Dataset Information

Functional contribution of sphingosine-1-phosphate to airway pathology in cigarette smoke-exposed mice.

ABSTRACT:

Background and purpose

A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD).

Experimental approach

C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed.

Key results

Cigarette smoke caused emphysematous changes throughout the lung parenchyma coupled to a progressive collagen deposition in both peribronchiolar and peribronchial areas. The high and low airways showed an increased reactivity to cholinergic stimulation and ?-smooth muscle actin overexpression. Similarly, an increase in airway reactivity and lung resistances following S1P challenge occurred in smoking mice. A high expression of S1P, Sph-K₂ , and S1P receptors (S1P₂ and S1P₃ ) has been detected in the lung of smoking mice. Sphingosine kinases inhibition reversed the increased cholinergic response in airways of smoking mice.

Conclusions and implications

S1P signalling up-regulation follows the disease progression in smoking mice and is involved in the development of airway hyperresponsiveness. Our study defines a therapeutic potential for S1P inhibitors in management of airways hyperresponsiveness associated to emphysema in smokers with both asthma and COPD.

SUBMITTER: De Cunto G

PROVIDER: S-EPMC6989954 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Publications

Functional contribution of sphingosine-1-phosphate to airway pathology in cigarette smoke-exposed mice.

De Cunto Giovanna G Brancaleone Vincenzo V Riemma Maria Antonietta MA Cerqua Ida I Vellecco Valentina V Spaziano Giuseppe G Cavarra Eleonora E Bartalesi Barbara B D'Agostino Bruno B Lungarella Giuseppe G Cirino Giuseppe G Lucattelli Monica M Roviezzo Fiorentina F

British journal of pharmacology 20191106 2

<h4>Background and purpose</h4>A critical role for sphingosine kinase/sphingosine-1-phosphate (S1P) pathway in the control of airway function has been demonstrated in respiratory diseases. Here, we address S1P contribution in a mouse model of mild chronic obstructive pulmonary disease (COPD).<h4>Experimental approach</h4>C57BL/6J mice have been exposed to room air or cigarette smoke up to 11 months and killed at different time points. Functional and molecular studies have been performed.<h4>Key ...[more]

PMID: 31499592

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Project description:BACKGROUND:Lung aging is characterized by a number of structural alterations including fibrosis, chronic inflammation and the alteration of inflammatory cell composition. Chronic exposure to cigarette smoke (CS) is known to induce similar alterations and may contribute to premature lung aging. Additionally, aging and CS exposure are associated with transcriptional alterations in the lung. The current work aims to explore the interaction between age- and CS- associated transcriptomic perturbations and develop a transcriptomic clock able to predict the biological age and the impact of external factors on lung aging. RESULTS:Our investigations revealed a substantial overlap between transcriptomic response to CS exposure and age-related transcriptomic alterations in the murine lung. Of particular interest is the strong upregulation of immunoglobulin genes with increased age and in response to CS exposure, indicating an important implication of B-cells in lung inflammation associated with aging and smoking. Furthermore, we used a machine learning approach based on Lasso regression to build a transcriptomic age model that can accurately predict chronological age in untreated mice and the deviations associated with certain exposures. Interestingly, CS-exposed-mice were predicted to be prematurely aged in contrast to mice exposed to fresh air or to heated tobacco products (HTPs). The accelerated aging rate associated with CS was reversed upon smoking cessation or switching to HTPs. Additionally, our model was able to predict premature aging associated with thoracic irradiation from an independent public dataset. CONCLUSIONS:Aging and CS exposure share common transcriptional alteration patterns in the murine lung. The massive upregulation of B-cell restricted genes during these processes shed light on the contribution of cell composition and particularly immune cells to the measured transcriptomic signal. Through machine learning approach, we show that gene expression changes can be used to accurately monitor the biological age and the modulations associated with certain exposures. Our findings also suggest that the premature lung aging is reversible upon the reduction of harmful exposures.

Project description:BackgroundThe coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a worldwide pandemic with over 627 million cases and over 6.5 million deaths. It was reported that smoking-related chronic obstructive pulmonary disease (COPD) might be a crucial risk for COVID-19 patients to develop severe condition. As cigarette smoke (CS) is the major risk factor for COPD, we hypothesize that barrier dysfunction and an altered cytokine response in CS-exposed airway epithelial cells may contribute to increased SARS-CoV-2-induced immune response that may result in increased susceptibility to severe disease. The aim of this study was to evaluate the role of CS on SARS-CoV-2-induced immune and inflammatory responses, and epithelial barrier integrity leading to airway epithelial damage.MethodsPrimary human airway epithelial cells were differentiated under air-liquid interface culture. Cells were then exposed to cigarette smoke medium (CSM) before infection with SARS-CoV-2 isolated from a local patient. The infection susceptibility, morphology, and the expression of genes related to host immune response, airway inflammation and damages were evaluated.ResultsCells pre-treated with CSM significantly caused higher replication of SARS-CoV-2 and more severe SARS-CoV-2-induced cellular morphological alteration. CSM exposure caused significant upregulation of long form angiotensin converting enzyme (ACE)2, a functional receptor for SARS-CoV-2 viral entry, transmembrane serine protease (TMPRSS)2 and TMPRSS4, which cleave the spike protein of SARS-CoV-2 to allow viral entry, leading to an aggravated immune response via inhibition of type I interferon pathway. In addition, CSM worsened SARS-CoV-2-induced airway epithelial cell damage, resulting in severe motile ciliary disorder, junctional disruption and mucus hypersecretion.ConclusionSmoking led to dysregulation of host immune response and cell damage as seen in SARS-CoV-2-infected primary human airway epithelia. These findings may contribute to increased disease susceptibility with severe condition and provide a better understanding of the pathogenesis of SARS-CoV-2 infection in smokers.

Dataset Information

Functional contribution of sphingosine-1-phosphate to airway pathology in cigarette smoke-exposed mice.

Background and purpose

Experimental approach

Key results

Conclusions and implications

Publications

Functional contribution of sphingosine-1-phosphate to airway pathology in cigarette smoke-exposed mice.

Similar Datasets

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