scholarly journals 27-Hydroxycholesterol accelerates cellular senescence in human lung resident cells

2016 ◽  
Vol 310 (11) ◽  
pp. L1028-L1041 ◽  
Author(s):  
Yuichiro Hashimoto ◽  
Hisatoshi Sugiura ◽  
Shinsaku Togo ◽  
Akira Koarai ◽  
Kyoko Abe ◽  
...  
Keyword(s):  
Cellular Senescence ◽  
Healthy Subjects ◽  
Tissue Repair ◽  
Airway Epithelial Cells ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Prostaglandin E ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Associated Proteins

Cellular senescence is reportedly involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). We previously showed that 27-hydroxycholesterol (27-OHC) is elevated in the airways of COPD patients compared with those in healthy subjects. The aim of this study was to investigate whether lung fibroblasts of COPD patients are senescent and to determine the effects of 27-OHC on senescence of lung resident cells, including fibroblasts and airway epithelial cells. Localization of senescence-associated proteins and sterol 27-hydroxylase was investigated in the lungs of COPD patients by immunohistochemical staining. To evaluate whether 27-OHC accelerates cellular senescence, lung resident cells were exposed to 27-OHC. Senescence markers and fibroblast-mediated tissue repair were investigated in the 27-OHC-treated cells. Expression of senescence-associated proteins was significantly enhanced in lung fibroblasts of COPD patients. Similarly, expression of sterol 27-hydroxylase was significantly upregulated in lung fibroblasts and alveolar macrophages in these patients. Treatment with the concentration of 27-OHC detected in COPD airways significantly augmented expression of senescence-associated proteins and senescence-associated β-galactosidase activity, and delayed cell growth through the prostaglandin E2-reactive nitrogen species pathway. The 27-OHC-treated fibroblasts impaired tissue repair function. Fibroblasts from lungs of COPD patients showed accelerated senescence and were more susceptible to 27-OHC-induced cellular senescence compared with those of healthy subjects. In conclusion, 27-OHC accelerates cellular senescence in lung resident cells and may play a pivotal role in cellular senescence in COPD.

scholarly journals Awakening efficacy of a vibrotactile device in patients on home nocturnal ventilatory assistance and healthy subjects as family caregiver proxies

2020 ◽  
Vol 17 ◽  
pp. 147997312098333
Author(s):  
Valerie Attali ◽  
Sophie Lavault ◽  
Antoine Guerder ◽  
Saba Al-Youssef ◽  
Benjamin Dudoignon ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Vibrotactile Stimulus ◽  
Chronic Obstructive ◽  
Vibrotactile Stimulation ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Random Intervals ◽  
Healthy Family ◽  
Central Hypoventilation ◽  
Hypoventilation Syndrome

The objective of this study was to test the capacity of vibrotactile stimulation transmitted to the wrist bones by a vibrating wristband to awaken healthy individuals and patients requiring home mechanical ventilation during sleep. Healthy subjects (n = 20) and patients with central hypoventilation (CH) (Congenital Central Hypoventilation syndrome n = 7; non-genetic form of CH n = 1) or chronic obstructive pulmonary disease (COPD) (n = 9), underwent a full-night polysomnography while wearing the wristband. Vibrotactile alarms were triggered five times during the night at random intervals. Electroencephalographic (EEG), clinical (trunk lift) and cognitive (record the time on a sheet of paper) arousals were recorded. Cognitive arousals were observed for 94% of the alarms in the healthy group and for 66% and 63% of subjects in the CH and COPD groups, respectively (p < 0.01). The percentage of participants experiencing cognitive arousals for all alarms, was 72% for healthy subjects, 37.5% for CH patients and 33% for COPD patients (ns) (94%, 50% and 44% for clinical arousals (p < 0.01) and 100%, 63% and 44% for EEG arousals (p < 0.01)). Device acceptance was good in the majority of cases, with the exception of one CH patient and eight healthy participants. In summary this study shows that a vibrotactile stimulus is effective to induce awakenings in healthy subjects, but is less effective in patients, supporting the notion that a vibrotactile stimulus could be an effective backup to a home mechanical ventilator audio alarm for healthy family caregivers.

Voluntary activation of the human diaphragm in health and disease

1998 ◽  
Vol 85 (6) ◽  
pp. 2146-2158 ◽  
Author(s):  
Christer Sinderby ◽  
Jennifer Beck ◽  
Jadranka Spahija ◽  
Jan Weinberg ◽  
Alex Grassino
Keyword(s):  
Healthy Subjects ◽  
Total Lung Capacity ◽  
Voluntary Activation ◽  
Chronic Obstructive ◽  
Quiet Breathing ◽  
Obstructive Pulmonary Disease ◽  
Transdiaphragmatic Pressure ◽  
Lung Capacity ◽  
Copd Patients ◽  
Crural Diaphragm

Intersubject comparison of the crural diaphragm electromyogram, as measured by an esophageal electrode, requires a reliable means for normalizing the signal. The present study set out 1) to evaluate which voluntary respiratory maneuvers provide high and reproducible diaphragm electromyogram root-mean-square (RMS) values and 2) to determine the relative diaphragm activation and mechanical and ventilatory outputs during breathing at rest in healthy subjects ( n = 5), in patients with severe chronic obstructive pulmonary disease (COPD, n = 5), and in restrictive patients with prior polio infection (PPI, n = 6). In all groups, mean voluntary maximal RMS values were higher during inspiration to total lung capacity than during sniff inhalation through the nose ( P = 0.035, ANOVA). The RMS (percentage of voluntary maximal RMS) during quiet breathing was 8% in healthy subjects, 43% in COPD patients, and 45% in PPI patients. Despite the large difference in relative RMS ( P = 0.012), there were no differences in mean transdiaphragmatic pressure ( P= 0.977) and tidal volumes ( P = 0.426). We conclude that voluntary maximal RMS is reliably obtained during an inspiration to total lung capacity but a sniff inhalation could be a useful complementary maneuver. Severe COPD and PPI patients breathing at rest are characterized by increased diaphragm activation with no change in diaphragm pressure generation.

scholarly journals Interleukin-1α drives the dysfunctional cross-talk of the airway epithelium and lung fibroblasts in COPD

2016 ◽  
Vol 48 (2) ◽  
pp. 359-369 ◽  
Author(s):  
Emmanuel T. Osei ◽  
Jacobien A. Noordhoek ◽  
Tillie L. Hackett ◽  
Anita I.R. Spanjer ◽  
Dirkje S. Postma ◽  
...  
Keyword(s):  
Inflammatory Mediators ◽  
Airway Epithelium ◽  
Fetal Lung ◽  
Bronchial Epithelial Cell ◽  
Airway Epithelial Cells ◽  
Lung Fibroblast ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
And Control

Chronic obstructive pulmonary disease (COPD) has been associated with aberrant epithelial–mesenchymal interactions resulting in inflammatory and remodelling processes. We developed a co-culture model using COPD and control-derived airway epithelial cells (AECs) and lung fibroblasts to understand the mediators that are involved in remodelling and inflammation in COPD.AECs and fibroblasts obtained from COPD and control lung tissue were grown in co-culture with fetal lung fibroblast or human bronchial epithelial cell lines. mRNA and protein expression of inflammatory mediators, pro-fibrotic molecules and extracellular matrix (ECM) proteins were assessed.Co-culture resulted in the release of pro-inflammatory mediators interleukin (IL)-8/CXCL8 and heat shock protein (Hsp70) from lung fibroblasts, and decreased expression of ECM molecules (e.g. collagen, decorin) that was not different between control and COPD-derived primary cells. This pro-inflammatory effect was mediated by epithelial-derived IL-1α and increased upon epithelial exposure to cigarette smoke extract (CSE). When exposed to CSE, COPD-derived AECs elicited a stronger IL-1α response compared with control-derived airway epithelium and this corresponded with a significantly enhanced IL-8 release from lung fibroblasts.We demonstrate that, through IL-1α production, AECs induce a pro-inflammatory lung fibroblast phenotype that is further enhanced with CSE exposure in COPD, suggesting an aberrant epithelial–fibroblast interaction in COPD.

scholarly journals A Novel Role of Growth Differentiation Factor (GDF)-15 in Overlap with Sedentary Lifestyle and Cognitive Risk in COPD

2020 ◽  
Vol 9 (9) ◽  
pp. 2737 ◽  
Author(s):  
Tsunahiko Hirano ◽  
Keiko Doi ◽  
Kazuto Matsunaga ◽  
Shun Takahashi ◽  
Tomohiro Donishi ◽  
...  
Keyword(s):  
Healthy Subjects ◽  
Sedentary Lifestyle ◽  
Japanese Version ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Entire Cohort ◽  
Differentiation Factor ◽  
Cognitive Risk ◽  
Copd Patients ◽  
Proapoptotic Protein

Sedentary behavior and cognitive impairment have a direct impact on patients’ outcomes. An energy metabolic disorder may be involved in the overlap of these comorbid conditions (motoric cognitive risk (MCR)) in patients with chronic obstructive pulmonary disease (COPD). We aimed to explore the linkage between a proapoptotic protein, growth differentiation factor (GDF)-15, and MCR. Physical activity (PA), cognitive function (Japanese version of the Montreal Cognitive Assessment: MOCA-J), and the serum GDF-15 levels were assessed in healthy subjects (n = 14), asthmatics (n = 22), and COPD patients (n = 28). In the entire cohort, serum GDF-15 had negative correlations with exercise (Ex) (ρ = −0.43, p < 0.001) and MoCA-J (ρ = −0.44, p < 0.001), and Ex and MOCA-J showed a positive correlation (ρ = 0.52, p < 0.0001). Compared to healthy subjects and asthmatics, COPD patients showed the highest serum GDF-15 levels and had a significantly higher proportion of subjects with MCR (both sedentary lifestyle (EX < 1.5) and cognitive risk (MoCA-J ≤ 25)). Also, we found that serum GDF-15 has a screening potential (100% sensitivity) greater than aging (67% sensitivity) for detecting MCR in COPD patients. In conclusion, higher serum GDF-15 had interrelationships with a sedentary lifestyle and cognitive risk. This protein was not disease-specific but could be a screening biomarker to detect MCR related to poor health outcomes of COPD patients.

Reproducibility and responsiveness of a noninvasive EMG technique of the respiratory muscles in COPD patients and in healthy subjects

2004 ◽  
Vol 96 (5) ◽  
pp. 1723-1729 ◽  
Author(s):  
Marieke L. Duiverman ◽  
Leo A. van Eykern ◽  
Peter W. Vennik ◽  
Gerard H. Koëter ◽  
Eric J. W. Maarsingh ◽  
...  
Keyword(s):  
Muscle Activity ◽  
Healthy Subjects ◽  
Respiratory Muscles ◽  
Emg Activity ◽  
Chronic Obstructive ◽  
Abdominal Muscles ◽  
Breathing Patterns ◽  
Obstructive Pulmonary Disease ◽  
Intercostal Muscles ◽  
Copd Patients

In the present study, we assessed the reproducibility and responsiveness of transcutaneous electromyography (EMG) of the respiratory muscles in patients with chronic obstructive pulmonary disease (COPD) and healthy subjects during breathing against an inspiratory load. In seven healthy subjects and seven COPD patients, EMG signals of the frontal and dorsal diaphragm, intercostal muscles, abdominal muscles, and scalene muscles were derived on 2 different days, both during breathing at rest and during breathing through an inspiratory threshold device of 7, 14, and 21 cmH2O. For analysis, we used the logarithm of the ratio of the inspiratory activity during the subsequent loads and the activity at baseline [log EMG activity ratio (EMGAR)]. Reproducibility of the EMG was assessed by comparing the log EMGAR values measured at test days 1 and 2 in both groups. Responsiveness (sensitivity to change) of the EMG was assessed by comparing the log EMGAR values of the COPD patients to those of the healthy subjects at each load. During days 1 and 2, log EMGAR values of the diaphragm and the intercostal muscles correlated significantly. For the scalene muscles, significant correlations were found for the COPD patients. Although inspiratory muscle activity increased significantly during the subsequent loads in all participants, the COPD patients displayed a significantly greater increase in intercostal and left scalene muscle activity compared with the healthy subjects. In conclusion, the present study showed that the EMG technique is a reproducible and sensitive technique to assess breathing patterns in COPD patients and healthy subjects.

scholarly journals Imbalance between IL-36 receptor agonist and antagonist drives neutrophilic inflammation in COPD

2021 ◽  
Author(s):  
Jonathan R Baker ◽  
Peter S Fenwick ◽  
Carolin K Koss ◽  
Harriet B Owles ◽  
Sarah L Elkin ◽  
...  
Keyword(s):  
Culture Media ◽  
Airway Epithelial Cells ◽  
Small Airway ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Obstructive Pulmonary Disease ◽  
Neutrophilic Inflammation ◽  
Copd Patients ◽  
Agonist And Antagonist ◽  
Underlying Pathophysiology

AbstractCurrent treatments fail to modify the underlying pathophysiology and disease progression of chronic obstructive pulmonary disease (COPD), necessitating novel therapies. Here, we show that COPD patients have increased IL-36γ and decreased IL-36 receptor antagonist (IL-36Ra) in bronchoalveolar and nasal fluid compared to control subjects. IL-36γ is derived mainly from small airway epithelial cells (SAEC) and further induced by a viral mimetic, whereas IL-36RA is derived from macrophages. IL-36γ stimulates release of the neutrophil chemoattractants CXCL1 and CXCL8, as well as elastolytic matrix metalloproteinases (MMPs) from small airway fibroblasts (SAF). Proteases released from COPD neutrophils cleave and activate IL-36γ thereby perpetuating IL-36 inflammation. Transfer of culture media from SAEC to SAF stimulated release of CXCL1, that was inhibited by exogenous IL-36RA. The use of a therapeutic antibody that inhibits binding to the IL-36 receptor (IL-36R) attenuated IL-36γ driven inflammation and cellular cross talk. We have demonstrated a novel mechanism for the amplification and propagation of neutrophilic inflammation in COPD and that blocking this cytokine family via a IL-36R neutralising antibody could be a promising new therapeutic strategy in the treatment of COPD.

scholarly journals miR-146a-5p plays an essential role in the aberrant epithelial–fibroblast cross-talk in COPD

2017 ◽  
Vol 49 (5) ◽  
pp. 1602538 ◽  
Author(s):  
Emmanuel T. Osei ◽  
Laura Florez-Sampedro ◽  
Hataitip Tasena ◽  
Alen Faiz ◽  
Jacobien A. Noordhoek ◽  
...  
Keyword(s):  
Airway Epithelial Cells ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Airway Epithelial ◽  
Single Nucleotide ◽  
Obstructive Pulmonary Disease ◽  
Bronchial Epithelial ◽  
Lung Epithelial ◽  
Inflammatory Phenotype

We previously reported that epithelial-derived interleukin (IL)-1α drives fibroblast-derived inflammation in the lung epithelial–mesenchymal trophic unit. Since miR-146a-5p has been shown to negatively regulate IL-1 signalling, we investigated the role of miR-146a-5p in the regulation of IL-1α-driven inflammation in chronic obstructive pulmonary disease (COPD).Human bronchial epithelial (16HBE14o-) cells were co-cultured with control and COPD-derived primary human lung fibroblasts (PHLFs), and miR-146a-5p expression was assessed with and without IL-1α neutralising antibody. Genomic DNA was assessed for the presence of the single nucleotide polymorphism (SNP) rs2910164. miR-146a-5p mimics were used for overexpression studies to assess IL-1α-induced signalling and IL-8 production by PHLFs.Co-culture of PHLFs with airway epithelial cells significantly increased the expression of miR-146a-5p and this induction was dependent on epithelial-derived IL-1α. miR-146a-5p overexpression decreased IL-1α-induced IL-8 secretion in PHLFs via downregulation of IL-1 receptor-associated kinase-1. In COPD PHLFs, the induction of miR-146a-5p was significantly less compared with controls and was associated with the SNP rs2910164 (GG allele) in the miR-146a-5p gene.Our results suggest that induction of miR-146a-5p is involved in epithelial–fibroblast communication in the lungs and negatively regulates epithelial-derived IL-1α induction of IL-8 by fibroblasts. The decreased levels of miR-146a-5p in COPD fibroblasts may induce a more pro-inflammatory phenotype, contributing to chronic inflammation in COPD.

Fibroblasts that resist cigarette smoke-induced senescence acquire profibrotic phenotypes

2014 ◽  
Vol 307 (5) ◽  
pp. L364-L373 ◽  
Author(s):  
Nobuhiro Kanaji ◽  
Hesham Basma ◽  
Amy Nelson ◽  
Maha Farid ◽  
Tadashi Sato ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Tissue Repair ◽  
Lung Fibroblasts ◽  
Chronic Obstructive ◽  
Receptor Kinase ◽  
Collagen Gels ◽  
Obstructive Pulmonary Disease ◽  
Adult Lung ◽  
Β Receptor ◽  
Extended Exposure

This study assessed the effect of extended exposure to cigarette smoke extract (CSE) on tissue repair functions in lung fibroblasts. Human fetal (HFL-1) and adult lung fibroblasts were exposed to CSE for 14 days. Senescence-associated β-galactosidase (SA β-gal) expression, cell proliferation, and tissue repair functions including chemotaxis and gel contraction were assessed. HFL-1 proliferation was inhibited by CSE and nearly half of the CSE-exposed cells were SA β-gal positive after 14 days exposure, whereas 33% of adult lung fibroblasts were SA β-gal positive in response to 10% CSE exposure. The SA β-gal-positive cells did not proliferate as indicated by bromodeoxyuridine incorporation. In contrast, cells negative for SA β-gal after CSE exposure proliferated faster than cells never exposed to CSE. These nonsenescent cells migrated more and contracted collagen gels more than control cells. CSE exposure stimulated TGF-β1 production, and both inhibition of TGF-β receptor kinase and TGF-β1 siRNA blocked CSE modulation of fibroblast function. Extended exposure to CSE might induce two different fibroblast phenotypes, a senescent and a profibrotic phenotype. The fibroblasts that resist CSE-induced cellular senescence may contribute to the pathogenesis of idiopathic pulmonary fibrosis and could contribute to fibrotic lesions in chronic obstructive pulmonary disease acting through a TGF-β1-mediated pathway. In contrast, the senescent cells may contribute to the pathogenesis of emphysema.

scholarly journals Absence of dynamic hyperinflation during exhaustive exercise in severe COPD reflects submaximal IC maneuvers rather than a nonhyperinflator phenotype

2020 ◽  
Vol 128 (3) ◽  
pp. 586-595 ◽  
Author(s):  
Yuan-Ming Luo ◽  
Zhi-Hui Qiu ◽  
Yuan Wang ◽  
Bai-Ting He ◽  
Hua Qin ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Healthy Subjects ◽  
Chronic Obstructive ◽  
Dynamic Hyperinflation ◽  
Respiratory Drive ◽  
Inspiratory Capacity ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients ◽  
Breathing Room

Approximately 20% of chronic obstructive pulmonary disease (COPD) patients have been considered to have a “nonhyperinflator phenotype.” However, this judgment depends on patients making a fully maximal inspiratory capacity (IC) maneuver at rest, since the IC during exercise is compared with this baseline measurement. We hypothesized that IC maneuvers at rest are sometimes submaximal and tested this hypothesis by measuring IC and associated neural respiratory drive at rest and during inhalation of CO2 and exercise in patients with COPD. Twenty-six COPD patients [age 66 ± 6 yr, mean forced expiratory volume in 1 s (FEV1) 40 ± 11% predicted] and 39 healthy subjects (age 39 ± 14 yr, FEV1 98 ± 12% predicted) were studied. IC and the diaphragm electromyogram (EMGdi) associated with it (EMGdi-IC) and forced inspiratory vital capacity (FIVC) and its corresponding EMGdi (EMGdi-FIVC) were measured during inhalation of 8% CO2 (8% CO2-92% O2) and room air. Incremental exhaustive cycle ergometer exercise was also performed in both patients with COPD and healthy subjects. IC, EMGdi-IC, FIVC, and EMGdi-FIVC during breathing 8% CO2 were significantly greater than those during breathing room air in both patients with COPD and healthy subjects (all P < 0.001). EMGdi-IC in patients with COPD constantly increased during exercise from 145 ± 40 µV at rest to 185 ± 52 µV at the end of exercise but change in IC was variable. Neural respiratory drive and its relevant IC increased during hypercapnia. Exercise-related hypercapnia in patients with COPD raises neural respiratory drives, which compensate for IC reduction, leading to underestimation of dynamic hyperinflation measured by IC at rest breathing room air. NEW & NOTEWORTHY Inspiratory capacity measured during hypercapnia is higher than that during eucapnia. Thus total lung capacity is not always be achieved by a standard inspiratory capacity maneuver, leading to risk of underestimation of dynamic hyperinflation in patients with severe chronic obstructive pulmonary disease after exhaustive exercise.

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