stage pathology of chronic obstructive pulmonary disease (COPD). COPD is associated with cellular senescence whereby cells undergo growth arrest and express the senescence-associated secretory phenotype (SASP) leading to chronic inflammation and tissue remodeling. Parenchymal-derived fibroblasts have been shown to display senescent properties in COPD, however small airway fibroblasts (SAFs) have not been investigated. Therefore, this study investigated the role of these cells in COPD and their potential contribution to SAD. To investigate the senescent and fibrotic phenotype of SAF in COPD, SAFs were isolated from nonsmoker, smoker, and COPD lung resection tissue (n = 9-17 donors). Senescence and fibrotic marker expressions were determined using iCELLigence (proliferation), qPCR, Seahorse assay, and ELISAs. COPD SAFs were further enriched for senescent cells using FACSAria Fusion based on cell size and autofluorescence (10% largest/autofluorescent vs. 10% smallest/nonautofluorescent). The phenotype of the senescence-enriched population was investigated using RNA sequencing and pathway analysis. Markers of senescence were observed in COPD SAFs, including senescence-associated ß-galactosidase, SASP release, and reduced proliferation. Because the pathways driving this phenotype were unclear, we used cell sorting to enrich senescent COPD SAFs. This population displayed increased p21CIP1 and p16INK4a expression and mitochondrial dysfunction. RNA sequencing suggested these senescent cells express genes involved in oxidative stress response, fibrosis, and mitochondrial dysfunction pathways. These data suggest COPD SAFs are senescent and may be associated with fibrotic properties and mitochondrial dysfunction. Further understanding of cellular senescence in SAFs may lead to potential therapies to limit SAD progression.NEW & NOTEWORTHY Fibroblasts and senescence are thought to play key roles in the pathogenesis of small airway disease and COPD; however, the characteristics of small airway-derived fibroblasts are not well explored. In this study we isolate and enrich the senescent small airway-derived fibroblast (SAF) population from COPD lungs and explore the pathways driving this phenotype using bulk RNA-seq.

Potential systemic effects of acquired CFTR dysfunction in COPD.

Chronic obstructive pulmonary disease (COPD) is characterized by airflow limitation, respiratory symptoms, inflammation of the airways, and systemic manifestations of the disease. Genetic susceptibility and environmental factors are important in the development of the disease, particularly exposure to cigarette smoke which is the most notable risk factor. Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene are the cause of cystic fibrosis (CF), which shares several pathophysiological pulmonary features with COPD, including airway obstruction, chronic airway inflammation and bacterial colonization; in addition, both diseases also present systemic defects leading to comorbidities such as pancreatic, gastrointestinal, and bone-related diseases. In patients with COPD, systemic CFTR dysfunction can be acquired by cigarette smoking, inflammation, and infection. This dysfunction is, on average, about half of that found in CF. Herein we review the literature focusing on acquired CFTR dysfunction and the potential role in the pathogenesis of comorbidities associated with COPD and chronic bronchitis.

Understanding the modulations of glycero-lysophospholipids in an elastase-induced murine emphysema model.

BACKGROUND: Increasing evidence indicates that bioactive lipid mediators are involved in chronic obstructive pulmonary disease (COPD) pathogenesis. Recently, glycero-lysophospholipids, such as lysophosphatidic acid (LysoPA) and lysophosphatidylserine (LysoPS), have been recognized as significant inflammation-related lipid mediators. However, their association with COPD remains unclear. METHODS: We used an elastase-induced murine emphysema model to analyze the levels of lysophospholipids and diacyl-phospholipids in the lungs. Additionally, we assessed the expression of LysoPS-related genes and published data on smokers. RESULTS: In the early phase of an elastase-induced murine emphysema model, the levels of LysoPS and its precursor (phosphatidylserine [PS]) were significantly reduced, without significant modulations in other glycero-lysophospholipids. Additionally, there was an upregulation in the expression of lysoPS receptors, specifically GPR34, observed in the lungs of a cigarette smoke-exposed mouse model and the alveolar macrophages of human smokers. Elastase stimulation induces GPR34 expression in a human macrophage cell line in vitro. CONCLUSIONS: Elastase-induced lung emphysema affects the LysoPS/PS-GPR34 axis, and cigarette smoking or elastase upregulates GPR34 expression in alveolar macrophages. This novel association may serve as a potential pharmacological target for COPD treatment.

IL-20 Cytokines Are Involved in the Repair of Airway Epithelial Barrier: Implication in Exposure to Cigarette Smoke and in COPD Pathology.

BACKGROUND: Dysregulated inflammation as seen in chronic obstructive pulmonary disease (COPD) is associated with impaired wound healing. IL-20 cytokines are known to be involved in wound healing processes. The purpose of this study was to use ex vivo and in vitro approaches mimicking COPD to evaluate the potential modulatory role of interleukin-20 (IL-20) on the inflammatory and healing responses to epithelial wounding. METHODS: The expression of IL-20 cytokines and their receptors was investigated in lung-derived samples collected from non-COPD and COPD patients, from mice chronically exposed to cigarette smoke and from airway epithelial cells from humans and mice exposed in vitro to cigarette smoke. To investigate the role of IL-20 cytokines in wound healing, experiments were performed using a blocking anti-IL-20Rb antibody. RESULTS: Of interest, IL-20 cytokines and their receptors were expressed in bronchial mucosa, especially on airway epithelial cells. Their expression correlated with the disease severity. Blocking these cytokines in a COPD context improved the repair processes after a lesion induced by scratching the epithelial layer. CONCLUSIONS: Collectively, this study highlights the implication of IL-20 cytokines in the repair of the airway epithelium and in the pathology of COPD. IL-20 subfamily cytokines might provide therapeutic benefit for patients with COPD to improve epithelial healing.

Effective-component compatibility of Bufei Yishen formula alleviates chronic obstructive pulmonary disease inflammation by regulating GSK3ß-mediated NLRP3 inflammasome activation.

Glycogen synthase kinase 3ß (GSK3ß) has been associated with sensing many different stimuli to trigger the NLRP3 inflammasome, which plays a crucial role in promoting the inflammatory response in diseases, including chronic obstructive pulmonary disease (COPD). Bufei Yishen formula (BYF), a traditional Chinese herbal medicine, has beneficial effects on COPD. Effective-component compatibility of BYF (ECC-BYF), optimized from BYF, is equally effective as BYF in inhibiting COPD inflammation. However, the exact mechanism by which ECC-BYF regulates the activation of NLRP3 inflammasome to inhibit COPD inflammation remains unclear. Hence, we investigated the mechanisms underlying the alleviation of COPD inflammation by ECC-BYF through the inhibition of GSK3ß-mediated NLRP3 inflammasome activation by experimental rat model of COPD and lipopolysaccharide/adenosine triphosphate (LPS/ATP) induced macrophages. The data showed that ECC-BYF significantly improved the lung function, attenuated histopathological damage, and alleviated inflammatory cell infiltration and alveolar destruction. Further, it significantly inhibited inflammatory cytokine production and downregulated the phosphorylation of GSK3ß by inhibiting the activation of NLRP3 inflammasome in the rat model of COPD. Moreover, ECC-BYF suppressed the activation of the NLRP3 inflammasome by increasing the phosphorylation at serine 9 and decreasing the phosphorylation at tyrosine 216 of GSK3ß, followed by the inhibition of IL-1ß secretion in macrophages. Together, ECC-BYF effectively ameliorates COPD by suppressing inflammation, which is dependent on the regulation of GSK3ß-mediated NLRP3 inflammasome activation.

Clinically Important Deterioration (CID) and Ageing in COPD: A Systematic Review and Meta-Regression Analysis According to PRISMA Statement.

Purpose: Clinically important deterioration (CID) is a composite endpoint developed to quantify the impact of pharmacological treatment in clinical trials for Chronic Obstructive Pulmonary Disease (COPD), also showing a prognostic value. CID is defined as any of the following condition: forced expiratory volume in 1 s decrease ≥100 mL from baseline, and/or St. George's Respiratory Questionnaire total score increase ≥4-unit from baseline, and/or the occurrence of a moderate-to-severe exacerbation of COPD. Although most COPD patients experience a clinical worsening as they get older, to date, no specific studies assessed the correlation between ageing and CID in COPD. Therefore, the aim of this study was to investigate the impact of ageing on CID in COPD patients. Patients and Methods: Data obtained from 55219 COPD patients were extracted from 17 papers, mostly post-hoc analyses. A pairwise meta-analysis and a meta-regression analysis were performed according to PRISMA-P guidelines to quantify the impact of pharmacological therapy on CID and to determine whether ageing might modulate the risk of CID in COPD patients. Results: Inhaled treatments resulted generally effective in reducing the risk of CID in COPD (relative risk: 0.81, 95% confidence interval 0.79-0.84; P < 0.001). The meta-regression analysis indicated a trend toward significance (P = 0.063) in the linear relationship between age and the risk of CID. Of note, age significantly (P < 0.05) increased the risk of CID when associated with lower post-bronchodilator FEV1. These results were not affected by a significant risk of bias. Conclusion: This quantitative synthesis suggests that inhaled therapy is effective in reducing the risk of CID in COPD, although such a protective effect may be affected in older patients with impaired lung function. Further studies specifically designed on CID in COPD are needed to confirm these results.

Immunohistochemical Study of Airways Fibrous Remodeling in Smoking Mice.

The fibrotic remodeling in chronic obstructive pulmonary disease (COPD) is held responsible for narrowing of small airways and thus for disease progression. Oxidant damage and cell senescence factors are recently involved in airways fibrotic remodeling. Unfortunately, we have no indications on their sequential expression at anatomical sites in which fibrotic remodeling develops in smoking subjects. Using immunohistochemical techniques, we investigated in two strains of mice after cigarette smoke (CS) exposure what happens at various times in airway areas where fibrotic remodeling occurs, and if there also exists correspondence among DNA damage induced by oxidants, cellular senescence, the presence of senescence-secreted factors involved in processes that affect transcription, metabolism as well as apoptosis, and the onset of fibrous remodeling that appears at later times in mice exposed to CS. A clear positivity for fibrogenic cytokines TGF-ß, PDGF-B, and CTGF, and for proliferation marker PCNA around airways that will be remodeled is observed in both strains. Increased expression of p16ink4A senescence marker and MyoD is also seen in the same areas. p16ink4A and MyoD can promote cell cycle arrest, terminal differentiation of myofibroblasts, and can oppose their dedifferentiation. Of interest, an early progressive attenuation of SIRT-1 is observed after CS exposure. This intracellular regulatory protein can reduce premature cell senescence. These findings suggest that novel agents, which promote myofibroblast dedifferentiation and/or the apoptosis of senescent cells, may dampen progression of airway changes in smoking COPD subjects.

Protease-armed, Pathogenic Extracellular Vesicles Link Smoking and Chronic Obstructive Pulmonary Disease.

Rationale: Mounting evidence demonstrates a role for extracellular vesicles (EVs) in driving lung disorders, such as chronic obstructive pulmonary disease (COPD). Although cigarette smoke (CS) is the primary risk factor for COPD, a link between CS and the EVs that could lead to COPD is unknown. Objective: To ascertain whether exposure to CS elicits a proteolytic EV signature capable of driving disease pathogenesis. Methods: Protease expression and enzymatic activity were measured in EVs harvested from the BAL fluid of smoke-exposed mice and otherwise healthy human smokers. Pathogenicity of EVs was examined using pathological tissue scoring after EV transfer into naive recipient mice. Measurements and Main Results: The analyses revealed a unique EV profile defined by neutrophil- and macrophage-derived EVs. These EVs are characterized by abundant surface expression of neutrophil elastase (NE) and matrix metalloproteinase 12 (MMP12), respectively. CS-induced mouse or human-derived airway EVs had a robust capacity to elicit rapid lung damage in naive recipient mice, with an additive effect of NE- and MMP12-expressing EVs. Conclusions: These studies demonstrate the capacity of CS to drive the generation of unique EV populations containing NE and MMP12. The coordinated action of these EVs is completely sufficient to drive emphysematous disease, and their presence could operate as a prognostic indicator for COPD development. Furthermore, given the robust capacity of these EVs to elicit emphysema in naive mice, they provide a novel model to facilitate preclinical COPD research. Indeed, the development of this model has led to the discovery of a previously unrecognized CS-induced protective mechanism against EV-mediated damage.