Philip Morris Research Laboratories bvba

Leuven, Belgium

Philip Morris Research Laboratories bvba

Leuven, Belgium
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Stinn W.,Philip Morris Research Laboratories GmbH | Buettner A.,Philip Morris Research Laboratories GmbH | Weiler H.,Philip Morris Research Laboratories GmbH | Friedrichs B.,Philip Morris Research Laboratories GmbH | And 7 more authors.
Toxicological Sciences | Year: 2013

Cigarette smoking is the leading cause of lung cancer and chronic obstructive pulmonary disease, yet there is little mechanistic information available in the literature. To improve this, laboratory models for cigarette mainstream smoke (MS) inhalation-induced chronic disease development are needed. The current study investigated the effects of exposing male A/J mice to MS (6h/day, 5 days/week at 150 and 300mg total particulate matter per cubic meter) for 2.5, 5, 10, and 18 months in selected combinations with postinhalation periods of 0, 4, 8, and 13 months. Histopathological examination of step-serial sections of the lungs revealed nodular hyperplasia of the alveolar epithelium and bronchioloalveolar adenoma and adenocarcinoma. At 18 months, lung tumors were found to be enhanced concentration dependently (up to threefold beyond sham exposure), irrespective of whether MS inhalation had been performed for the complete study duration or was interrupted after 5 or 10 months and followed by postinhalation periods. Morphometric analysis revealed an increase in the extent of emphysematous changes after 5 months of MS inhalation, which did not significantly change over the following 13 months of study duration, irrespective of whether MS exposure was continued or not. These changes were found to be accompanied by a complex pattern of transient and sustained pulmonary inflammatory changes that may contribute to the observed pathogeneses. Data from this study suggest that the A/J mouse model holds considerable promise as a relevant model for investigating smoking-related emphysema and adenocarcinoma development. © The Author 2012. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.


Stinn W.,Philip Morris Research Laboratories GmbH | Berges A.,Philip Morris Research Laboratories bvba | Meurrens K.,Philip Morris Research Laboratories bvba | Gebel S.,Philip Morris Research Laboratories GmbH | And 5 more authors.
Toxicology | Year: 2013

A generally accepted and validated laboratory model for smoking-associated pulmonary tumorigenesis would be useful for both basic and applied research applications, such as the development of early diagnostic endpoints or the evaluation of modified risk tobacco products, respectively. The A/J mouse is susceptible for developing both spontaneous and induced lung adenomas and adenocarcinomas, and increased lung tumor multiplicities were also observed in previous cigarette smoke inhalation studies. The present study was designed to collect data useful towards the validation of an 18-month mainstream smoke (MS) inhalation model. Male and female A/J mice were exposed whole-body at three MS concentration levels for 6. h/day, and the results were compared to a previous study in the same laboratory and with a similar design. A linear MS concentration-dependent increase in lung tumorigenesis was observed with similar slopes for both sexes and both studies and a maximal 5-fold increase in multiplicity beyond sham control. The minimal detectable difference in lung tumor multiplicity for the current study was 37%. In the larynx, papillomas were detectable in all MS-exposed groups in a non-concentration dependent manner. No other extra-pulmonary MS-dependent neoplastic lesions were found. Gene expression signatures of lung tumor tissues allowed a clear differentiation of sham- and high dose MS-exposed mice. In combination with data from previous smoke inhalation studies with A/J mice, the current data suggest that this model for MS inhalation-induced pulmonary tumorigenesis is reliable and relevant, two crucial requirements towards validation of such a model. © 2013 Elsevier Ireland Ltd.


Stolle K.,Philip Morris Research Laboratories GmbH | Berges A.,Philip Morris Research Laboratories bvba | Lietz M.,Philip Morris Research Laboratories GmbH | Lebrun S.,Philip Morris Products S.A. | Wallerath T.,Philip Morris Research Laboratories GmbH
Toxicology Letters | Year: 2010

Cigarette smoke, hyperlipidemia, and hypertension with the risk of development and progression of atherosclerosis and associated pathologies such as abdominal aortic aneurysm (AAA) are correlated. We examined the interaction of cigarette mainstream smoke (MS) and angiotensin-II (Ang II)-induced hypertension in the atherosclerotic process using hyperlipidemic apolipoprotein E-knockout (ApoE-/-) mice. ApoE-/- mice were treated with Ang II for 4 weeks and then further exposed to MS or to fresh air for 4 weeks. AAA formation was observed in all mice treated with Ang II, regardless of smoke exposure; however, smoke exposure increased the incidence of AAA in these mice. Ang II treatment resulted in higher gene expression of matrix metalloproteinases (MMP)-2, -3, -8, -9, and -12 in the abdominal aortas, which was further increased by MS exposure. The proteolytic activity of MMP-2 and MMP-9 was also enhanced in Ang II-treated mice exposed to MS, but only minor changes were seen with either smoke exposure or Ang II treatment alone. This study shows for the first time that both formation and severity of AAA in hypertensive ApoE-/- mice are accelerated by exposure to MS and that the proteolytic activity of MMPs is enhanced by the combination of Ang II and MS. © 2010 Elsevier Ireland Ltd.


Schramke H.,Philip Morris Products SA | Roemer E.,Philip Morris Products SA | Dempsey R.,Philip Morris Products SA | Hirter J.,Philip Morris Products SA | And 6 more authors.
Regulatory Toxicology and Pharmacology | Year: 2014

The biological activity of mainstream smoke from experimental kretek cigarettes with and without three mixes of ingredients was assessed in a 90-day rat inhalation study and in a 4-day in vivo micronucleus assay. 350 ingredients, commonly used in various combinations and in a limited number in a given brand in the manufacture of marketed kretek cigarettes, were applied at a low and a high target level to test cigarettes with a typical Indonesian blend of tobaccos and cloves. In the 90-day inhalation study, effects commonly seen in rat inhalation studies with mainstream smoke were observed. In general, no ingredients-related histopathological changes were found in the respiratory tract. In the 4-day micronucleus assay exposure of male rats to mainstream smoke from the test cigarettes containing any of the three mixes did not increase the proportions of micronucleated cells in peripheral blood and bone marrow over the proportion of micronucleated cells in the control group. Based on the results of these studies, it can be concluded that the addition of ingredients commonly used in the manufacture of kretek cigarettes did not change the overall in vivo toxicity profile of the mainstream smoke. © 2014 Elsevier Inc.


Lietz M.,Philip Morris Research Laboratories GmbH | Berges A.,Philip Morris Research Laboratories bvba | Lebrun S.,Philip Morris Products S.A. | Meurrens K.,Philip Morris Research Laboratories bvba | And 11 more authors.
Atherosclerosis | Year: 2013

Tobacco smoke exerts perturbations on lipid metabolism and arterial cell function that accelerate atherosclerosis. Lipidomics has emerged as a key technology in helping to elucidate the lipid-related mechanisms of atherosclerosis. In this study, we investigated the effects of smoking cessation on plaque development and aortic arch content of various lipid molecular classes and species. Apolipoprotein E-deficient mice were exposed to fresh air (sham) or to mainstream cigarette smoke (CS) for 6 months, or to CS for 3 months followed by sham for 3 months (cessation group). Lipids from plasma and aortic arches, plasma lipoprotein profiles and plaque morphometry measurements were analyzed. We already showed that CS exposure accelerated plaque size and total cholesterol content of the aortic arch at 3 and 6 months. Marked increases were seen in the relative enrichment of cholesteryl esters, phospholipids, sphingomyelins, and glycosphingolipids. Smoking cessation slowed plaque progression and resulted in lower levels of many lipid species in plasma and aortic arch. While CS exposure promoted rapid lipid accumulation in mouse aorta, smoking cessation translated into a slow removal of lipids from the vessel wall. Despite the smoking cessation-dependent metabolic changes leading to increased animal body weight, accumulation of proatherogenic lipids in the vessel was halted after exposure cessation, indicating that the clinical benefits of smoking cessation translate directly to the vessel wall and its lipid makeup. © 2013 The Authors.


Piade J.-J.,Philip Morris Products SA | Roemer E.,Philip Morris Products SA | Dempsey R.,Philip Morris Products SA | Weiler H.,Philip Morris Research Laboratories GmbH | And 4 more authors.
Regulatory Toxicology and Pharmacology | Year: 2014

A typical Indonesian kretek cigarette brand and an experimental kretek reference cigarette were compared to the reference cigarette 2R4F in two 90-day inhalation studies. Male and female rats were exposed nose-only to mainstream smoke for 6 hours daily, for 90 consecutive days. Biological endpoints were assessed according to OECD guideline 413, with special emphasis on respiratory tract histopathology and on lung inflammation (broncho-alveolar lavage fluid levels of neutrophils, macrophages and lymphocytes). Histopathological alterations included: in the nose, hyperplasia and squamous metaplasia of the respiratory epithelium and squamous metaplasia and atrophy of the olfactory epithelium; in the larynx, epithelial squamous metaplasia and hyperplasia; in the lungs, accumulation of macrophages in alveoli and goblet cell hyperplasia in bronchial epithelium. The findings were qualitatively consistent with observations from previous similar studies on conventional cigarettes. Compared to 2R4F cigarette, however, kretek smoke exposure was associated with a pronounced attenuation of pulmonary inflammation and less severe histopathological changes in the respiratory tract. Neutrophilic inflammation was also significantly lower (>70%). These results are consistent with the observations made on smoke chemistry and in vitro toxicology. They do not support any increased toxicity of the smoke of kretek cigarettes compared to conventional American-blended cigarettes. © 2014 Elsevier Inc.


Roemer E.,Philip Morris Products SA | Dempsey R.,Philip Morris Products SA | Van Overveld F.J.,Philip Morris Research Laboratories bvba | Berges A.,Philip Morris Research Laboratories bvba | And 5 more authors.
Regulatory Toxicology and Pharmacology | Year: 2014

The biological effects of mainstream smoke (MS) from Indonesian-blended cigarettes with and without added cloves, cloves extracted with hot ethanol, and extracted cloves replenished with eugenol or clove oil were assessed in a 90-day inhalation study in rats. A separate 35-day inhalation study in rats was performed with MS from American-blended cigarettes with 0%, 2.5%, 5% or 10% added eugenol. Effects commonly seen in inhalation studies with MS were observed. These included histopathological changes indicative of irritation in the entire respiratory tract and inflammatory responses in the lung. Adding cloves to American- or Indonesian-blended cigarettes reduced the inflammatory response in the lung but with no difference between the two blend types. When the clove oil was extracted (~75% reduction of eugenol achieved) from cloves, the inflammatory response in the lung was still reduced similarly to whole cloves but the severity of histopathological changes in the upper respiratory tract was less reduced. Add back of clove oil or pure eugenol reduced this response to a level similar to what was seen with whole cloves. When eugenol was added to American-blended cigarettes, similar findings of reduced lung inflammation and severity of histopathological changes in respiratory the tract was confirmed. These studies demonstrate a clear effect of cloves, and in particular eugenol, in explaining these findings. © 2014 Elsevier Inc.


Gebe S.,Philip Morris Research Laboratories GmbH | Dieh S.,Philip Morris Research Laboratories GmbH | Pype J.,Philip Morris Research Laboratories bvba | Friedrichs B.,Philip Morris Research Laboratories GmbH | And 6 more authors.
Toxicological Sciences | Year: 2010

Cigarette smoke (CS) imposes a strong oxidative burden on exposed tissues resulting in a severely disturbed oxidant/antioxidant balance, which in the context of chronic exposure is assumed to be a key contributor to CS-related diseases. Because of its emerging central role in orchestrating the general cellular antioxidant response, the pathway leading to the activation of the transcription factor Nrf2 has received mounting attention over the past decade in investigations aimed at elucidating CS-induced pathophysiological mechanisms. To comprehensively characterize the impact of Nrf2 in acute and subchronic smoking scenarios, Nrf 2-/- mice and their wild-type (wt) ICR littermates were exposed to either ambient air (sham exposure) or one of three doses of CS for up to 5 months, with two postexposure endpoints of 1 and 13 days. The lungs of the mice were monitored for transcriptomic changes on a genome-wide level, which confirmed an impaired expression of antioxidant and phase 2-related genes in CS-exposed Nrf 2-/- mice. Importantly, in comparison to wt mice, an attenuated cell cycle/mitotic response and intensified stress gene expression pattern were observed in exposed Nrf 2-/- mice, which was paralleled by clear dose-dependent effects on alveolar destruction and impaired lung function. In contrast, the inflammation-related transcriptional response and scores for various bronchioalveolar inflammation parameters were qualitatively and quantitatively similar in CS-exposed mice of both genotypes. Taken together, these results confirm the protective nature of Nrf2 in oxidative stress scenarios and suggest that the enhanced emphysematous phenotype exhibited by CS-exposed Nrf 2-/- mice is more likely caused by an imbalance in cell loss and regeneration than by increased inflammation. © The Author 2010. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved.


PubMed | Philip Morris Research Laboratories bvba, Philip Morris Research Laboratories GmbH and Philip Morris Products SA
Type: | Journal: Regulatory toxicology and pharmacology : RTP | Year: 2014

The biological activity of mainstream smoke from experimental kretek cigarettes with and without three mixes of ingredients was assessed in a 90-day rat inhalation study and in a 4-day in vivo micronucleus assay. 350 ingredients, commonly used in various combinations and in a limited number in a given brand in the manufacture of marketed kretek cigarettes, were applied at a low and a high target level to test cigarettes with a typical Indonesian blend of tobaccos and cloves. In the 90-day inhalation study, effects commonly seen in rat inhalation studies with mainstream smoke were observed. In general, no ingredients-related histopathological changes were found in the respiratory tract. In the 4-day micronucleus assay exposure of male rats to mainstream smoke from the test cigarettes containing any of the three mixes did not increase the proportions of micronucleated cells in peripheral blood and bone marrow over the proportion of micronucleated cells in the control group. Based on the results of these studies, it can be concluded that the addition of ingredients commonly used in the manufacture of kretek cigarettes did not change the overall in vivo toxicity profile of the mainstream smoke.

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