Neuchâtel, Switzerland
Neuchâtel, Switzerland

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Xiang Y.,Philip Morris Research and Development | Kogel U.,Philip Morris Research and Development | Gebel S.,Philip Morris Research Laboratories GmbH | Peck M.J.,Philip Morris Research and Development | And 3 more authors.
Gene Regulation and Systems Biology | Year: 2014

Chronic obstructive pulmonary disease (COPD) is a respiratory disorder caused by extended exposure of the airways to noxious stimuli, principally cigarette smoke (CS). The mechanisms through which COPD develops are not fully understood, though it is believed that the disease process includes a genetic component, as not all smokers develop COPD. To investigate the mechanisms that lead to the development of COPD/emphysema, we measured whole genome gene expression and several COPD-relevant biological endpoints in mouse lung tissue after exposure to two CS doses for various lengths of time. A novel and powerful method, reverse engineering and forward simulation (REFS™), was employed to identify key molecular drivers by integrating the gene expression data and four measured COPD-relevant endpoints (matrix metalloproteinase (MMP) activity, MMP-9 levels, tissue inhibi-tor of metalloproteinase-1 levels and lung weight). An ensemble of molecular networks was generated using REFS™, and simulations showed that it could successfully recover the measured experimental data for gene expression and COPD-relevant endpoints. The ensemble of networks was then employed to simulate thousands of in silico gene knockdown experiments. Thirty-three molecular key drivers for the above four COPD-relevant endpoints were therefore identified, with the majority shown to be enriched in inflammation and COPD. © the authors, publisher and licensee Libertas Academica Limited.


Majeed S.,Philip Morris Research and Development | Frentzel S.,Philip Morris Research and Development | Wagner S.,Eurofins | Kuehn D.,Philip Morris Research and Development | And 5 more authors.
Chemistry Central Journal | Year: 2014

Background: Only a few exposure systems are presently available that enable cigarette smoke exposure of living cells at the air-liquid interface, of which one of the most versatile is the Vitrocell® system (Vitrocell® Systems GmbH). To assess its performance and optimize the exposure conditions, we characterized a Vitrocell® 24/48 system connected to a 30-port carousel smoking machine. The Vitrocell® 24/48 system allows for simultaneous exposure of 48 cell culture inserts using dilution airflow rates of 0-3.0 L/min and exposes six inserts per dilution. These flow rates represent cigarette smoke concentrations of 7-100%. Results: By characterizing the exposure inside the Vitrocell® 24/48, we verified that (I) the cigarette smoke aerosol distribution is uniform across all inserts, (II) the utility of Vitrocell® crystal quartz microbalances for determining the online deposition of particle mass on the inserts, and (III) the amount of particles deposited per surface area and the amounts of trapped carbonyls and nicotine were concentration dependent. At a fixed dilution airflow of 0.5 L/min, the results showed a coefficient of variation of 12.2% between inserts of the Vitrocell® 24/48 module, excluding variations caused by different runs. Although nicotine and carbonyl concentrations were linear over the tested dilution range, particle mass deposition increased nonlinearly. The observed effect on cell viability was well-correlated with increasing concentration of cigarette smoke. Conclusions: Overall, the obtained results highlight the suitability of the Vitrocell® 24/48 system to assess the effect of cigarette smoke on cells under air-liquid interface exposure conditions, which is closely related to the conditions occurring in human airways. © 2014 Majeed et al.; licensee Chemistry Central Ltd.


PubMed | Philip Morris Research and Development and Eurofins
Type: Journal Article | Journal: Chemistry Central journal | Year: 2014

Only a few exposure systems are presently available that enable cigarette smoke exposure of living cells at the air-liquid interface, of which one of the most versatile is the Vitrocell system (Vitrocell Systems GmbH). To assess its performance and optimize the exposure conditions, we characterized a Vitrocell 24/48 system connected to a 30-port carousel smoking machine. The Vitrocell 24/48 system allows for simultaneous exposure of 48 cell culture inserts using dilution airflow rates of 0-3.0L/min and exposes six inserts per dilution. These flow rates represent cigarette smoke concentrations of 7-100%.By characterizing the exposure inside the Vitrocell 24/48, we verified that (I) the cigarette smoke aerosol distribution is uniform across all inserts, (II) the utility of Vitrocell crystal quartz microbalances for determining the online deposition of particle mass on the inserts, and (III) the amount of particles deposited per surface area and the amounts of trapped carbonyls and nicotine were concentration dependent. At a fixed dilution airflow of 0.5L/min, the results showed a coefficient of variation of 12.2% between inserts of the Vitrocell 24/48 module, excluding variations caused by different runs. Although nicotine and carbonyl concentrations were linear over the tested dilution range, particle mass deposition increased nonlinearly. The observed effect on cell viability was well-correlated with increasing concentration of cigarette smoke.Overall, the obtained results highlight the suitability of the Vitrocell 24/48 system to assess the effect of cigarette smoke on cells under air-liquid interface exposure conditions, which is closely related to the conditions occurring in human airways.

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