scholarly journals Immunoproteasomes as a novel antiviral mechanism in rhinovirus-infected airways

2018 ◽  
Vol 132 (15) ◽  
pp. 1711-1723 ◽  
Author(s):  
Kris Genelyn Dimasuay ◽  
Amelia Sanchez ◽  
Niccolette Schaefer ◽  
Jorge Polanco ◽  
Deborah A. Ferrington ◽  
...  
Keyword(s):  
Viral Load ◽  
Antigen Processing ◽  
Lower Airway ◽  
Chronic Obstructive ◽  
Deficient Mouse ◽  
Obstructive Pulmonary Disease ◽  
Tracheal Epithelial Cells ◽  
And Function

Rhinovirus (RV) infection is involved in acute exacerbations of asthma and chronic obstructive pulmonary disease (COPD). RV primarily infects upper and lower airway epithelium. Immunoproteasomes (IP) are proteolytic machineries with multiple functions including the regulation of MHC class I antigen processing during viral infection. However, the role of IP in RV infection has not been explored. We sought to investigate the expression and function of IP during airway RV infection. Primary human tracheobronchial epithelial (HTBE) cells were cultured at air–liquid interface (ALI) and treated with RV16, RV1B, or interferon (IFN)-λ in the absence or presence of an IP inhibitor (ONX-0914). IP gene (i.e. LMP2) deficient mouse tracheal epithelial cells (mTECs) were cultured for the mechanistic studies. LMP2-deficient mouse model was used to define the in vivo role of IP in RV infection. IP subunits LMP2 and LMP7, antiviral genes MX1 and OAS1 and viral load were measured. Both RV16 and RV1B significantly increased the expression of LMP2 and LMP7 mRNA and proteins, and IFN-λ mRNA in HTBE cells. ONX-0914 down-regulated MX1 and OAS1, and increased RV16 load in HTBE cells. LMP2-deficient mTECs showed a significant increase in RV1B load compared with the wild-type (WT) cells. LMP2-deficient (compared with WT) mice increased viral load and neutrophils in bronchoalveolar lavage (BAL) fluid after 24 h of RV1B infection. Mechanistically, IFN-λ induction by RV infection contributed to LMP2 and LMP7 up-regulation in HTBE cells. Our data suggest that IP are induced during airway RV infection, which in turn may serve as an antiviral and anti-inflammatory mechanism.

scholarly journals The role of microRNAs in chronic respiratory disease: recent insights

2018 ◽  
Vol 399 (3) ◽  
pp. 219-234 ◽  
Author(s):  
Lindsay R. Stolzenburg ◽  
Ann Harris
Keyword(s):  
Respiratory Disease ◽  
Inflammatory Cells ◽  
Chronic Respiratory Disease ◽  
Chronic Obstructive ◽  
Lung Pathology ◽  
Obstructive Pulmonary Disease ◽  
Chronic Respiratory Diseases ◽  
And Function ◽  
Mirna Abundance

AbstractChronic respiratory diseases encompass a group of diverse conditions affecting the airways, which all impair lung function over time. They include cystic fibrosis (CF), idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and asthma, which together affect hundreds of millions of people worldwide. MicroRNAs (miRNAs), a class of small non-coding RNAs involved in post-transcriptional gene repression, are now recognized as major regulators in the development and progression of chronic lung disease. Alterations in miRNA abundance occur in lung tissue, inflammatory cells, and freely circulating in blood and are thought to function both as drivers and modifiers of disease. Their importance in lung pathology has prompted the development of miRNA-based therapies and biomarker tools. Here, we review the current literature on miRNA expression and function in chronic respiratory disease and highlight further research that is needed to propel miRNA treatments for lung disorders towards the clinic.

scholarly journals Dysregulation of the glutaredoxin/S-glutathionylation redox axis in lung diseases

2020 ◽  
Vol 318 (2) ◽  
pp. C304-C327 ◽  
Author(s):  
Shi B. Chia ◽  
Evan A. Elko ◽  
Reem Aboushousha ◽  
Allison M. Manuel ◽  
Cheryl van de Wetering ◽  
...  
Keyword(s):  
Lung Diseases ◽  
Defense Mechanism ◽  
Protein S ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Mixed Disulfide ◽  
Glutathione S Transferases ◽  
And Function ◽  
Redox Buffer

Glutathione is a major redox buffer, reaching millimolar concentrations within cells and high micromolar concentrations in airways. While glutathione has been traditionally known as an antioxidant defense mechanism that protects the lung tissue from oxidative stress, glutathione more recently has become recognized for its ability to become covalently conjugated to reactive cysteines within proteins, a modification known as S-glutathionylation (or S-glutathiolation or protein mixed disulfide). S-glutathionylation has the potential to change the structure and function of the target protein, owing to its size (the addition of three amino acids) and charge (glutamic acid). S-glutathionylation also protects proteins from irreversible oxidation, allowing them to be enzymatically regenerated. Numerous enzymes have been identified to catalyze the glutathionylation/deglutathionylation reactions, including glutathione S-transferases and glutaredoxins. Although protein S-glutathionylation has been implicated in numerous biological processes, S-glutathionylated proteomes have largely remained unknown. In this paper, we focus on the pathways that regulate GSH homeostasis, S-glutathionylated proteins, and glutaredoxins, and we review methods required toward identification of glutathionylated proteomes. Finally, we present the latest findings on the role of glutathionylation/glutaredoxins in various lung diseases: idiopathic pulmonary fibrosis, asthma, and chronic obstructive pulmonary disease.

scholarly journals Pack Years and Lower Lung Function is Associated With Ultra-short Telomeres in Copd: Evidence From Lung Tissue

2020 ◽  
Author(s):  
Huseyin Cagsin ◽  
Nedime Serakinci ◽  
Ali Uzan ◽  
Finn Rasmussen
Keyword(s):  
Lung Function ◽  
Telomere Length ◽  
Lung Tissue ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Significant Difference ◽  
Lower Lung ◽  
Bronchial Washing

Abstract BackgroundChronic obstructive pulmonary disease (COPD) is driven by a complicated mix of factors such as lifestyle and environmental exposures. Tobacco smoking is the main risk factor for forming chronic inflammation in COPD. Association between cigarette smoking and the role of telomere shortening in COPD has been studied mainly based on the assessment of mean telomere length on leukocytes instead of lung tissue where the primary damage occurs. Here we investigate this association in bronchoalveolar samples by using a new assay that specifically evaluates critically short telomeres, namely, ultra-short telomeres that have sizes less than 1.5kb.MethodsThe study was carried out on materials from the patients eligible for bronchoscopy as well as mild to severe persistent airway obstruction, defined as a post-bronchodilator ratio of less than 70%. Bronchial washing (BW) and leukocyte samples were collected from 32 patients diagnosed with COPD. Telomere length evaluation was done with isolated DNA using Universal STELA to specifically identify the presence of ultra-short telomeres in samples. A t-Student, ANOVA, Chi2, and Paired Sample T-test were used to test differences in means and proportions in statistical analysis. Two-tailed p-values ≤ 0.05 were considered significantResultsThe location of BW did not show a significant difference when compared in terms of the presence of ultra-short telomeres (p>0.05). Higher total pack-years was found amongst patients with ultra-short telomeres (32 packyears versus 16 packyears; p=0.045), lower lung function (FEV1%) (51% versus 82%; p<0.001) when compared with subjects with telomere length more than 1.5kbs in BW. An increasing number of total pack-years, older age and lower FEV1% was observed through the groups comprising subjects with ultra-short telomeres in both BW and leukocytes, subjects with ultra-short telomeres only in BW and subjects with telomeres longer than 1.5kbs(all p<0.01) ConclusionsOur results emphasize the role of ultra-short telomeres in COPD, in vivo, especially when the lung tissue instead of leukocytes is investigated. Additionally, our results demonstrated a dose-response association between pack-years of smoking, low lung function, and ultra-short telomere length in COPD.

scholarly journals Role of Atypical Chemokines and Chemokine Receptors Pathways In the Pathogenesis of Copd

2020 ◽  
Vol 27 ◽  
Author(s):  
Francesco Nucera ◽  
Federica Lo Bello ◽  
Sj S. Shen ◽  
Paolo Ruggeri ◽  
Irene Coppolino ◽  
...  
Keyword(s):  
Chemokine Receptors ◽  
Animal Studies ◽  
High Mobility ◽  
Inflammatory Cells ◽  
Lower Airway ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Inflammatory Processes ◽  
Inflammatory Drugs

: Chronic obstructive pulmonary disease (COPD) represents a heightened inflammatory response in the lung resulting generally from tobacco smoking-induced recruitment and activation of inflammatory cells and/or activation of lower airway structural cells. Several mediators can modulate activation and recruitment of these cells, particularly those belonging to the chemokines (conventional and atypical) family. There is emerging evidence for complex roles of atypical chemokines and their receptors [such as high mobility group box 1 (HMGB1), antimicrobial peptides, receptor for advanced glycosylation end product (RAGE) or toll-like receptors (TLRs)] in the pathogenesis of COPD, both in the stable disease and during exacerbations. Modulators of these pathways represent potential novel therapies for COPD and many are now in pre-clinical development. Inhibition of only a single atypical chemokine or receptor may not block inflammatory processes, be-cause there is redundancy in this network. However, there are many animal studies that encourage studies for modulating the atypical chemokine network in COPD. Thus, few pharmaceutical companies maintain a significant interest in developing agents that target these molecules as potential anti-inflammatory drugs. Antibody-based (biological) and small molecule drug (SMD)-based therapies targeting atypical chemokines and/or their receptors are mostly at the preclinical stage and their progression to clinical trials is eagerly awaited. These agents will most likely enhance our knowledge about the role of a typical chemokines in COPD pathophysiology and thereby improve COPD management.

scholarly journals MTMR14 Alleviates Chronic Obstructive Pulmonary Disease as a Regulator in Inflammation and Emphysema

2022 ◽  
Vol 2022 ◽  
pp. 1-21
Author(s):  
Yiya Gu ◽  
Jinkun Chen ◽  
Qian Huang ◽  
Yuan Zhan ◽  
Ting Wang ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Mitochondrial Function ◽  
Lavage Fluid ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Copd Patients

Extensive inflammation and apoptosis in structural cells of the lung are responsible for the progression and pathogenesis of chronic obstructive pulmonary disease (COPD). Myotubularin-related protein 14 (MTMR14) has been shown to participate in various biological processes, including apoptosis, inflammation, and autophagy. Nonetheless, the role of MTMR14 in COPD remains elusive. In the present study, we explored the expression of MTMR14 in human lung tissues and investigated the effects of overexpressed MTMR14 on in vitro and in vivo COPD models. Moreover, one of the possible mechanisms of MTMR14 alleviating COPD was explored based on mitochondrial function and mitophagy homeostasis. The results showed that MTMR14 expression was reduced in COPD patients’ lungs in comparison to control subjects. MTMR14 overexpression inhibited cigarette smoke extract-induced inflammation and apoptosis and improved mitochondrial function and mitophagy in vitro. Further verification was carried out in COPD model mice. MTMR14 overexpression inhibited lung inflammation and reduced levels of IL-6 and KC in bronchoalveolar lavage fluid, as well as prevented emphysema and a decline in lung function. Furthermore, MTMR14 overexpression improved mitochondrial function and mitophagy to a certain extent. Collectively, our data support the hypothesis that MTMR14 participates in the pathogenesis of COPD. Improving mitochondrial function and mitophagy homeostasis may be one of the mechanisms by which MTMR14 alleviates COPD and may potentially be a novel therapeutic target for COPD.

Role of exhaled nitric oxide in predicting steroid response in chronic obstructive pulmonary disease

2010 ◽  
Vol 151 (51) ◽  
pp. 2083-2088 ◽  
Author(s):  
Balázs Antus
Keyword(s):  
Nitric Oxide ◽  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Exhaled Nitric Oxide ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Steroid Response

A kilégzett levegőben mérhető nitrogén-monoxid a legszélesebb körben vizsgált légúti biomarker. A stabil állapotú krónikus obstruktív tüdőbetegségben a kilégzett nitrogén-monoxid-szint hasonló vagy csak kismértékben emelkedett az egészségesekhez képest. Mivel a nitrogén-monoxid-szint szoros összefüggést mutat a légúti eosinophilia mértékével, és mivel az eosinophil típusú légúti gyulladás szteroidokra érzékenyebb, az emelkedett nitrogén-monoxid-szinttel rendelkező betegek jobb válaszkészséget mutatnak az inhalációs vagy szisztémás kortikoszteroidkezelésre. A krónikus obstruktív tüdőbetegség akut exacerbatiója során a kilégzett nitrogén-monoxid szintje megemelkedik, majd ennek kezelése után csökken. Mivel a nitrogén-monoxid-szint és a kezelés során elért légzésfunkciós javulás szoros korrelációt mutat egymással, a nitrogén-monoxid-méréssel a terápiás válasz megjósolható. Összefoglalva: a nitrogén-monoxid-méréssel a krónikus obstruktív tüdőbetegségben szenvedő betegek olyan alcsoportját lehet elkülöníteni, amelynek szteroidérzékenysége nagyobb. Orv. Hetil., 2010, 151, 2083–2088.

Participation of ABCA1 transporter in development of chronic obstructive pulmonary disease

2020 ◽  
Vol 28 (3) ◽  
pp. 360-370
Author(s):  
Stanislav N. Kotlyarov ◽  
Anna A. Kotlyarova
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Significant Contribution ◽  
Modern Medicine ◽  
Lipid Homeostasis ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Reverse Transport ◽  
Current Paradigm

Despite all achievements of the modern medicine, the problem of chronic obstructive pulmonary disease (COPD) does not lose its relevance. The current paradigm suggests a key role of macrophages in inflammation in COPD. Macrophages are known to be heterogeneous in their functions. This heterogeneity is determined by their immunometabolic profile and also by peculiarities of lipid homeostasis of cells. Aim. To analyze the role of the ABCA1 transporter, a member of the ABC A subfamily, in the pathogenesis of COPD. The expression of ABCA1 in lung tissues is on the second place after the liver, which shows the important role of the carrier and of lipid homeostasis in the function of lungs. Analysis of the literature shows that participation of the transporter in inflammation consists in regulation of the content of cholesterol in the lipid rafts of the membranes, in phagocytosis and apoptosis. Conclusion. Through regulation of the process of reverse transport of cholesterol in macrophages of lungs, ABCA1 can change their inflammatory response, which makes a significant contribution to the pathogenesis of COPD.

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