Cigarette smoke alters inflammatory genes and the extracellular matrix — investigations on viable sections of peripheral human lungs

AbstractChronic obstructive pulmonary disease (COPD) is a complex chronic respiratory disorder often caused by cigarette smoke. Cigarette smoke contains hundreds of toxic substances. In our study, we wanted to identify initial mechanisms of cigarette smoke induced changes in the distal lung. Viable slices of human lungs were exposed 24 h to cigarette smoke condensate, and the dose–response profile was analyzed. Non-toxic condensate concentrations and lipopolysaccharide were used for further experiments. COPD-related protein and gene expression was measured. Cigarette smoke condensate did not induce pro-inflammatory cytokines and most inflammation-associated genes. In contrast, lipopolysaccharide significantly induced IL-1α, IL-1β, TNF-α and IL-8 (proteins) and IL1B, IL6, and TNF (genes). Interestingly, cigarette smoke condensate induced metabolism- and extracellular matrix–associated proteins and genes, which were not influenced by lipopolysaccharide. Also, a significant regulation of CYP1A1 and CYP1B1, as well as MMP9 and MMP9/TIMP1 ratio, was observed which resembles typical findings in COPD. In conclusion, our data show that cigarette smoke and lipopolysaccharide induce significant responses in human lung tissue ex vivo, giving first hints that COPD starts early in smoking history.

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Smoking tends to decrease glutathione and increase malondialdehyde levels in medical students

Zinc supplementation improves heme biosynthesis in rats exposed to lead ◽

10.18051/univmed.2016.v35.89-95 ◽

2016 ◽

Vol 35 (2) ◽

pp. 89 ◽

Cited By ~ 1

Author(s):

Safyudin Safyudin ◽

Subandrate Subandrate

Keyword(s):

Medical Students ◽

Cigarette Smoke ◽

The Body ◽

Smoking History ◽

Chronic Obstructive ◽

Toxic Substances ◽

Cross Sectional ◽

Obstructive Pulmonary Disease ◽

Significant Difference ◽

Endogenous Antioxidant

Background Smoking is the act of introducing toxic substances into the body. Cigarette smoke contains chemicals that may cause several disorders, including cardiovascular disease, cancer, and chronic obstructive pulmonary disease. Toxic substances in cigarette smoke have the potential to increase free radicals, malondialdehyde (MDA) levels and to decrease endogenous antioxidant (glutathione/GSH) levels. This study aims to determine the relationship of smoking with plasma GSH and MDA levels in medical students. Methods This study was analytical observational with cross-sectional approach. The study was conducted from April to December 2015. The subjects in this study were medical students, consisting of 20 smokers and 20 nonsmokers. Plasma GSH and MDA levels were determined biochemically using Sigma GSH Assay Kit and Sigma MDA Assay Kit. Data was analyzed using the independent t test. Results The results showed that there was no significant difference between mean GSH in smokers (1.74 ± 0.91 mmol/L) and nonsmokers (2.42 ± 1.19 µmol/L) (p=0.441). Mean smokers MDA level of 2.06 ± 1.39 nmol/mL was not significantly different compared with mean nonsmokers MDA level (1.32 ± 0.90 nmol/mL) (p=0.092). Conclusions Smoking tends to decrease plasma GSH levels and increase plasma MDA levels in medical students. Smoking history could be evidence of oxidative stress and an impaired oxidant defense system. In particular, young smokers should quit promptly before health problems arise, so as to have the optimal benefits of cessation.

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Host and viral determinants for efficient SARS-CoV-2 infection of the human lung

10.21203/rs.3.rs-40123/v1 ◽

2020 ◽

Author(s):

Hin Chu ◽

Bingjie Hu ◽

Xiner Huang ◽

Yue Chai ◽

Yixin Wang ◽

...

Keyword(s):

Human Lung ◽

Ex Vivo ◽

Sialic Acids ◽

Lung Epithelial Cells ◽

Human Lung Tissue ◽

Human Lungs ◽

Lung Epithelial ◽

Viral Determinants ◽

Attachment Factor ◽

Human Lung Epithelial Cells

Abstract SARS-CoV-2 has affected over 9 million patients with more than 460,000 deaths in about 6 months. Understanding the factors that contribute to efficient SARS-CoV-2 infection of human cells, which are not previously reported, may provide insights on SARS-CoV-2 transmissibility and pathogenesis, and reveal targets of intervention. Here, we reported key host and viral determinants that were essential for efficient SARS-CoV-2 infection in the human lung. First, we identified heparan sulfate as an important attachment factor for SARS-CoV-2 infection. Second, we demonstrated that while cell surface sialic acids significantly restricted SARS-CoV infection, SARS-CoV-2 could largely overcome sialic acid-mediated restriction in both human lung epithelial cells and ex vivo human lung tissue explants. Third, we demonstrated that the inserted furin-like cleavage site in SARS-CoV-2 spike was required for efficient virus replication in human lung but not intestine tissues. Overall, these findings contributed to our understanding on efficient SARS-CoV-2 infection of human lungs.

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Matrine reduces cigarette smoke-induced airway neutrophilic inflammation by enhancing neutrophil apoptosis

Clinical Science ◽

10.1042/cs20180912 ◽

2019 ◽

Vol 133 (4) ◽

pp. 551-564 ◽

Cited By ~ 9

Author(s):

Xuhua Yu ◽

Huei Jiunn Seow ◽

Hao Wang ◽

Desiree Anthony ◽

Steven Bozinovski ◽

...

Keyword(s):

Cigarette Smoke ◽

Lung Inflammation ◽

Therapeutic Potential ◽

Proteolytic Enzymes ◽

Ex Vivo ◽

Lavage Fluid ◽

Airflow Limitation ◽

Chronic Obstructive ◽

Neutrophilic Inflammation ◽

Anti Inflammatory

AbstractChronic Obstructive Pulmonary Disease (COPD) is a major incurable global health burden and will become the third largest cause of death in the world by 2030. It is well established that an exaggerated inflammatory and oxidative stress response to cigarette smoke (CS) leads to, emphysema, small airway fibrosis, mucus hypersecretion, and progressive airflow limitation. Current treatments have limited efficacy in inhibiting chronic inflammation and consequently do not reverse the pathology that initiates and drives the long-term progression of disease. In particular, there are no effective therapeutics that target neutrophilic inflammation in COPD, which is known to cause tissue damage by degranulation of a suite of proteolytic enzymes including neutrophil elastase (NE). Matrine, an alkaloid compound extracted from Sophora flavescens Ait, has well known anti-inflammatory activity. Therefore, the aim of the present study was to investigate whether matrine could inhibit CS-induced lung inflammation in mice. Matrine significantly reduced CS-induced bronchoalveolar lavage fluid (BALF) neutrophilia and NE activity in mice. The reduction in BALF neutrophils in CS-exposed mice by matrine was not due to reductions in pro-neutrophil cytokines/chemokines, but rather matrine’s ability to cause apoptosis of neutrophils, which we demonstrated ex vivo. Thus, our data suggest that matrine has anti-inflammatory actions that could be of therapeutic potential in treating CS-induced lung inflammation observed in COPD.

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Cigarette smoke induction of S100A9 contributes to chronic obstructive pulmonary disease

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00207.2020 ◽

2020 ◽

Vol 319 (6) ◽

pp. L1021-L1035

Author(s):

Christopher Railwah ◽

Alnardo Lora ◽

Kanza Zahid ◽

Hannah Goldenberg ◽

Michael Campos ◽

...

Keyword(s):

Chronic Obstructive Pulmonary Disease ◽

Extracellular Matrix ◽

Lung Function ◽

Matrix Metalloproteinase ◽

Pulmonary Disease ◽

Cigarette Smoke ◽

Lung Fibroblasts ◽

Chronic Obstructive ◽

Obstructive Pulmonary Disease ◽

Acute And Chronic Exposure

S100 calcium-binding protein A9 (S100A9) is elevated in plasma and bronchoalveolar lavage fluid (BALF) of patients with chronic obstructive pulmonary disease (COPD), and aging enhances S100A9 expression in several tissues. Currently, the direct impact of S100A9-mediated signaling on lung function and within the aging lung is unknown. Here, we observed that elevated S100A9 levels in human BALF correlated with age. Elevated lung levels of S100A9 were higher in older mice compared with in young animals and coincided with pulmonary function changes. Both acute and chronic exposure to cigarette smoke enhanced S100A9 levels in age-matched mice. To examine the direct role of S100A9 on the development of COPD, S100a9−/− mice or mice administered paquinimod were exposed to chronic cigarette smoke. S100A9 depletion and inhibition attenuated the loss of lung function, pressure-volume loops, airway inflammation, lung compliance, and forced expiratory volume in 0.05 s/forced vital capacity, compared with age-matched wild-type or vehicle-administered animals. Loss of S100a9 signaling reduced cigarette smoke-induced airspace enlargement, alveolar remodeling, lung destruction, ERK and c-RAF phosphorylation, matrix metalloproteinase-3 (MMP-3), matrix metalloproteinase-9 (MMP-9), monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6), and keratinocyte-derived chemokine (KC) release into the airways. Paquinimod administered to nonsmoked, aged animals reduced age-associated loss of lung function. Since fibroblasts play a major role in the production and maintenance of extracellular matrix in emphysema, primary lung fibroblasts were treated with the ERK inhibitor LY3214996 or the c-RAF inhibitor GW5074, resulting in less S100A9-induced MMP-3, MMP-9, MCP-1, IL-6, and IL-8. Silencing Toll-like receptor 4 (TLR4), receptor for advanced glycation endproducts (RAGE), or extracellular matrix metalloproteinase inducer (EMMPRIN) prevented S100A9-induced phosphorylation of ERK and c-RAF. Our data suggest that S100A9 signaling contributes to the progression of smoke-induced and age-related COPD.

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Cigarette smoke and CFTR: implications in the pathogenesis of COPD

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00039.2013 ◽

2013 ◽

Vol 305 (8) ◽

pp. L530-L541 ◽

Cited By ~ 87

Author(s):

Andras Rab ◽

Steven M. Rowe ◽

S. Vamsee Raju ◽

Zsuzsa Bebok ◽

Sadis Matalon ◽

...

Keyword(s):

Cystic Fibrosis ◽

Cigarette Smoke ◽

Inflammatory Responses ◽

Common Mechanism ◽

Chronic Obstructive ◽

Respiratory Disorder ◽

Chronic Infections ◽

Gene Encoding ◽

Obstructive Pulmonary Disease ◽

Copd Patients

Chronic obstructive pulmonary disease (COPD) is a progressive respiratory disorder consisting of chronic bronchitis and/or emphysema. COPD patients suffer from chronic infections and display exaggerated inflammatory responses and a progressive decline in respiratory function. The respiratory symptoms of COPD are similar to those seen in cystic fibrosis (CF), although the molecular basis of the two disorders differs. CF is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator ( CFTR) gene encoding a chloride and bicarbonate channel (CFTR), leading to CFTR dysfunction. The majority of COPD cases result from chronic oxidative insults such as cigarette smoke. Interestingly, environmental stresses including cigarette smoke, hypoxia, and chronic inflammation have also been implicated in reduced CFTR function, and this suggests a common mechanism that may contribute to both the CF and COPD. Therefore, improving CFTR function may offer an excellent opportunity for the development of a common treatment for CF and COPD. In this article, we review what is known about the CF respiratory phenotype and discuss how diminished CFTR expression-associated ion transport defects may contribute to some of the pathological changes seen in COPD.

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Smoke and viruses–a hindrance to relaxing the airways?

Clinical Science ◽

10.1042/cs20160139 ◽

2016 ◽

Vol 130 (10) ◽

pp. 839-841

Author(s):

Aran Singanayagam ◽

Sebastian L. Johnston

Keyword(s):

Cigarette Smoke ◽

Ex Vivo ◽

Influenza Infection ◽

Chronic Obstructive ◽

Airway Reactivity ◽

Obstructive Pulmonary Disease ◽

Adrenoceptor Agonists ◽

Respiratory Virus Infection ◽

Exacerbation Of Copd ◽

Precision Cut Lung Slices

Inhaled β2-adrenoceptor agonists are a mainstay of therapy for airways diseases and are almost universally prescribed for patients with asthma or chronic obstructive pulmonary disease (COPD). Very few studies have evaluated the efficacy of these commonly used therapies during acute disease exacerbations which are frequently triggered by viral infection. In this edition of Clinical Science, Donovan et al. assess the ex vivo effects of the most commonly used short-acting β2-agonist salbutamol on small airway reactivity using precision cut lung slices (PCLS) from a mouse model of virus-induced exacerbation of COPD. They demonstrate that combined challenge with cigarette smoke and influenza infection in mice markedly impairs salbutamol-mediated airway relaxation. The findings of the present study suggest that cigarette smoke and respiratory virus infection may intefere with the ability of commonly prescribed therapies to effectively bronchodilate the airways.

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Collagen VI Is Upregulated in COPD and Serves Both as an Adhesive Target and a Bactericidal Barrier for Moraxella catarrhalis

Journal of Innate Immunity ◽

10.1159/000381213 ◽

2015 ◽

Vol 7 (5) ◽

pp. 506-517 ◽

Cited By ~ 16

Author(s):

Suado M. Abdillahi ◽

Marta Bober ◽

Sara Nordin ◽

Oskar Hallgren ◽

Maria Baumgarten ◽

...

Keyword(s):

Extracellular Matrix ◽

Moraxella Catarrhalis ◽

Ex Vivo ◽

Chronic Obstructive ◽

Collagen Vi ◽

Gram Negative ◽

Bacterial Surface ◽

Copd Patients ◽

Fibrillar Component

Moraxella catarrhalis is a Gram-negative human mucosal commensal and pathogen. It is a common cause of exacerbation in chronic obstructive pulmonary disease (COPD). During the process of infection, host colonization correlates with recognition of host molecular patterns. Importantly, in COPD patients with compromised epithelial integrity the underlying extracellular matrix is exposed and provides potential adhesive targets. Collagen VI is a ubiquitous fibrillar component in the airway mucosa and has been attributed both adhesive and killing properties against Gram-positive bacteria. However, less is known regarding Gram-negative microorganisms. Therefore, in the present study, the interaction of M. catarrhalis with collagen VI was characterized. We found that collagen VI is upregulated in the airways of COPD patients and exposed upon epithelial desquamation. Ex vivo, we inoculated airway biopsies and fibroblasts from COPD patients with M. catarrhalis. The bacteria specifically adhered to collagen VI-containing matrix fibrils. In vitro, purified collagen VI microfibrils bound to bacterial surface structures. The primary adhesion target was mapped to the collagen VI α2-chain. Upon exposure to collagen VI, bacteria were killed by membrane destabilization in physiological conditions. These previously unknown properties of collagen VI provide novel insights into the extracellular matrix innate immunity by quickly entrapping and killing pathogen intruders.

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Cigarette smoke induces overexpression of active human cathepsin S in lungs from current smokers with or without COPD

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00061.2019 ◽

2019 ◽

Vol 317 (5) ◽

pp. L625-L638 ◽

Cited By ~ 5

Author(s):

Pierre-Marie Andrault ◽

Andrea C. Schamberger ◽

Thibault Chazeirat ◽

Damien Sizaret ◽

Justine Renault ◽

...

Keyword(s):

Cigarette Smoking ◽

Cigarette Smoke ◽

Lung Diseases ◽

Smoking History ◽

Cathepsin S ◽

Chronic Obstructive ◽

P2x7 Receptors ◽

Aberrant Expression ◽

Never Smokers ◽

Expression And Activity

Cigarette smoking has marked effects on lung tissue, including induction of oxidative stress, inflammatory cell recruitment, and a protease/antiprotease imbalance. These effects contribute to tissue remodeling and destruction resulting in loss of lung function in chronic obstructive pulmonary disease (COPD) patients. Cathepsin S (CatS) is a cysteine protease that is involved in the remodeling/degradation of connective tissue and basement membrane. Aberrant expression or activity of CatS has been implicated in a variety of diseases, including arthritis, cancer, cardiovascular, and lung diseases. However, little is known about the effect of cigarette smoking on both CatS expression and activity, as well as its role in smoking-related lung diseases. Here, we evaluated the expression and activity of human CatS in lung tissues from never-smokers and smokers with or without COPD. Despite the presence of an oxidizing environment, CatS expression and activity were significantly higher in current smokers (both non-COPD and COPD) compared with never-smokers, and correlated positively with smoking history. Moreover, we found that the exposure of primary human bronchial epithelial cells to cigarette smoke extract triggered the activation of P2X7 receptors, which in turns drives CatS upregulation. The present data suggest that excessive CatS expression and activity contribute, beside other proteases, to the deleterious effects of cigarette smoke on pulmonary homeostasis.

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Human lung extracellular matrix hydrogels resemble the stiffness and viscoelasticity of native lung tissue

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00451.2019 ◽

2020 ◽

Vol 318 (4) ◽

pp. L698-L704 ◽

Cited By ~ 4

Author(s):

R. H. J. de Hilster ◽

P. K. Sharma ◽

M. R. Jonker ◽

E. S. White ◽

E. A. Gercama ◽

...

Keyword(s):

Extracellular Matrix ◽

Lung Tissue ◽

Viscoelastic Properties ◽

Human Lung ◽

Chronic Obstructive Lung Disease ◽

Chronic Obstructive ◽

Human Lung Tissue ◽

Native Tissue ◽

Maxwell Element ◽

Chronic Lung Diseases

Chronic lung diseases such as idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are associated with changes in extracellular matrix (ECM) composition and abundance affecting the mechanical properties of the lung. This study aimed to generate ECM hydrogels from control, severe COPD [Global Initiative for Chronic Obstructive Lung Disease (GOLD) IV], and fibrotic human lung tissue and evaluate whether their stiffness and viscoelastic properties were reflective of native tissue. For hydrogel generation, control, COPD GOLD IV, and fibrotic human lung tissues were decellularized, lyophilized, ground into powder, porcine pepsin solubilized, buffered with PBS, and gelled at 37°C. Rheological properties from tissues and hydrogels were assessed with a low-load compression tester measuring the stiffness and viscoelastic properties in terms of a generalized Maxwell model representing phases of viscoelastic relaxation. The ECM hydrogels had a greater stress relaxation than tissues. ECM hydrogels required three Maxwell elements with slightly faster relaxation times (τ) than that of native tissue, which required four elements. The relative importance (Ri) of the first Maxwell element contributed the most in ECM hydrogels, whereas for tissue the contribution was spread over all four elements. IPF tissue had a longer-lasting fourth element with a higher Ri than the other tissues, and IPF ECM hydrogels did require a fourth Maxwell element, in contrast to all other ECM hydrogels. This study shows that hydrogels composed of native human lung ECM can be generated. Stiffness of ECM hydrogels resembled that of whole tissue, while viscoelasticity differed.

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