Biomedical subjects

Michael I Luster

Publications and source records attributed to Michael I Luster.

30 records · Page 2Linked to original sources

PubMed2003

Consensus workshop on methods to evaluate developmental immunotoxicity.

A workshop cosponsored by the National Institute of Environmental Health Sciences and the National Institute for Occupational Safety and Health was convened in Washington, DC, on 17-18 October 2001 with the goal of developing a consensus document on the most appropriate experimental approaches and assays available to assess developmental immunotoxicity. The work group was composed of scientists from academia, the chemical and pharmaceutical industries, and federal agencies with expertise in developmental immunology, developmental toxicology, immunotoxicology, and risk evaluation. This consensus document presents an overview of the major summations made by the work group. A summary of early work in the field is provided, which includes potential immunotoxic agents, followed by brief discussions of our current understanding of developmental immunology. This report concludes with the work group's consensus of the most appropriate experimental design and tests to screen for potential developmental immunotoxic agents in experimental models, including potential limitations and data gaps.

Environmental Pollutants↗

PubMed2003

Arsenic exposure accelerates atherogenesis in apolipoprotein E(-/-) mice.

Epidemiologic studies have shown an association between elevated arsenic levels in drinking water and an increased risk of atherosclerosis and vascular diseases. The studies presented here were performed to evaluate the atherogenic potential of arsenic using a well-established and controlled animal model of human atherosclerosis, mice deficient in apolipoprotein E (ApoE), and in vitro systems including primary human vascular cells. Wild-type and ApoE-deficient mice were exposed to 20 or 100 microg/mL sodium arsenite in drinking water for 24 weeks. As assessed morphometrically, the size of grossly discernible lesions covering the intimal area of aorta were increased significantly in arsenic-treated ApoE-deficient mice compared with nontreated transgenic mice. This effect was not associated with increased levels of serum cholesterol but was accompanied by an accumulation of arsenic in the vessel wall. Introduction of cocoa butter into the diet for 2 weeks resulted in higher serum cholesterol levels and only slight increases in the lesion size in control or arsenic-exposed ApoE-deficient mice. There were no lesions observed in the wild-type C57BL6 mice, resistant to atherosclerosis, whether they received arsenic or control drinking water. In vitro studies, including primary aorta endothelial or smooth muscle cells, were conducted to evaluate whether arsenic induces cellular mechanisms relevant to atherogenesis such as endothelial dysfunction, lipid oxidation, and smooth muscle cell proliferation. Arsenic treatment does not modulate endothelial cell-mediated lipid oxidation or smooth muscle cell proliferation but induced the expression of genes coding inflammatory mediators, including interleukin-8. Induction of endothelial inflammatory activity may play a role in arsenic-related vascular effects.

Animals↗

PubMed2003

Cytokine polymorphisms in chronic inflammatory diseases with reference to occupational diseases.

Genes which encode inflammatory cytokines are subject to polymorphisms in their regulatory regions that may effect both the level and ratio of cytokines produced in response to exogenous stimuli. These variant alleles are observed in a large percent of the population and are often associated with increased or decreased susceptibility or severity (modifiers) to infectious, immune or inflammatory diseases. Environmental factors can also play either a direct (i.e., causative factor) or indirect (modifying factor) role in these diseases. Thus, it would follow that gene-environment interactions would effect the expression and/or progression of the disease. In the present review, the concept that some of the common allelic variants found in cytokine genes represent modifying factors in chronic inflammatory diseases associated with occupational exposure is discussed.

Animals↗

PubMed2002

IL-1beta gene polymorphisms influence hepatitis B vaccination.

Considerable variability exists in the vaccine response to hepatitis B with 5-10% of healthy young adults demonstrating no or inadequate responses following a standard vaccination schedule. As the interleukin-1beta (IL-1beta) cytokine has been shown to be important in the development of immune responses, we determined whether vaccine efficacy is influenced by genetic polymorphisms associated with IL-1beta expression. Ninety-two healthy individuals who were negative for antibodies to hepatitis B antigen (anti-HBs) were vaccinated against hepatitis B according to a standardized schedule. At selected times, antibody titers and lymphoproliferative capacity to hepatitis B surface antigen (HBsAg) were determined. DNA genotyping for IL-1beta polymorphisms using a polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) technique demonstrated that both the anti-HBs titer and the T-cell lymphoproliferative response to HBsAg are significantly increased in individuals possessing the IL-1beta (+3953) minor allelic variant.

Adult↗

PubMed2002

Insights into the quantitative relationship between sensitization and challenge for allergic contact dermatitis reactions.

The ability of chemical or pharmaceutical agents to induce allergic contact dermatitis (ACD) is of major health and regulatory concern. As such, tests to identify their sensitizing capacity, such as the guinea pig maximization test and the more recently developed local lymph node assay, are broadly used. Ideally, for risk assessment it is useful to translate results from animal data into establishing safe or no-effect levels for occupational or environmental agents. This, of course, would require consideration of the quantitative relationships between sensitizing and challenge doses as well as other exposure conditions. In the present studies, we modeled two sensitizers, 2,4-dinitrochlorobenzene and squaric acid dibutyl ester, over a large range of concentrations using the LLNA and more traditional tests that measure both sensitization and elicitation responses. Both the sensitization and challenge phases provided similar dose-response curves, demonstrating a threshold followed by a shallow linear increase and eventual plateau at increasing doses. Extending earlier studies by P. S. Friedmann (1994, Immunotoxicology and Immunopharmacology, pp. 589-616, Raven Press, New York) in humans, we observed that the minimum dose required to elicit sensitization or challenge was not static, but rather reflected a "sliding-scale." That is, as the sensitization dose was increased, the concentration required to elicit a challenge response was decreased. Correspondingly, as the challenge dose was increased, the dose required for sensitization was lessened. Taken together, these findings indicate that there is a need to consider dose-response relationships for sensitization and challenge in establishing minimum exposure levels for chemicals that cause ACD.

Adjuvants, Immunologic↗

PubMed2002

Physiological role of tumor necrosis factor alpha in traumatic muscle injury.

degenerative and regenerative roles of tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory cytokine with pleiotropic functions, were investigated by using TNF receptor 1 and 2 double knockout (TNFR-DKO) and TNF-alpha antibody neutralized mice following traumatic freeze injury to the tibialis anterior muscle. In wild-type control mice, TNF-alpha mRNA transcripts and protein increased following injury and gradually returned to control (uninjured) levels by 13 days. A reduction in MyoD mRNA expression occurred in TNF-alpha-deficient mice, although there were no visible differences in MyoD immunostaining or histological characteristics in regenerating muscles. At 5 days post-injury, the reductions in isometric strength in TNFR-DKO and TNF-alpha-depleted mice did not differ from that of wild-type mice but by 13 days after injury, the TNFR-DKO and TNF-alpha-depleted mice exhibited strength deficits twice that of wild-type mice (i.e., 27-31% vs 13%). Muscle injury was also accompanied by increased expression of interleukin-6 (IL-6), but IL-6-deficient mice demonstrated MyoD expression and recovery of isometric strength similar to that of wild-type mice. These data indicate that TNF-alpha is involved in the recovery of muscle function after traumatic muscle injury, and this effect might be associated with modulation of muscle regulatory genes, including MyoD.

Animals↗

PubMed2002

Mice deficient in TNF receptors are protected against dopaminergic neurotoxicity: implications for Parkinson's disease.

The pathogenic mechanisms underlying idiopathic Parkinson's disease (PD) remain enigmatic. Recent findings suggest that inflammatory processes are associated with several neurodegenerative disorders, including PD. Enhanced expression of the proinflammatory cytokine, tumor necrosis factor (TNF)-alpha, has been found in association with glial cells in the substantia nigra of patients with PD. To determine the potential role for TNF-alpha in PD, we examined the effects of the 1-methyl-4-phenyl-1,2,3,4-tetrahydropyridine (MPTP), a dopaminergic neurotoxin that mimics some of the key features associated with PD, using transgenic mice lacking TNF receptors. Administration of MPTP to wild-type (+/+) mice resulted in a time-dependent expression of TNF-alpha in striatum, which preceded the loss of dopaminergic markers and reactive gliosis. In contrast, transgenic mice carrying homozygous mutant alleles for both the TNF receptors (TNFR-DKO), but not the individual receptors, were completely protected against the dopaminergic neurotoxicity of MPTP. The data indicate that the proinflammatory cytokine TNF-alpha is an obligatory component of dopaminergic neurodegeneration. Moreover, because TNF-alpha is synthesized predominantly by microglia and astrocytes, our findings implicate the participation of glial cells in MPTP-induced neurotoxicity. Similar mechanisms may underlie the etiopathogenesis of PD.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗

PubMed2002

Role of tumor necrosis factor in toluene diisocyanate asthma.

Nearly 9 million workers are exposed to chemical agents associated with occupational asthma, with isocyanates representing the chemical class most responsible. Isocyanate-induced asthma has been difficult to diagnose and control, in part because the biologic mechanisms responsible for the disease and the determinants of exposure have not been well defined. Isocyanate-induced asthma is characterized by airway inflammation, and we hypothesized that inflammation is a prerequisite of isocyanate-induced asthma, with tumor necrosis factor (TNF)-alpha being critical to this process. To explore this hypothesis, wild-type mice, athymic mice, TNF-alpha receptor knockout (TNFR), and anti-TNF-alpha antibody-treated mice were sensitized by subcutaneous injection (20 micro l on Day 1; 5 micro l, Days 4 and 11), and challenged 7 d later by inhalation (100 ppb; Days 20, 22, and 24) with toluene diisocyanate (TDI). Airway inflammation, goblet cell metaplasia, epithelial cell damage, and nonspecific airway reactivity to methacholine challenge, measured 24 h following the last challenge, were reduced to baseline levels in TNF-alpha null mice and athymic mice. TNF-alpha deficiency also markedly abrogated TDI-induced Th2 cytokines in airway tissues, indicating a role in the development of Th2 responses. Despite abrogation of all indicators of asthma pathology, TNF-alpha neutralization had no effect on serum IgE levels or IgG-specific TDI antibodies, suggesting the lack of importance of a humoral response in the manifestation of TDI-induced asthma. Instillation studies with fluorescein-conjugated isothiocyanate and TDI suggested that TNF-alpha deficiency also resulted in a significant reduction in the migration of airway dendritic cells to the draining lymph nodes. Taken together, these results suggest that, unlike protein antigens, TNF-alpha has multiple and central roles in TDI-induced asthma, influencing both nonspecific inflammatory processes and specific immune events.

Allergens↗

PubMed2001

c-Src-dependent activation of the epidermal growth factor receptor and mitogen-activated protein kinase pathway by arsenic. Role in carcinogenesis.

Environmental or occupational exposure to arsenic is associated with a greatly increased risk of skin, urinary bladder, and respiratory tract cancers in arseniasis-endemic areas throughout the world. Arsenic shares many properties of tumor promoters by affecting specific cell signal transduction pathways responsible for cell proliferation. The activation of the epidermal growth factor receptor (EGFR)-extracellular signal-regulated protein kinase (ERK) pathway is important in mediating gene expression related to regulation of cellular growth. In the current studies, we demonstrate that arsenic activates EGFR and ERK in a human uroepithelial cell line. The EGFR phosphorylation by arsenic is ligand-independent and does not involve the major autophosphorylation site Tyr(1173). c-Src activity is also induced by arsenic and is a prerequisite for the EGFR and ERK activation. Consistent with these in vitro observations, exposure of mice to arsenic in drinking water, which has been found previously to be associated with AP-1 activation and epithelial proliferation, induces EGFR and ERK activation in the urinary bladder. This response is also accompanied with an increase in c-Src levels interacting with EGFR. These findings represent a potential pathway for mediating arsenic-induced phenotypic changes in the uroepithelium.

Active Transport, Cell Nucleus↗

PubMedDate not supplied

The comparative immunotoxicity of five selected compounds following developmental or adult exposure.

It is well established that human diseases associated with abnormal immune function, including some common infectious diseases and asthma, are considerably more prevalent at younger ages. Although not established absolutely, it is generally believed that development constitutes a period of increased immune system susceptibility to xenobiotics, since adverse effects may occur at lower doses and/or immunomodulation may be more persistent, thus increasing the relative risk of xenobiotic exposure to the immunologically immature organism. To address this issue, a brief overview of immune maturation in humans is provided to demonstrate that functional immaturity alone predisposes the young to infection. Age-dependent differences in the immunotoxic effects of five diverse compounds, diethylstilbestrol (DES), diazepam (DZP), lead (Pb), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), and tributyltin oxide (TBTO), which have undergone adult and developmental immunotoxicity testing in rodents, are then reviewed, as are human data when available. For all five chemicals, the developing immune system was found to be at greater risk than that of the adult, either because lower doses produced immunotoxicity, adverse effects were more persistent, or both.

Animals↗

PubMedDate not supplied

Cytokine polymorphisms in silicosis and other pneumoconioses.

Silicosis and coal workers' pneumoconiosis are complex multifactorial lung diseases whose etiopathogenesis are not well defined. It is generally accepted that fibrotic lung disorders are mediated by macrophage-derived cytokines and growth factors. There is evidence showing a crucial role for tumor necrosis factor-a (TNF-alpha) and interleukin-1 (IL-1) in inflammation caused by silica dust and in the transition from simple to progressive massive fibrosis. In this review we discuss genetic polymorphisms responsible for regulating the production of these proinflammatory cytokines and their role in modifying silicosis severity.

Genotype↗

PubMedDate not supplied

Arsenic carcinogenicity: relevance of c-Src activation.

Environmental and occupational exposure to arsenic is associated with increased risk of skin, urinary bladder and respiratory tract cancers. Increasing evidence indicates that arsenic acts at the level of tumor promotion by modulating the signaling pathways responsible for cell growth. One of this pathways might include c-Src dependent EGFR and MAPK activation.

Arsenic↗