Michael Lietz's scientific contributionswhile working at Philip Morris International (Genève, Switzerland) and other institutions

Publications (25)

Publications citing this author (161)

    • Atherosclerosis in the abdominal aorta can lead to the development of abdominal aortic aneurysms, which are reported to be about nine times more common in smokers than in non-smokers [82] . This process was investigated in an Apoe −/− mouse model with angiotensin II-induced hypertension, which developed aneurysms in association with enhanced matrix metalloproteinase (MMP) gene expression [83] . Exposure to CS further upregulated MMP expression in the abdominal aorta, and exacerbated the development and severity of aneurysms.
    [Show abstract] [Hide abstract] ABSTRACT: Atherosclerosis-prone apolipoprotein E-deficient (Apoe(-/-)) mice display poor lipoprotein clearance with subsequent accumulation of cholesterol ester-enriched particles in the blood, which promote the development of atherosclerotic plaques. Therefore, the Apoe(-/-) mouse model is well established for the study of human atherosclerosis. The systemic proinflammatory status of Apoe(-/-) mice also makes them good candidates for studying chronic obstructive pulmonary disease, characterized by pulmonary inflammation, airway obstruction, and emphysema, and which shares several risk factors with cardiovascular diseases, including smoking. Herein, we review the results from published studies using Apoe(-/-) mice, with a particular focus on work conducted in the context of cigarette smoke inhalation studies. The findings from these studies highlight the suitability of this animal model for researching the effects of cigarette smoking on atherosclerosis and emphysema.
    Full-text · Article · Dec 2016
    • This type of study provides an initial assessment of an MRTP's impact on key pathways of toxicity. Second, we assess the impact of the whole MRTP aerosol in comparison with whole cigarette smoke on disease mechanisms using in vitro assay systems designed to recapitulate the structure of the human epithelial tissues exposed to aerosol/smoke (Kuehn et al., 2015; Mathis et al., 2013; Schlage et al., 2014; Talikka et al., 2014) and/or key events in disease pathways (Poussin et al., 2014Poussin et al., , 2015; van der Toorn et al., 2015a). Third, we have complemented in vivo studies conducted under OECD guidelines (Kogel et al., 2014; Phillips et al., 2015a) with systems toxicology methods to quantify the impact of candidate MRTP aerosols on biological mechanisms perturbed by CC smoke, in conjunction with the physiological and toxicological endpoints measured under the OECD guidelines.
    [Show abstract] [Hide abstract] ABSTRACT: This publication introduces a series of eight other publications describing the non-clinical assessment and initial clinical study of a candidate modified risk tobacco product (MRTP) – the Tobacco Heating System 2.2 (THS2.2). This paper presents background information on tobacco harm reduction, to complement the approaches of increasing smoking cessation and reducing smoking initiation to reduce the morbidity and mortality caused by cigarette smoking. THS2.2 heats tobacco without combustion, and the subsequent formation of harmful and potentially harmful constituents (HPHC) is greatly reduced compared with cigarette smoke. Assessment of the THS2.2 aerosol in vitro and in vivo reveals reduced toxicity and no new hazards. Additional mechanistic endpoints, measured as part of in vivo studies, confirmed reduced impact on smoking-related disease networks. The clinical study confirmed the reduced exposure to HPHCs in smokers switching to THS2.2, and the associated transcriptomic study confirmed the utility of a gene expression signature, consisting of only 11 genes tested in the blood transcriptome of subjects enrolled in the clinical study, as a complementary measure of exposure response. The potential of THS2.2 as an MRTP is demonstrated by the assessment and additional publications cited in this series.
    Full-text · Article · Jul 2016
    • Extensive research and literature reviews have shown the strong influence of cigarette smoke and its components on early atherogenesis, particularly in endothelial cells. Published data from clinical and animal studies, as well as investigative results have demonstrated that vascular dysfunction induced by smoking is initiated by the reduced bioavailability of NO and additionally by increasing of the expression of adhesion molecules and subsequent endothelial dysfunction[18,19,1]. In addition to the physical damage to the endothelial cells, smoking induces the remodeling of tissues together with the activation processes of systemic inflammatory signals, which contribute to an effective action of proinflammatory cytokines.
    [Show abstract] [Hide abstract] ABSTRACT: Introduction: Nitric oxide (NO) modulates inflammatory reactions, having beneficial or toxic effects depending on the concentration. Its elevation can cause proinflammatory effects amplifying the inflammatory process with the participation of cytokines. Smoking has a negative impact on health and is considered one of the risk factors that influence disease development facilitating inflammatory processes. Aim: To compare the serum concentration of NO and cytokines in smokers at baseline and after 4months of abstinence treatment. Methods: Blood samples which were collected to obtain the serum, at baseline and after 4months, were stored at -80°C until analysis. NO was measured by the total dose of nitrite determined by the Greiss method. CBA was the used technique to determine the concentration of cytokines in supernatants serum. The initial and final results of NO, TNF-α, IL-1, IL-6, IL-8, IL-10 and IL-12 that remained after 4months treatment were compared. Wilcoxon test was used to compare the data and Spearman test for correlations between NO and other variables. A significance level of p<0.05 was adopted. Results: The analysis of NO observed a significant reduction (p=0.001) of the initial median value of 18.80 (3.55-80.01) μmol/L to 8.10 (2.85-14.97) μmol/L after 4months of treatment. There were no significant differences in cytokines from baseline to the end of treatment. Conclusion: The results may not mean harm to the body, but an adaptive process, decreasing the metabolism of abstinents due to the reduction of the use of nicotine.
    Full-text · Article · Dec 2016
    • Equally important, the carbonyl compounds present in the smoke, given their extremely hydrophilic nature, pass through the airway epithelial barrier affecting systemic oxidative status and causing carbonylation, an irreversible modification of different proteins, thereby deeply altering intracellular signaling pathways. The pro-oxidative effects of smoke have been demonstrated also by in vivo studies in ApoE À/À mice, showing an increase of markers of oxidative stress, oxidized LDL, cholesterol esters and ceramide[9]. Oxidized LDL represents the key substrate for the formation of the lipidic core inside the plaque.
    Full-text · Article · Jan 2017
    • Our study objectives were: (i) to assess reduced exposure effects, compared with conventional cigarette smoke (CS), for THS2.2 aerosol in a chronic inhalation toxicity study; (ii) to investigate the effects of cessation or switching to THS2.2 aerosol; and, (iii) to investigate disease end points related to both CVD and COPD in one mouse model, leveraging state-of-theart systems toxicology approaches. Apolipoprotein E-deficient (Apoe −/− ) transgenic mice are commonly used as a model for atherogenesis (Veniant et al., 2001), particularly to investigate smoking-related atherosclerosis (Boue et al., 2012, Chan, 2012, Lietz et al., 2013, von Holt et al., 2009), as well as CS-induced lung inflammation and emphysema (Arunachalam et al., 2010, Boue et al., 2013, Han et al., 2012). They were therefore chosen in the present study to investigate indicators of both COPD and CVD in the same animals exposed to either mainstream CS, or to the mainstream aerosol from THS2.2 (nicotine concentration matched to CS: 29.9 mg/m 3 ) over an 8-month period, using P a g e | 6 physiological, histological, and molecular evaluations.
    [Show abstract] [Hide abstract] ABSTRACT: Smoking cigarettes is a major risk factor in the development and progression of cardiovascular disease (CVD) and chronic obstructive pulmonary disease (COPD). Modified risk tobacco products (MRTPs) are being developed to reduce smoking-related health risks. The goal of this study was to investigate hallmarks of COPD and CVD over an 8-month period in apolipoprotein E-deficient mice exposed to conventional cigarette smoke (CS) or to the aerosol of a candidate MRTP, THS2.2. In addition to chronic exposure, cessation or switching to THS2.2 after 2 months of CS exposure was assessed. Engaging a systems toxicology approach, exposure effects were investigated using physiology and histology combined with transcriptomics, lipidomics, and proteomics. CS induced nasal epithelial hyperplasia and metaplasia, lung inflammation, and emphysematous changes (impaired pulmonary function and alveolar damage). Atherogenic effects of CS exposure included altered lipid profiles and aortic plaque formation. Exposure to THS2.2 aerosol (nicotine concentration matched to CS, 29.9 mg/m(3)) did not induce lung inflammation or emphysema, nor did it consistently change the lipid profile or enhance the plaque area. Cessation or switching to THS2.2 reversed the inflammatory responses and halted progression of initial emphysematous changes and the aortic plaque area. Biological processes, including senescence, inflammation, and proliferation, were significantly impacted by CS, but not by THS2.2 aerosol. Both, cessation and switching to THS2.2 reduced these perturbations to almost sham exposure levels. In conclusion, in this mouse model cessation or switching to THS2.2 retarded the progression of CS-induced atherosclerotic and emphysematous changes, while THS2.2 aerosol alone had minimal adverse effects.
    Full-text · Article · Nov 2015
    • Some examples of the use of gene microarrays to model genome-scale metabolic reconstructions have been recently reported (Palsson, 2009; Hyduke et al., 2013; Aung et al., 2014). In this regard, it is possible to analyze and predict metabolic behaviors at different cell levels in order to determine how an individual component interacts in the systems and influences on the total cell function (Schlage et al., 2011; Agren et al., 2012; Sertba¸sSertba¸s et al., 2014). Specific metabolic models applied to different human brain systems have been developed previously, including astrocyteneuron coupled models in an environment that simulates metabolic variations experienced in different neurodegenerative diseases (Cakir et al., 2007; Lewis et al., 2010; Somersalo, 2012, 2013).In this aspect, astrocyte models have been developed to determine calcium waves during astrocyte interaction with other cells (Gibson et al., 2008).
    [Show abstract] [Hide abstract] ABSTRACT: Astrocytes are the most abundant cells of the central nervous system; they have a predominant role in maintaining brain metabolism. In this sense, abnormal metabolic states have been found in different neuropathological diseases. Determination of metabolic states of astrocytes is difficult to model using current experimental approaches given the high number of reactions and metabolites present. Thus, genome-scale metabolic networks derived from transcriptomic data can be used as a framework to elucidate how astrocytes modulate human brain metabolic states during normal conditions and in neurodegenerative diseases. We performed a Genome-Scale Reconstruction of the Human Astrocyte Metabolic Network with the purpose of elucidating a significant portion of the metabolic map of the astrocyte. This is the first global high-quality, manually curated metabolic reconstruction network of a human astrocyte. It includes 5,007 metabolites and 5,659 reactions distributed among 8 cell compartments, (extracellular, cytoplasm, mitochondria, endoplasmic reticle, Golgi apparatus, lysosome, peroxisome and nucleus). Using the reconstructed network, the metabolic capabilities of human astrocytes were calculated and compared both in normal and ischemic conditions. We identified reactions activated in these two states, which can be useful for understanding the astrocytic pathways that are affected during brain disease. Additionally, we also showed that the obtained flux distributions in the model, are in accordance with literature-based findings. Up to date, this is the most complete representation of the human astrocyte in terms of inclusion of genes, proteins, reactions and metabolic pathways, being a useful guide for in-silico analysis of several metabolic behaviors of the astrocyte during normal and pathologic states.
    Full-text · Article · Feb 2017