scholarly journals Lymphatic Thrombosis and Impaired Lymph Drainage in Cigarette Smoke-Associated Emphysema

2021 ◽  
Author(s):  
Barbara D. Summers ◽  
Kihwan Kim ◽  
Zohaib Khan ◽  
Sangeetha Thangaswamy ◽  
Cristina C. Clement ◽  
...  
Keyword(s):  
Disease Severity ◽  
Cigarette Smoke ◽  
Lymphatic Endothelial Cell ◽  
Lymphatic Drainage ◽  
Cigarette Smoke Exposure ◽  
Leukocyte Trafficking ◽  
Cell Integrity ◽  
Human Lung Tissue ◽  
Lymphatic Function

Abstract The lymphatic vasculature is critical for lung function, but defects in lymphatic function in the pathogenesis of lung disease is understudied. In mice, lymphatic dysfunction alone is sufficient to cause lung injury that resembles human emphysema. Whether lymphatic function is disrupted in cigarette smoke (CS)-induced emphysema is unknown. In this study, we investigated lung lymphatic function in the pathogenesis of CS-induced emphysema. Analysis of human lung tissue revealed significant lung lymphatic thrombosis in patients with emphysema compared to control smokers that increased with disease severity. In vitro assays demonstrated a direct effect of CS on lymphatic endothelial cell integrity. In a mouse model, CS exposure led to lung lymphatic thrombosis, decreased lymphatic drainage, and impaired leukocyte trafficking that preceded emphysema. Proteomic analysis of lymph confirmed upregulation of coagulation and inflammatory pathways in the lymphatics of CS-exposed mice compared to control mice. These data suggest that CS exposure results in lung lymphatic dysfunction with thrombosis, impaired leukocyte trafficking, and changes in the composition of lymph. In patients with emphysema, lung lymphatic thrombosis is seen with increasing disease severity. These studies for the first time demonstrate lung lymphatic dysfunction after cigarette smoke exposure and suggest a novel component in the pathogenesis of emphysema.

scholarly journals Lymphatic Thrombosis and Impaired Lymph Drainage in Cigarette Smoke-Associated Emphysema

2021 ◽  
Author(s):  
Barbara D. Summers ◽  
Kihwan Kim ◽  
Zohaib Khan ◽  
Sangeetha Thangaswamy ◽  
Cristina C. Clement ◽  
...  
Keyword(s):  
Disease Severity ◽  
Cigarette Smoke ◽  
Lymphatic Endothelial Cell ◽  
In Vitro Assays ◽  
Cigarette Smoke Exposure ◽  
Leukocyte Trafficking ◽  
Cell Integrity ◽  
Human Lung Tissue ◽  
Lymphatic Function

The lymphatic vasculature is critical for lung function, but defects in lymphatic function in the pathogenesis of lung disease is understudied. In mice, lymphatic dysfunction alone is sufficient to cause lung injury that resembles human emphysema. Whether lymphatic function is disrupted in cigarette smoke (CS)-induced emphysema is unknown. In this study, we investigated lung lymphatic function in the pathogenesis of CS-induced emphysema. Analysis of human lung tissue revealed significant lung lymphatic thrombosis in patients with emphysema compared to control smokers that increased with disease severity. In vitro assays demonstrated a direct effect of CS on lymphatic endothelial cell integrity. In a mouse model, CS exposure led to lung lymphatic thrombosis, decreased lymphatic drainage, and impaired leukocyte trafficking that preceded emphysema. Proteomic analysis of lymph confirmed upregulation of coagulation and inflammatory pathways in the lymphatics of CS-exposed mice compared to control mice. These data suggest that CS exposure results in lung lymphatic dysfunction with thrombosis, impaired leukocyte trafficking, and changes in the composition of lymph. In patients with emphysema, lung lymphatic thrombosis is seen with increasing disease severity. These studies for the first time demonstrate lung lymphatic dysfunction after cigarette smoke exposure and suggest a novel component in the pathogenesis of emphysema.

Humic-like substances in cigarette smoke condensate and lung tissue of smokers

1994 ◽  
Vol 266 (4) ◽  
pp. L382-L388 ◽  
Author(s):  
A. J. Ghio ◽  
J. Stonehuerner ◽  
D. R. Quigley
Keyword(s):  
Free Radical ◽  
Cigarette Smoke ◽  
Lung Tissue ◽  
Cigarette Smoke Exposure ◽  
Cigarette Smoke Condensate ◽  
Free Radical Generation ◽  
Carboxylate Content ◽  
Radical Generation

Deposition of pigmented matter in the lower respiratory tract correlates with the extent of emphysema in smokers as well as with free radical generation and iron accumulation. Pulmonary emphysema is postulated to be mediated by free radical generation which is either directly or indirectly associated with cigarette smoke exposure. The hypothesis was tested that 1) incomplete combustion of tobacco yields humic-like substances (HLS) which 2) deposit in the lung as pigmented particulates, 3) complex iron cations in vitro and in vivo, and 4) have a capacity to catalyze oxidant formation. HLS, isolated by alkali extraction of cigarette smoke condensate (CSC) (Tobacco Health Research Institute, University of Kentucky), demonstrated a high carbon and low carboxylate content on elemental and functional group analyses, respectively, compared with values for HLS sequestered from soils. The HLS isolated from CSC had a capacity to complex iron in vitro and accumulated the metal in vivo after intratracheal instillation in an animal model. Both HLS and its iron complex generated free radicals, and some portion of this oxidant generation was metal dependent. Lung tissue collected at autopsy from smokers contained HLS with an infrared spectrum almost identical to that of the material isolated from CSC. Associations between particulate deposition, metal accumulation, and free radical generation suggest a possible role of HLS in the induction of lung disease following cigarette exposure.

scholarly journals Assessment of an in vitro whole cigarette smoke exposure system: The Borgwaldt RM20S 8-syringe smoking machine

2011 ◽  
Vol 5 (1) ◽  
Author(s):  
Jason Adamson ◽  
David Azzopardi ◽  
Graham Errington ◽  
Colin Dickens ◽  
John McAughey ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Exposure System

scholarly journals The impact of cigarette smoke exposure, and COPD or asthma status on ABC transporter gene expression in human airway epithelial cells

2018 ◽  
Author(s):  
Jennifer A. Aguiar ◽  
Andrea Tamminga ◽  
Briallen Lobb ◽  
Ryan D. Huff ◽  
Jenny Nguyen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Cigarette Smoke ◽  
Abc Transporters ◽  
Airway Epithelial Cells ◽  
Cigarette Smoke Exposure ◽  
Airway Epithelial ◽  
Respiratory Mucosa

AbstractRationaleThe respiratory mucosa coordinates responses to infections, allergens, and exposures to air pollution. A relatively unexplored aspect of the respiratory mucosa are the expression and function of ATP Binding Cassette (ABC) transporters. ABC transporters are conserved in prokaryotes and eukaryotes, with humans expressing 48 transporters divided into 7 classes (ABCA, ABCB, ABCC, ABCD, ABDE, ABCF, and ABCG). Throughout the human body, ABC transporters regulate cAMP levels, chloride secretion, lipid transport, and anti-oxidant responses. A deeper exploration of the expression patterns of ABC transporters in the respiratory mucosa is warranted to determine their relevance in lung health and disease.MethodsWe used a bioinformatic approach complemented with in vitro experimental methods for validation of candidate ABC transporters. We analyzed the expression profiles of all 48 human ABC transporters in the respiratory mucosa using bronchial epithelial cell gene expression datasets available in NCBI GEO from well-characterized patient populations of healthy subjects and individuals that smoke cigarettes, or have been diagnosed with COPD or asthma. The Calu-3 airway epithelial cell line was used to interrogate selected results using a cigarette smoke extract exposure model.ResultsUsing 9 distinct gene-expression datasets of primary human airway epithelial cells, we completed a focused analysis on 48 ABC transporters in samples from healthy subjects and individuals that smoke cigarettes, or have been diagnosed with COPD or asthma. In situ gene expression data demonstrate that ABC transporters are i) variably expressed in epithelial cells from different airway generations (top three expression levels - ABCA5, ABCA13, and ABCC5), ii) regulated by cigarette smoke exposure (ABCA13, ABCB6, ABCC1, and ABCC3), and iii) differentially expressed in individuals with COPD and asthma (ABCA13, ABCC1, ABCC2, ABCC9). An in vitro cell culture model of cigarette smoke exposure was able to recapitulate the in situ changes observed in cigarette smokers for ABCA13 and ABCC1.ConclusionsOur in situ human gene expression data analysis reveals that ABC transporters are expressed throughout the airway generations in airway epithelial cells and can be modulated by environmental exposures important in chronic respiratory disease (e.g. cigarette smoking) and in individuals with chronic lung diseases (e.g. COPD or asthma). Our work highlights select ABC transporter candidates of interest and a relevant in vitro model that will enable a deeper understanding of the contribution of ABC transporters in the respiratory mucosa in lung health and disease.

scholarly journals Linking increased airway hydration, ciliary beating, and mucociliary clearance through ENaC inhibition

2015 ◽  
Vol 308 (1) ◽  
pp. L22-L32 ◽  
Author(s):  
Annika B. M. Åstrand ◽  
Martin Hemmerling ◽  
James Root ◽  
Cecilia Wingren ◽  
Jelena Pesic ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Mucociliary Clearance ◽  
Short Circuit ◽  
Beat Frequency ◽  
Bacterial Overgrowth ◽  
Cigarette Smoke Exposure ◽  
Duration Of Action ◽  
Compound A

Airway dehydration causes mucus stasis and bacterial overgrowth in cystic fibrosis and chronic bronchitis (CB). Rehydration by hypertonic saline is efficacious but suffers from a short duration of action. We tested whether epithelial sodium channel (ENaC) inhibition would rehydrate normal and dehydrated airways to increase mucociliary clearance (MCC) over a significant time frame. For this, we used a tool compound (Compound A), which displays nanomolar ENaC affinity and retention in the airway surface liquid (ASL). Using normal human bronchial epithelial cultures (HBECs) grown at an air-liquid interface, we evaluated in vitro potency and efficacy using short-circuit current ( Isc) and ASL height measurements where it inhibited Isc and increased ASL height by ∼50% (0.052 μM at 6 h), respectively. The in vivo efficacy was investigated in a modified guinea pig tracheal potential difference model, where we observed an effective dose (ED50) of 5 μg/kg (i.t.), and by MCC measures in rats and sheep, where we demonstrated max clearance rates at 100 μg/kg (i.t.) and 75 μg/kg (i.t.), respectively. Acute cigarette smoke-induced ASL height depletion in HBECs was used to mimic the situation in patients with CB, and pretreatment prevented both cigarette smoke-induced ASL dehydration and lessened the decrease in ciliary beat frequency. Furthermore, when added after cigarette smoke exposure, Compound A increased the rate of ASL rehydration. In conclusion, Compound A demonstrated significant effects and a link between increased airway hydration, ciliary function, and MCC. These data support the hypothesis that ENaC inhibition may be efficacious in the restoration of mucus hydration and transport in patients with CB.

Cigarette smoke extract increases albumin flux across pulmonary endothelium in vitro

1989 ◽  
Vol 66 (1) ◽  
pp. 443-449 ◽  
Author(s):  
W. E. Holden ◽  
J. M. Maier ◽  
M. R. Malinow
Keyword(s):  
Cigarette Smoke ◽  
Morphological Changes ◽  
Cell Damage ◽  
Divalent Cations ◽  
Endothelial Permeability ◽  
Cigarette Smoke Exposure ◽  
Pulmonary Endothelium ◽  
Cytoskeletal Elements

Cigarette smoking causes lung inflammation, and a characteristic of inflammation is an increase in vascular permeability. To determine if cigarette smoke could alter endothelial permeability, we studied flux of radiolabeled albumin across monolayers of porcine pulmonary artery endothelium grown in culture on microporous membranes. Extracts (in either dimethylsulfoxide or phosphate-buffered saline) of cigarette smoke in a range estimate of concentrations simulating cigarette smoke exposure to the lungs in vivo caused a dose-dependent increase in albumin flux that was dependent on extracellular divalent cations and associated with polymerization of cellular actin. The effect was reversible, independent of the surface of endothelial cells exposed (either luminal or abluminal), and due primarily to components of the vapor phase of smoke. The effects occurred without evidence of cell damage, but subtle morphological changes were produced by exposure to the smoke extracts. These findings suggest that cigarette smoke can alter permeability of the lung endothelium through effects on cytoskeletal elements.

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