scholarly journals Excess mucus viscosity and airway dehydration impact COPD airway clearance

2019 ◽  
Vol 55 (1) ◽  
pp. 1900419 ◽  
Author(s):  
Vivian Y. Lin ◽  
Niroop Kaza ◽  
Susan E. Birket ◽  
Harrison Kim ◽  
Lloyd J. Edwards ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Repeated Measures ◽  
Mucociliary Clearance ◽  
Beat Frequency ◽  
Airway Epithelial Cells ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Mucus Clearance

The mechanisms by which cigarette smoking impairs airway mucus clearance are not well understood. We recently established a ferret model of cigarette smoke-induced chronic obstructive pulmonary disease (COPD) exhibiting chronic bronchitis. We investigated the effects of cigarette smoke on mucociliary transport (MCT).Adult ferrets were exposed to cigarette smoke for 6 months, with in vivo mucociliary clearance measured by technetium-labelled DTPA retention. Excised tracheae were imaged with micro-optical coherence tomography. Mucus changes in primary human airway epithelial cells and ex vivo ferret airways were assessed by histology and particle tracking microrheology. Linear mixed models for repeated measures identified key determinants of MCT.Compared to air controls, cigarette smoke-exposed ferrets exhibited mucus hypersecretion, delayed mucociliary clearance (−89.0%, p<0.01) and impaired tracheal MCT (−29.4%, p<0.05). Cholinergic stimulus augmented airway surface liquid (ASL) depth (5.8±0.3 to 7.3±0.6 µm, p<0.0001) and restored MCT (6.8±0.8 to 12.9±1.2 mm·min−1, p<0.0001). Mixed model analysis controlling for covariates indicated smoking exposure, mucus hydration (ASL) and ciliary beat frequency were important predictors of MCT. Ferret mucus was hyperviscous following smoke exposure in vivo or in vitro, and contributed to diminished MCT. Primary cells from smokers with and without COPD recapitulated these findings, which persisted despite the absence of continued smoke exposure.Cigarette smoke impairs MCT by inducing airway dehydration and increased mucus viscosity, and can be partially abrogated by cholinergic secretion of fluid secretion. These data elucidate the detrimental effects of cigarette smoke exposure on mucus clearance and suggest additional avenues for therapeutic intervention.

scholarly journals Pneumocystis murina Infection and Cigarette Smoke Exposure Interact To Cause Increased Organism Burden, Development of Airspace Enlargement, and Pulmonary Inflammation in Mice

2008 ◽  
Vol 76 (8) ◽  
pp. 3481-3490 ◽  
Author(s):  
Paul J. Christensen ◽  
Angela M. Preston ◽  
Tony Ling ◽  
Ming Du ◽  
W. Bradley Fields ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Pulmonary Inflammation ◽  
Airflow Obstruction ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Respiratory Pathogens ◽  
Obstructive Pulmonary Disease ◽  
Immunocompetent Mice

ABSTRACT Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow obstruction and lung destruction with airspace enlargement. In addition to cigarette smoking, respiratory pathogens play a role in pathogenesis, but specific organisms are not always identified. Recent reports demonstrate associations between the detection of Pneumocystis jirovecii DNA in lung specimens or respiratory secretions and the presence of emphysema in COPD patients. Additionally, human immunodeficiency virus-infected individuals who smoke cigarettes develop early emphysema, but a role for P. jirovecii in pathogenesis remains speculative. We developed a new experimental model using immunocompetent mice to test the interaction of cigarette smoke exposure and environmentally acquired Pneumocystis murina infection in vivo. We hypothesized that cigarette smoke and P. murina would interact to cause increases in total lung capacity, airspace enlargement, and pulmonary inflammation. We found that exposure to cigarette smoke significantly increases the lung organism burden of P. murina. Pulmonary infection with P. murina, combined with cigarette smoke exposure, results in changes in pulmonary function and airspace enlargement characteristic of pulmonary emphysema. P. murina and cigarette smoke exposure interact to cause increased lung inflammatory cell accumulation. These findings establish a novel animal model system to explore the role of Pneumocystis species in the pathogenesis of COPD.

Cigarette smoke disrupts VEGF165-VEGFR-2 receptor signaling complex in rat lungs and patients with COPD: morphological impact of VEGFR-2 inhibition

2006 ◽  
Vol 290 (5) ◽  
pp. L897-L908 ◽  
Author(s):  
John A. Marwick ◽  
Christopher S. Stevenson ◽  
June Giddings ◽  
William MacNee ◽  
Keith Butler ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Cigarette Smoke ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Vegf Receptor ◽  
Obstructive Pulmonary Disease ◽  
Signaling Complex ◽  
Rat Lungs

VEGF is fundamental in the development and maintenance of the vasculature. VEGF165 signaling through VEGF receptor (VEGFR)-2/kinase insert domain receptor (KDR) is a highly regulated process involving the formation of a tertiary complex with glypican (GYP)-1 and neuropilin (NRP)-1. Both VEGF and VEGFR-2 expression are reduced in emphysematous lungs; however, the mechanism of regulation of VEGF165 signaling through the VEGFR-2 complex in response to cigarette smoke exposure in vivo, and in smokers with and without chronic obstructive pulmonary disease (COPD), is still unknown. We hypothesized that cigarette smoke exposure disrupts the VEGF165-VEGFR-2 complex, a potential mechanism in the pathogenesis of emphysema. We show that cigarette smoke exposure reduces NRP-1 and GYP-1 as well as VEGF and VEGFR-2 levels in rat lungs and that VEGF, VEGFR-2, GYP-1, and NRP-1 expression in the lungs of both smokers and patients with COPD are also reduced compared with nonsmokers. Moreover, our data suggest that specific inhibition of VEGFR-2 alone with NVP-AAD777 would appear not to result in emphysema in the adult rat lung. As both VEGF165 and VEGFR-2 expression are reduced in emphysematous lungs, decreased GYP-1 and NRP-1 expression may yet further disrupt VEGF165-VEGFR-2 signaling. Whether or not this by itself is critical for inducing endothelial cell apoptosis and decreased vascularization of the lung seen in emphysema patients is still unclear at present. However, targeted therapies to restore VEGF165-VEGFR-2 complex may promote endothelial cell survival and help to ameliorate emphysema.

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.

scholarly journals Mouse Protocadherin-1 Gene Expression Is Regulated by Cigarette Smoke Exposure In Vivo

PLoS ONE ◽  
2014 ◽  
Vol 9 (7) ◽  
pp. e98197 ◽  
Author(s):  
Henk Koning ◽  
Antoon J. M. van Oosterhout ◽  
Uilke Brouwer ◽  
Lisette E. den Boef ◽  
Renée Gras ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cigarette Smoke ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Exposure In Vivo

scholarly journals Retinal tissue develops an inflammatory reaction to tobacco smoke and electronic cigarette vapor in mice

2021 ◽  
Author(s):  
Feng Wang ◽  
Stefan Hadzic ◽  
Elsa T. Roxlau ◽  
Baerbel Fuehler ◽  
Annabella Janise-Libawski ◽  
...  
Keyword(s):  
Cigarette Smoke ◽  
Exposure Time ◽  
Inflammatory Reaction ◽  
Smoke Exposure ◽  
Age Related Macular Degeneration ◽  
Controlled Study ◽  
Cigarette Smoke Exposure ◽  
List Type ◽  
Retinal Tissue

Abstract Cigarette smoke has been identified as a major risk factor for the development of age-related macular degeneration (AMD). As an alternative to conventional cigarettes (C-cigarette), electronic cigarettes (E-cigarette) have been globally promoted and are currently widely used. The increasing usage of E-cigarettes raises concerns with regard to short- (2 weeks), medium- (3 months), and long- (8 months) term consequences related to retinal tissue. In this report, a controlled study in mouse models was conducted to probe the comprehensive effects of E-cigarette vapor on retina, retinal pigmented epithelium (RPE), and choroidal tissues by (1) comparing the effects of C-cigarette smoke and E-cigarette vapor on retina separately and (2) determining the effects of E-cigarette vapor on the RPE and analyzing the changes with regard to inflammatory (IL-1β, TNFα, iNOS) and angiogenic (VEGF, PEDF) mediators in retina/RPE/choroid by ELISA assays. The data showed that C-cigarette smoke exposure promoted an inflammatory reaction in the retina in vivo. Mice exposed to E-cigarette (nicotine-free) vapor developed inflammatory and angiogenic reactions more pronounced in RPE and choroid as compared to retinal tissue, while nicotine-containing E-cigarette vapor caused even a more serious reaction. Both inflammatory and pro-angiogenic reactions increased with the extension of exposure time. These results demonstrate that exposure to C-cigarette smoke is harmful to the retina. Likewise, the exposure to E-cigarette vapor (with or without nicotine) increases the occurrence and progression of inflammatory and angiogenic stimuli in the retina, which might also be related to the onset of wet AMD in humans. Key messages C-cigarette smoke exposure promotes an inflammatory reaction in the retina in vivo. Mice exposed to E-cigarette (nicotine-free) vapor develop inflammatory and angiogenic reactions more pronounced in RPE and choroid compared to retinal tissue, while nicotine-containing E-cigarette vapor causes even a more serious reaction. Both inflammatory and pro-angiogenic reactions increase with the extension of E-cigarette vapor exposure time.

scholarly journals Chronic Cigarette Smoke Exposure Primes NK Cell Activation in a Mouse Model of Chronic Obstructive Pulmonary Disease

2010 ◽  
Vol 184 (8) ◽  
pp. 4460-4469 ◽  
Author(s):  
Gregory T. Motz ◽  
Bryan L. Eppert ◽  
Brian W. Wortham ◽  
Robyn M. Amos-Kroohs ◽  
Jennifer L. Flury ◽  
...  
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Mouse Model ◽  
Pulmonary Disease ◽  
Cigarette Smoke ◽  
Cell Activation ◽  
Nk Cell ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease

scholarly journals Total particulate matter concentration skews cigarette smoke's gene expression profile

2016 ◽  
Vol 2 (4) ◽  
pp. 00029-2016 ◽  
Author(s):  
Anna Dvorkin-Gheva ◽  
Gilles Vanderstocken ◽  
Ali Önder Yildirim ◽  
Corry-Anke Brandsma ◽  
Ma'en Obeidat ◽  
...  
Keyword(s):  
Gene Expression ◽  
Particulate Matter ◽  
Cigarette Smoke ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Smoke Exposure ◽  
Cigarette Smoke Exposure ◽  
Chronic Obstructive ◽  
Total Particulate Matter ◽  
Xenobiotic Detoxification

Exposure of small animals to cigarette smoke is widely used as a model to study the pathogenesis of chronic obstructive pulmonary disease. However, protocols and exposure systems utilised vary substantially and it is unclear how these different systems compare.We analysed the gene expression profile of six publically available murine datasets from different cigarette smoke-exposure systems and related the gene signatures to three clinical cohorts.234 genes significantly regulated by cigarette smoke in at least one model were used to construct a 55-gene network containing 17 clusters. Increasing numbers of differentially regulated clusters were associated with higher total particulate matter concentrations in the different datasets. Low total particulate matter-induced genes mainly related to xenobiotic/detoxification responses, while higher total particulate matter activated immune/inflammatory processes in addition to xenobiotic/detoxification responses. To translate these observations to the clinic, we analysed the regulation of the revealed network in three human cohorts. Similar to mice, we observed marked differences in the number of regulated clusters between the cohorts. These differences were not determined by pack-year.Although none of the experimental models exhibited a complete alignment with any of the human cohorts, some exposure systems showed higher resemblance. Thus, depending on the cohort, clinically observed changes in gene expression may be mirrored more closely by specific cigarette smoke exposure systems. This study emphasises the need for careful validation of animal models.

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