Biomedical subjects

Silvio De Flora

Publications and source records attributed to Silvio De Flora.

At least 19 recordsLinked to original sources

PubMed2006

Interplay between Helicobacter pylori and host gene polymorphisms in inducing oxidative DNA damage in the gastric mucosa.

Infection by Helicobacter pylori is the most important risk factor for gastric cancer. However, only a small fraction of colonized individuals, representing at least half of the world's population, develop this malignancy. In order to shed light on host-microbial interactions, gastric mucosa biopsies were collected from 119 patients suffering from dyspeptic symptoms. 8-Hydroxy-2'-deoxyguanosine (8-oxo-dG) levels in the gastric mucosa were increased in carriers of H.pylori, detected either by cultural method or by polymerase chain reaction, and were further increased in subjects infected with strains positive for the cagA gene, encoding the cytotoxin-associated protein, cagA. Oxidative DNA damage was more pronounced in males, in older subjects, and in H.pylori-positive subjects suffering from gastric dysplasia. Moreover, 8-oxo-dG levels were significantly higher in a small subset of subjects having a homozygous variant allele of the 8-oxoguanosine-glycosylase 1 (OGG1) gene, encoding the enzyme removing 8-oxo-dG from DNA. Conversely, they were not significantly elevated in glutathione S-transferase M1 (GSTM1)-null subjects. Thus, both bacterial and host gene polymorphisms affect oxidative stress and DNA damage, which is believed to represent a key mechanism in the pathogenesis of gastric cancer. The interplay between bacterial and host gene polymorphisms may explain why gastric cancer only occurs in a small fraction of H.pylori-infected individuals.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2006

Oral chromium(VI) does not affect the frequency of micronuclei in hematopoietic cells of adult mice and of transplacentally exposed fetuses.

Chromium(VI) compounds are genotoxic in a variety of cellular systems. Their potential carcinogenicity is affected by toxicokinetic patterns restricting bioavailability to certain targets, and by metabolic pathways affecting interaction of chromate-derived reactive species with DNA. Epidemiological data indicate that chromium(VI) can be carcinogenic to the human respiratory tract following inhalation at doses that are only achieved in certain occupational settings. However, concern has been raised that adverse effects may also result from oral intake. In order to further explore this issue, we performed studies in BDF1 and Swiss mice of both genders and various age. Sodium dichromate dihydrate and potassium dichromate were administered either with the drinking water, up to a concentration of 500 mg chromium(VI)/l for up to 210 consecutive days, or in a single intragastric dose of 17.7 mg/kg body weight. Under these conditions, no increase of the micronucleus frequency was observed in either bone marrow or peripheral blood erythrocytes. Conversely, the same compounds induced a clastogenic damage following intraperitoneal injection, which by-passes detoxification mechanisms. In addition, due to the hypothesis that susceptibility may be increased during the period of embryogenesis, we treated pregnant mice, up to a concentration of 10mg chromium(VI)/l drinking water. There was no effect on the numbers of fetuses/dam and on body weight of fetuses. Again, no toxic or genotoxic effect was observed either in bone marrow of pregnant mice or in liver and peripheral blood of their fetuses. Thus, even at doses that largely exceed drinking water standards (up to 10,000 times) or by massive intragastric administration, chromium(VI) is not genotoxic to hematopoietic cells of either adult mice or transplacentally exposed fetuses. These conclusions are consistent with the poor toxicity and lack of carcinogenicity of oral chromium(VI), and are mechanistically explained by the high efficiency of chromium(VI) detoxification processes in the gastrointestinal tract.

Administration, Oral↗

PubMed2006

Development of novel cancer chemopreventive agents in Europe--neglected Cinderella or rising phoenix? A critical commentary. ESF Workshop on Cancer Chemoprevention, DKFZ, Heidelberg, September 18-20, 2005.

Agents that prevent cancer, delay its onset, or revert premalignant conditions could have dramatic beneficial impacts on human health. Although there is an urgent need to develop cancer chemopreventive agents, researchers in the field suspect that this area of scientific endeavour in Europe leads a Cinderella existence, both in terms of perception of importance and research funding. In order to review current activities in this prevention field and to seek a consensus position, an exploratory workshop was held in September 2005 at the German Cancer Research Center (DKFZ) in Heidelberg, Germany, sponsored mainly by the European Science Foundation (ESF), and also supported by the European Association for Cancer Research (EACR) and the German Cancer Society (DKG). The 35 experts from European countries and the United States of America assessed state-of-the-art cancer chemoprevention research in Europe. The aims that the workshop organizers had pre-defined were: i) assessment of the usefulness of animal models for agent identification; ii) review of ongoing preclinical and clinical work on novel agents; iii) discussion of potential biomarkers predictive for cancer preventive efficacy; and finally iv) the potential role that European pharmaceutical industries could play in furthering chemopreventive agent development. Overall the workshop aimed at raising awareness among European clinical and laboratory researchers of the importance of the development of novel, efficacious and safe cancer preventive agents.

Antineoplastic Agents↗

PubMed2006

Influence of FHIT on benzo[a]pyrene-induced tumors and alopecia in mice: chemoprevention by budesonide and N-acetylcysteine.

The FHIT gene has many hallmarks of a tumor-suppressor gene and is involved in a large variety of cancers. We treated A/J mice and (C57BL/6J x 129/SvJ)F1 (B6/129 F1) mice, either wild-type or FHIT+/-, with multiple doses of benzo[a]pyrene (B[a]P) by gavage. B[a]P caused a time-related increase of micronuclei in peripheral blood erythrocytes. Both A/J and B6/129 F1 mice, irrespective of their FHIT status, were sensitive to induction of forestomach tumors, whereas B[a]P induced glandular stomach hyperplasia and a high multiplicity of lung tumors in A/J mice only. Preneoplastic lesions of the uterus were more frequent in FHIT+/- mice. B6/129 F1 mice underwent spontaneous alopecia areata and hair bulb cell apoptosis, which were greatly accelerated either by FHIT heterozygosity or by B[a]P treatment, thus suggesting that FHIT plays a role in the pathogenesis of alopecia areata. The oral administration of either budesonide or N-acetyl-L-cysteine (NAC) inhibited the occurrence of this inflammatory skin disease. In addition, these agents prevented B[a]P-induced glandular stomach hyperplasia and decreased the size of both forestomach tumors and lung tumors in A/J mice. Budesonide also attenuated lung tumor multiplicity. In B6/129 F1 mice, NAC significantly decreased the proliferating cell nuclear antigen in lung tumors. Both budesonide and NAC inhibited B[a]P-induced forestomach tumors and preneoplastic lesions of the respiratory tract in B6/129 F1 mice. In conclusion, heterozygosity for FHIT affects susceptibility of mice to spontaneous alopecia areata and B[a]P-induced preneoplastic lesions of the uterus and does not alter responsiveness to budesonide and NAC.

Acetylcysteine↗

PubMed2006

Early loss of Fhit in the respiratory tract of rodents exposed to environmental cigarette smoke.

The Fhit gene, encompassing the most active common human chromosomal fragile region, FRA3B, has been shown to act as a tumor suppressor. Several studies have shown significant Fhit alterations or Fhit protein loss in lung cancers from smokers compared with lung cancers from nonsmokers. To evaluate the role of Fhit under controlled experimental conditions, we exposed rodents to environmental cigarette smoke (ECS) and evaluated Fhit expression or Fhit protein in the respiratory tract. After 14 days of exposure to ECS, loss of Fhit protein in the bronchial/bronchiolar epithelium affected half of the tested B6-129(F(1)) mice, either wild type or Fhit(+/-). After 28 days, it affected the vast majority of the tested SKH-1 hairless mice and of A/J mice and all (UL53-3 x A/J)F(1) mice, either wild type or P53(+/-). In Sprague-Dawley rats, exposure to ECS for up to 30 days caused a time-dependent loss of Fhit in pulmonary alveolar macrophages. Moreover, ECS down-regulated Fhit expression and significantly decreased Fhit protein in the rat bronchial epithelium. The oral administration of N-acetylcysteine attenuated the ECS-related loss of Fhit, whereas oltipraz, 5,6-benzoflavone, phenethyl isothiocyanate, and indole 3-carbinol, and their combinations had no significant effect. Parallel studies evaluated a variety of molecular, biochemical, and cytogenetic alterations in the respiratory tract of the same animals. In conclusion, there is unequivocal evidence that Fhit is an early, critical target in smoke-related lung carcinogenesis in rodents, and that certain chemopreventive agents can attenuate the occurrence of this gene alteration.

Acetylcysteine↗

PubMed2006

[Open angle glaucoma: epidemiology, pathogenesis and prevention].

There is growing evidence that reactive oxygen species (ROS) play a key role in the pathogenesis of primary open angle glaucoma (POAG). The occurrence of oxidative DNA damage in trabecular meshwork (TM) has been demonstrated by measuring the increase of 8-hydroxy-2'-deoxyguanosine, the most abundant DNA oxidative alteration, which is significantly increased in glaucoma-bearing subjects as compared with unaffected controls. Several lines of evidence support the hypothesis that ROS play a fundamental pathogenic role, including the following: (a) outflow resistance in the anterior chamber increases in the presence of high levels of hydrogen peroxide; (b) TM possesses abundant antioxidant activities; (c) significant increases in superoxide dismutase and glutathione peroxidase activities were detected in the aqueous humour of glaucoma patients; (d) hydrogen peroxide compromises TM integrity. The existence of a significant correlation between oxidative DNA damage and intraocular pressure in glaucoma patients has been reported. POAG patients appear to have a genetic predisposition rendering them susceptible to ROS-induced damage because of a more frequent deletion, as compared to controls, of the gene encoding for glutathione-S-transferase M1, a pivotal anti-oxidant activity. Furthermore, oxidative stress, occurring not only in TM but also in retinal cells, appears to be involved in the neuronal cell death that characterizes POAG. These considerations could bear relevance for POAG prevention and suggest that genetic analyses and the use of drugs or dietary measures attenuating the effects of ROS, if validated in future studies, could be useful tools contributing to the control of this disease.

Adrenergic beta-Antagonists↗

PubMed2006

Induction by 7,12-dimethylbenz(a)anthracene of molecular and biochemical alterations in transformed human mammary epithelial stem cells, and protection by N-acetylcysteine.

Several lines of evidence suggest that stem cells are major targets for carcinogens. A normal human breast epithelial cell type was previously shown to possess stem cell characteristics. Further cell lines were derived following sequential transfection with SV40 large T-antigen (immortal, non-tumorigenic M13SV1 cells), exposure to X-rays (weakly tumorigenic M13SV1R2 cells), and ectopic expression of c-erbB2/neu (highly tumorigenic M13SV1R2N1 cells). We evaluated some characteristics of these cells and their susceptibility to the breast carcinogen 7,12-dimethylbenz(a)anthracene (DMBA). Compared to M13SV1 cells, the two untreated tumorigenic cell lines displayed higher levels of connexin 43 expression and NF-kappaB nuclear translocation, and a higher frequency of fhit loss. The baseline nuclear translocation of AP-1 and pCREB was particularly evident in M13SV1R2N1 cells and was further enhanced by DMBA treatment, indicating an interaction between c-erbB2/neu and DMBA-induced signalling. Treatment with DMBA did neither affect the baseline fhit loss nor p53 mutation, whereas it increased NF-kappaB nuclear translocation, the proportion of apoptotic cells, and the levels of connexin 43, common 4977-bp mitochondrial DNA deletion, and bulky adducts to nuclear DNA. DMBA-treated M13SV1 cells underwent significant oxidative DNA damage and exhibited the highest DNA adduct levels, while they had the lowest apoptotic rate. Co-treatment of cells with N-acetylcysteine (NAC) attenuated DMBA-induced toxicity and DNA alterations, particularly in M13SV1 cells. Thus, the immortal cell line derived from the normal human adult breast stem cell without further tumorigenic progression is the most susceptible both to DMBA-related alterations and to the protective effects of NAC.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed2005

Modulation of apoptosis by cancer chemopreventive agents.

A review of almost 2000 studies showed that the large majority of 39 putative cancer chemopreventive agents induced "spontaneous" apoptosis. Inhibition of the programmed cell death triggered by a variety of stimuli was consistently reported only with ascorbic acid, alpha-tocopherol, and N-acetylcysteine (NAC). We performed experimental studies in rodents exposed to cigarette smoke, either mainstream (MCS) or environmental (ECS), and UV-A/B-containing light. The nonsteroidal anti-inflammatory drug sulindac did not affect the apoptotic process in the skin of light-exposed mice and in the lungs of ECS-exposed mice. Likewise, 5,6-benzoflavone, indole-3-carbinol, 1,2-dithiole-3-thione and oltipraz failed to modulate apoptosis in the respiratory tract of ECS-exposed rats. Phenethyl isothiocyanate further enhanced the frequency of apoptosis in pulmonary alveolar macrophages and bronchial epithelial cells, and upregulated several genes in the lung of ECS-exposed rats. Both individually and in combination with oltipraz, NAC inhibited apoptosis in the respiratory tract of rats exposed either to MCS or ECS. Moreover, NAC attenuated the ECS-related overexpression of proapoptotic genes and normalized the levels of proapoptotic proteins in rat lung. The transplacental administration of NAC to mice considerably attenuated gene overexpression in the liver of fetuses exposed to ECS throughout pregnancy. Inhibition of apoptosis by chemopreventive agents reflects their ability to counteract certain upstream signals, such as genotoxic damage, redox imbalances, and other forms of cellular stress that trigger apoptosis. On the other hand, enhancement of apoptosis is a double-edged sword, since it represents a protective mechanism in carcinogenesis but may contribute to the pathogenesis of other degenerative diseases. We suggest that stimulation of apoptosis by so many chemopreventive agents, as reported in the literature, may often reflect the occurrence of toxic effects at high doses.

Animals↗

PubMed2005

Overview of mechanisms of cancer chemopreventive agents.

Epidemiological data provide evidence that it is possible to prevent cancer and other chronic diseases, some of which share common pathogenetic mechanisms, such as DNA damage, oxidative stress, and chronic inflammation. An obvious approach is avoidance of exposure to recognized risk factors. As complementary strategies, it is possible to render the organism more resistant to mutagens/carcinogens and/or to inhibit progression of the disease by administering chemopreventive agents. In a primary prevention setting, addressed to apparently healthy individuals, it is possible to inhibit mutation and cancer initiation by triggering protective mechanisms either in the extracellular environment or inside cells, e.g., by modifying transmembrane transport, modulating metabolism, blocking reactive species, inhibiting cell replication, maintaining DNA structure, modulating DNA metabolism and repair, and controlling gene expression. Tumor promotion can be counteracted by inhibiting genotoxic effects, favoring antioxidant and anti-inflammatory activity, inhibiting proteases and cell proliferation, inducing cell differentiation, modulating apoptosis and signal transduction pathways, and protecting intercellular communications. In a secondary prevention setting, when a premalignant lesion has been detected, it is possible to inhibit tumor progression via the same mechanisms, and in addition by affecting the hormonal status and the immune system in various ways, and by inhibiting tumor angiogenesis. Although tertiary prevention, addressed to cancer patients after therapy, is outside the classical definition of chemoprevention, it exploits similar mechanisms. It is also possible to affect cell-adhesion molecules, to activate antimetastasis genes, and to inhibit proteases involved in basement membrane degradation.

Anticarcinogenic Agents↗

PubMed2005

Mechanistic approaches to chemoprevention of mutation and cancer.

This is the eighth special issue of 'Mutation Research' to focus on antimutagenesis and anticarcinogenesis. It covers a wide range of mechanisms from prevention of cancer initiation by antimutagens through to inhibition of tumour angiogenesis and selective estrogen receptor modulators. New screening methods and new biomarkers are also elucidated. There is increasing reason to believe that the long-term use of a combination of anticarcinogens, over an extended time span, may provide a realistic prospect of reducing the current burden of human cancers.

Animals↗

PubMed2005

Multiple drug resistance, antimutagenesis and anticarcinogenesis.

Many cells are protected from excess levels of exogenous chemicals, including mutagens and carcinogens as well as pharmaceutical agents, by being actively extruded through the action of one or more of a series of ATP-binding cassette drug transporter proteins. Those known to be important in humans are the multidrug resistance proteins (P-glycoproteins, encoded by the mdr1 and 3 genes), multidrug-resistance-associated proteins (MRP1-7) and the breast cancer resistance protein (BCRP). These proteins have overlapping but distinct cellular locations and substrate specificities, and jointly govern the likelihood of penetration or distribution of a given mutagen or carcinogen into various tissues including the brain, testis, ovaries and fetus. Thus, they can affect the absorption, distribution and excretion of mutagens and carcinogens, as well as of their metabolites and conjugates, in most cases acting to prevent or reduce mutagenesis or carcinogenesis. However, because ABC transporters may limit the success of chemotherapy, there has been a considerable effort by the pharmaceutical industry to develop inhibitors of this transport process, and these are increasing in use. In general, the mutagenicity of many chemicals may be increased at the cellular levels by the action of these inhibitors, while the altered absorption characteristics favour greater uptake into the body. Thus, in many cases, such inhibitors may counter the antimutagenic and anticarcinogenic effect of the multidrug resistance mechanisms. There are exceptions, however. An increasing number of single nucleotide polymorphisms in multidrug resistance genes are being identified in humans, and may account for many of the significant differences in inter-individual susceptibility to exogenous and endogenous mutagenic and carcinogenic insults.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2005

Modulation of multigene expression and proteome profiles by chemopreventive agents.

Analysis of transcriptome and proteome profiles by microarray technologies provides a formidable, new tool in cancer chemoprevention research. An ideal chemopreventive agent should not excessively alter per se the basal make-up of multigene expression and protein synthesis and should at the same time be able to attenuate alterations induced by risk factors. In order to validate this working hypothesis, we previously performed a series of studies in animal models using the thiol N-acetyl-l-cysteine (NAC) and the nonsteroidal antiinflammatory drug sulindac. We report herein the results of new studies evaluating modulation of DNA adduct levels and expression of 4858 genes in lung and liver of Sprague-Dawley rats, either unexposed or exposed to environmental cigarette smoke (ECS). The tested chemopreventive agents included NAC, oltipraz (OPZ), 5,6-benzoflavone (5,6-BF), phenethyl isothiocyanate (PEITC), and indole 3-carbinol (I3C). Combinations of OPZ with NAC and of PEITC with I3C were also assayed. Excepting OPZ, all treatments inhibited by at least 50% the formation of bulky DNA adducts in the lung of ECS-exposed rats. Hierarchical cluster analysis and principal component analysis allowed us to classify the agents according to their influence on basal gene expression and their ability to attenuate ECS-induced transcriptome alterations. PEITC and I3C were the most effective but the least safe agents. 5,6-BF displayed intermediate patterns. OPZ was poorly effective in lung and considerably altered the basal gene expression in liver. NAC had a medium efficacy and was the safest agent, as also supported by the analysis of 518 proteins in rat lung.

Acetylcysteine↗

PubMed2005

Chemoprevention of genome, transcriptome, and proteome alterations induced by cigarette smoke in rat lung.

Post-genomic methodologies have provided novel tools for evaluating safety and efficacy of cancer chemopreventive agents. We exposed rats to environmental cigarette smoke (ECS) for 28 days, with or without oral administration of N-acetylcysteine (NAC). As assessed by 32P-postlabelling, ECS caused a 10-fold increase of DNA adduct levels, which were significantly reduced by NAC. Of 518 proteins tested by antibody microarray, ECS stimulated 56 activities involved in stress response, protein removal, cell replication, apoptosis, phagocytosis, and immune response. NAC alone did not change the amounts of any protein, whereas it significantly decreased the amounts of 6 ECS-induced proteins. The intensity of expression of 278 related genes, assessed by cDNA microarray, was significantly correlated with protein amounts. These observed molecular alterations, which can be attenuated by NAC, represent in part adaptive responses and in part reflect mechanisms contributing to the pathogenesis of smoke-related diseases, including lung cancer, asthma, chronic bronchitis, and emphysema.

Animals↗

PubMed2005

K-ras mutations in lung tumors from p53 mutant mice exposed to cigarette smoke.

In this study, we used p53 transgenic mice to investigate whether mice carrying this germline mutation would be susceptible to tobacco smoke-induced lung tumorigenesis. We subjected male transgenic mice and their wild-type littermates to whole-body exposure to environmental cigarette smoke (ECS) for up to 9.5 months. K-ras gene expression was significantly increased, 28 days after ECS exposure, in the apparently healthy lung of p53 mutant mice. An increase of lung tumor incidence and multiplicity was observed in p53 transgenic mice after exposure to ECS for either 5 months, followed by recovery in air for 4.5 months, or 9.5 continuative months of exposure. Conversely, no tumorigenic effect was observed in their wild-type littermates. Sequence analysis of the K-ras gene indicated that mutations had occurred at codon 12, 13 or codon 61 in tumors both from the air control group and tobacco smoke treatment groups. K-ras mutations were found in 100 %, 100 % and 77 % of tumors from animals exposed to air, ECS for 5 months, followed by recovery in air for 4.5 months, and ECS for 9.5 continuative months, respectively. The K-ras mutations were seemingly not related to the p53 genotype of the animals or to ECS exposure. The mutation spectrum was similar in tumors from the different groups. An apparently higher incidence of K-ras codon 12 mutations in the 9.5 months ECS group was not statistically significant. These findings provide evidence that mice carrying a mutant p53 transgene appear to be more sensitive to ECS-induced lung tumors than the corresponding wild-type littermates. K-ras mutations seem to be independent of the p53 status but the early overexpression of this oncogene is related to the p53 status in ECS-exposed mice. These results suggest that tobacco smoke enhances lung tumorigenesis primarily through promoting spontaneously occurring K-ras mutations.

Animals↗

PubMed2005

The epidemiological revolution of the 20th century.

Until 100 years ago the epidemiological scenario of human diseases had substantially remained unchanged. The 20th century has been characterized by a fantastic advance in life expectancy and by a shift from infectious to chronic degenerative diseases as prevailing causes of death. As an example of the epidemiological revolution in a developed country, we reconstructed, year by year from 1901 to 2000, the situation in Italy. Reference to the situation in other countries is also made. Both crude and age-adjusted mortality data were made available for males and females. A new turning point became evident in the second half of the 20th century with the decline of mortality for cardiovascular diseases and, more recently, for tumors. This review discusses the roots and rationale for these epidemiological changes. The discoveries made in the area of biomedical sciences, the progress in preventive and curative medicine, and the improvement of hygienic conditions have been so spectacular that 1 million lives are saved every year in Italy as compared with the late 19th century.

Cause of Death↗

PubMed2004

Modulation of light-induced skin tumors by N-acetylcysteine and/or ascorbic acid in hairless mice.

The light emitted by halogen quartz bulbs contains a broad spectrum of UV wavelengths, is strongly genotoxic and is a potent inducer of skin tumors in hairless mice. By using a UVC filter, this light mimics solar radiation and induces a variety of genomic and transcriptional alterations in mouse skin. UV-related carcinogenesis involves depletion of antioxidants and glutathione in skin cells. On this basis, we evaluated modulation of carcinogenicity of UVC-filtered halogen lamps in SKH-1 hairless mice by the antioxidants N-acetyl-l-cysteine (NAC) and ascorbic acid (AsA). Both agents were given in the drinking water, either individually or in combination. The earliest skin lesions were detected after 300 days' exposure to light and became confluent in a number of mice after 480 days. NAC administration prolonged the latency time by 90 days. Moreover, NAC considerably and significantly decreased both incidence and multiplicity of light-induced skin tumors, prevented the occurrence of malignant lesions (squamocellular carcinomas) and reduced the tumor size. In contrast, AsA, which may behave as a prooxidant rather than an antioxidant, increased the multiplicity of total skin tumors, carcinomas in situ and squamocellular carcinomas. Co-administration of NAC with AsA significantly attenuated the negative effect of AsA, presumably due to the ability of this thiol to maintain a reduced environment. Therefore, in agreement with our previous in vitro findings, oral NAC is able to attenuate the detrimental effects of AsA.

Acetylcysteine↗

PubMed2004

Gene expression in the lung of p53 mutant mice exposed to cigarette smoke.

We showed previously that p53 mutations play a role in cigarette smoke-related carcinogenesis not only in humans but also in A/J mice. In fact, (UL53-3 x A/J)F(1) mice, carrying a dominant-negative germ-line p53 mutation, responded to exposure to environmental cigarette smoke more efficiently than their wild-type (wt) littermate controls in terms of molecular alterations, cytogenetic damage, and lung tumor yield. To clarify the mechanisms involved, we analyzed by cDNA array the expression of 1,185 cancer-related genes in the lung of the same mice. Neither environmental cigarette smoke nor the p53 status affected the expression of the p53 gene, but the p53 mutation strikingly increased the basal levels of p53 nuclear protein in the lung. Environmental cigarette smoke increased p53 protein levels in wt mice only. The p53 mutation enhanced the expression of positive cell cycle regulators in sham-exposed mice, which suggests a physiologic protective role of p53. In environmental cigarette smoke-exposed mice, the p53 mutation resulted in a lack of induction of proapoptotic genes and in overexpression of genes involved in cell proliferation, signal transduction, angiogenesis, inflammation, and immune response. Mutant mice and wt mice reacted to environmental cigarette smoke in a similar manner regarding genes involved in metabolism of xenobiotics, multidrug resistance, and protein repair. Irrespective of the p53 status, environmental cigarette smoke poorly affected the expression of oncogenes, tumor suppressor genes, and DNA repair genes. Taken together, these findings may explain the increased susceptibility of p53 mutant mice to smoke-related alterations of intermediate biomarkers and lung carcinogenesis.

Animals↗

PubMed2004

Alterations of gene expression in skin and lung of mice exposed to light and cigarette smoke.

We previously showed that sunlight-mimicking light induces genotoxic damage not only in skin but also even in lung, bone marrow, and peripheral blood of hairless mice. Moreover, light and smoke acted synergically in the respiratory tract. To clarify the mechanisms involved, we investigated by cDNA-arrays the expression of 746 toxicologically relevant genes in skin and lungs of mice exposed for 28 days to light and/or environmental cigarette smoke. Glutathione-S-transferase-Pi and catalase were overexpressed in the lungs of mice exposed to light only. Moreover, the light induced in skin the expression of genes involved in carcinogenesis, photoaging, and production of genotoxic and oxidizing derivatives traveling at a distance. Smoke induced the expression of multiple genes in both skin and lung, which reflect adaptive responses and mechanisms related to cancer and, possibly, to emphysema and stroke. As shown in mice exposed to both light and smoke, the light tended to increase smoke-induced gene expression in lungs, while smoke tended to attenuate light-induced gene expression in skin. The oral administration of the nonsteroidal anti-inflammatory drug sulindac inhibited the light-induced overexpression of cyclooxygenase-2 and oxidative stress-related genes in skin, and down-regulated smoke-induced genes involved in oxidative stress, removal of damaged proteins, inflammation, and immune response in lung. These results provide a mechanistic insight explaining the systemic alterations induced by both light and smoke in mouse skin and lungs.

Animals↗