RESUMO
Progressive massive fibrosis (PMF) is a chronic interstitial lung disease with a complex aetiology that can occur after cumulative dust exposure. A case-control study was conducted to test the hypothesis that single nucleotide polymorphisms (SNPs) within genes involved in inflammatory and fibrotic processes modulate the risk of PMF development. The study population consisted of 648 underground coal miners participating in the National Coal Workers Autopsy Study, of which 304 were diagnosed with PMF. SNPs that influence the regulation of interleukin (IL)-1, IL-6, tumour necrosis factor-alpha, transforming growth factor-beta1, vascular endothelial growth factor (VEGF), epidermal growth factor intercellular cell adhesion molecule (ICAM)-1 and matrix metalloproteinase-2 genes were determined using a 5'-nuclease real-time PCR assay. There were no significant differences in the distribution of any individual SNP or haplotype between the PMF and control groups. However, the polygenotype of VEGF +405/ICAM-1 +241/IL-6 -174 (C-A-G) conferred an increased risk for PMF (odds ratio 3.4, 95% confidence interval 1.3-8.8). The present study suggests that the examined genetic variations that help regulate inflammatory and fibrotic processes are unlikely to strongly influence susceptibility to this interstitial lung disease, although the role of vascular endothelial growth factor, intercellular cell adhesion molecule-1 and interleukin-6 polymorphisms in the development of progressive massive fibrosis may require further investigation.
Assuntos
Minas de Carvão , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único , Fibrose Pulmonar/genética , Idoso , Estudos de Casos e Controles , Humanos , Molécula 1 de Adesão Intercelular/genética , Interleucina-6/genética , Interleucina-6/imunologia , Masculino , Fibrose Pulmonar/imunologia , Fator A de Crescimento do Endotélio Vascular/genéticaRESUMO
BACKGROUND: Oxidative stress plays a major role in the pathogenesis of interstitial lung diseases. The antioxidant enzymes glutathione S-transferases (GST) and manganese superoxide dismutase (MnSOD) are important components of lung defence against oxidative stress, and polymorphisms in the genes which regulate their expression may represent important disease modifiers. METHODS: A matched case-control study was conducted to determine the influence of the GSTP1, GSTT1 and MnSOD polymorphisms on susceptibility to progressive massive fibrosis (PMF). Seven hundred ex-coal miners were included in the study; 350 were classified as PMF cases while 350 with a similar underground mining tenure but no clinical or histological evidence of lung disease served as controls. Genotype analysis was performed on genomic DNA, using a 5' nuclease PCR assay. RESULTS: None of the individual investigated polymorphisms and two-way gene-gene interactions had a statistically significant association with PMF. CONCLUSION: The results of this study suggest that polymorphic genotypes within the GST gene cluster and MnSOD do not affect individual susceptibility to PMF.
Assuntos
Minas de Carvão , Glutationa Transferase/genética , Isoenzimas/genética , Pneumoconiose/genética , Polimorfismo Genético/genética , Superóxido Dismutase/genética , Idoso , Antioxidantes , Estudos de Casos e Controles , Frequência do Gene , Predisposição Genética para Doença/genética , Glutationa S-Transferase pi , Humanos , Mutação/genética , Reação em Cadeia da Polimerase/métodosRESUMO
The accuracy of extended histopathology to detect immunotoxic chemicals in female B6C3F1 mice was evaluated under the auspices of the National Toxicology Program (NTP). A workgroup was formed consisting of four pathologists who conducted extended histopathological evaluation of lymphoid tissues obtained from a subset of NTP toxicology studies, in which previously detailed immunotoxicity assessment was performed. In addition, a positive control data set of three known immunosuppressive agents, one negative control data set, and an additional negative control group composed of the vehicle only treated groups were included. Data obtained from extended histopathology evaluations were compared to more traditional immune test results (both functional and nonfunctional) from previously conducted immunotoxicity assessments. Analyses of the data indicated that the ability to identify immunotoxic chemicals using histological endpoints decreased linearly as the level of stringency used to determine significant histopathological changes increased. A relatively high (80%) accuracy level was achieved when histological changes were considered in toto (i.e., any histological abnormality in the three tissues examined), using minimal or mild criteria for scoring. When minimal or mild histological changes were considered significant for a specific tissue, a 60% level of accuracy in identifying immunotoxic chemicals was obtained as compared to a 90% accuracy level that was achieved with this data set using the antibody plaque forming cell response, considered to represent the most predictive functional test. A minimal classification was obtained in the analyses of the negative control groups, suggesting that use of the minimal classification for hazard identification is inappropriate as it will likely result in a high incidence of false positives. This was not the case when mild classifications were used as an indicator of significance, which in most instances allowed the successful identification of negatives. When moderate to marked histopathological changes were used to identify immunotoxic chemicals, the level of accuracy that could be achieved was poor. A considerably higher level of accuracy was obtained for the positive control data set than the test chemical data set suggesting that the ability to detect an immunotoxic agent histologically is proportional to the potency of the immunotoxic agent. Comparison of immune function test results and histopathological results obtained from the high-dose treatment groups and the lower-dose treatment group did not reveal any significant differences between the two endpoints to predict immunotoxicity as a function of dose. Of the three lymphoid organs examined, (i.e., lymph node, thymus, and spleen), the most consistent and discernible histological lesions were observed in the thymus cortical region. These lesions correlated with thymus: body weight ratios and to a slightly lesser extent, the antibody plaque forming cell response. Addition of general toxicological endpoints such as body weight and leukocyte counts did not significantly improve the sensitivity of extended histopathology for this data set. Taken together, these data suggest that, while not as sensitive as functional analyses, extended histopathology may provide a reasonable level of accuracy as a screening test to identify immunotoxic chemicals, provided the level of stringency used to score histological lesions is carefully considered to allow for detection of immunotoxic agents while limiting false positives.
Assuntos
Sistema Imunitário/efeitos dos fármacos , Linfonodos/patologia , Baço/patologia , Timo/patologia , Testes de Toxicidade/métodos , Animais , Peso Corporal/efeitos dos fármacos , Relação Dose-Resposta a Droga , Determinação de Ponto Final , Reações Falso-Positivas , Técnica de Placa Hemolítica , Imunidade Celular/efeitos dos fármacos , Linfonodos/citologia , Linfonodos/imunologia , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos , Tamanho do Órgão/efeitos dos fármacos , Especificidade de Órgãos , Veículos Farmacêuticos , Valor Preditivo dos Testes , Reprodutibilidade dos Testes , Baço/imunologia , Timo/imunologiaRESUMO
There has been considerable interest in the use of expanded histopathology as a primary screen for immunotoxicity assessment. To determine the utility of a semiquantitative histopathology approach for examining specific structural and architectural changes in lymphoid tissues, a validation effort was initiated. This study addresses the interlaboratory reproducibility of extended histopathology, using tissues from studies of ten test chemicals and both negative and positive controls from the National Toxicology Program's immunotoxicology testing program. We examined the consistency between experienced toxicologic pathologists, who had varied expertise in immunohistopathology in identifying lesions in immune tissues, and in the sensitivity of the individual and combined histopathological endpoints to detect chemical effects and dose response. Factor analysis was used to estimate the association of each pathologist with a so-called "common factor" and analysis-of-variance methods were used to evaluate biases. Agreement between pathologists was highest in the thymus, in particular, when evaluating cortical cellularity of the thymus; good in spleen follicular cellularity and in spleen and lymph node-germinal center development; and poorest in spleen red-pulp changes. In addition, the ability to identify histopathological change in lymphoid tissues was dependent upon the experience/training that the individual pathologist possessed in examining lymphoid tissue and the apparent severity of the specific lesion.
Assuntos
Alergia e Imunologia/normas , Sistema Imunitário/efeitos dos fármacos , Laboratórios/normas , Toxicologia/normas , Animais , Biologia Computacional , Interpretação Estatística de Dados , Relação Dose-Resposta a Droga , Histologia/normas , Modelos Estatísticos , Reprodutibilidade dos Testes , Terminologia como AssuntoRESUMO
Hepatic expression of the proinflammatory cytokine tumor necrosis factor-alpha (TNFalpha) occurs in many acute and chronic liver diseases, as well as following exposure to hepatotoxic chemicals, and is believed to help influence both the damage and repair processes that occur following these insults by regulating additional mediators. We examined the role of TNFalpha in transgenic mice deficient in TNF receptors (TNFR) utilizing carbon tetrachloride (CCl(4)) as a model hepatotoxic agent that allowed for the evaluation of necrosis, inflammation, and fibrosis. Hepatocyte damage, as evident by local areas of liver necrosis and elevated levels of serum transaminase, occurred to a similar degree in wild-type and TNFR-deficient knockout (KO) mice following acute exposure to CCl(4). In contrast, the inflammatory response, manifested as an inflammatory cell influx, as well as induction of chemokines and adhesion molecules that occurred in wild-type mice following treatment with CCl(4), was not as evident in TNFR-KO mice. This response was associated primarily with type-1 (TNFR1) rather than type-2 (TNFR2) receptor responses. Liver fibrosis resulting from chronic CCl(4) exposure was also markedly dependent upon TNFalpha as demonstrated by almost a complete histological absence of fibrosis in TNFR-deficient mice. This was further supported by marked reductions in procollagen and transforming growth factor beta synthesis in TNFR-deficient mice. Taken together, these results indicate that TNFalpha is responsible for regulating products that induce inflammation and fibrosis but not direct hepatocyte damage in CCl(4)-induced hepatotoxicity.
Assuntos
Tetracloreto de Carbono/toxicidade , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Cirrose Hepática/induzido quimicamente , Fígado/efeitos dos fármacos , Receptores do Fator de Necrose Tumoral/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia , Alanina Transaminase/sangue , Animais , Aspartato Aminotransferases/sangue , Doença Hepática Induzida por Substâncias e Drogas/imunologia , Colágenos Fibrilares/metabolismo , Regulação da Expressão Gênica , Histocitoquímica , Molécula 1 de Adesão Intercelular/análise , Molécula 1 de Adesão Intercelular/biossíntese , Fígado/patologia , Cirrose Hepática/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Peroxidase/metabolismo , Distribuição Aleatória , Receptores do Fator de Necrose Tumoral/genética , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Dermal wounding is accompanied by inflammation and the resulting proinflammatory cytokines, including interleukin (IL)-6, are thought to play an important role in the repair process. IL-6 is produced by normal human keratinocytes to various dermatological diseases and we have recently shown it is also required for normal wound repair. However, neither the events responsible for its induction nor its role in repair have been clearly identified. Using a recently developed in vitro wounding model, we demonstrate that IL-6 mRNA is expressed and immunoreactive IL-6 is released from cultures of human epidermal keratinocytes (NHEKs) following wounding. The transcription factors, NF kappa B and NF-IL-6 (C/EBP beta), which coordinately help regulate IL-6 expression, were activated following wounding and preceded the appearance of IL-6. Addition of IL-1 alpha to NHEK cultures increased IL-6 production and activated NF kappa B and C/EBP beta. Addition of the IL-1 alpha receptor antagonist inhibited both IL-6 mRNA expression and the transcription factors following wounding. Immunoreactive IL-1 alpha was detected in the medium following wounding in the absence of new message. Furthermore, addition of IL-6 to NHEK cultures decreased the expression of keratins 1 and 10, differentiation markers of keratinocytes, while proliferation was not affected. Taken together, these data indicate that constitutive keratinocyte-derived IL-1 alpha is a stimulus for IL-6 production in wounded epidermis, the response involves NF kappa B and C/EBP beta transcription factors, and IL-6 may be associated with modulation of keratinocyte differentiation rather than proliferation.
Assuntos
Células Epiteliais/metabolismo , Interleucina-6/metabolismo , Interleucina-6/fisiologia , Queratinócitos/metabolismo , Cicatrização , Adulto , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Diferenciação Celular , Divisão Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , DNA/metabolismo , Ativação Enzimática , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Interleucina-1/biossíntese , Interleucina-6/biossíntese , Queratinas/biossíntese , NF-kappa B/metabolismo , Ligação Proteica , RNA/metabolismo , RNA Mensageiro/metabolismo , Receptores de Interleucina-1/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Pele/citologia , Fatores de Tempo , Transcrição GênicaRESUMO
It has been postulated that the inflammatory response that occurs after cutaneous wounding is a prerequisite for healing and that inflammatory cytokines, such as interleukin-6 (IL-6) are involved in this process. We showed previously that IL-6-deficient mice display delayed wound healing, which could be reversed by administration of a murine IL-6 expression plasmid or recombinant murine IL-6 (rMuIL-6). In the present study, we observed that delayed cutaneous wound healing, which occurs as a result of glucocorticoid-induced immunosuppression, can also be reversed by rMuIL-6, as evidenced by epithelialization, granulation tissue formation, and wound closure. In vehicle control mice, rMuIL-6 did not augment healing but rather delayed the process. Immunochemical studies indicated that the expression of matrix metalloproteinase-10 (MMP-10) was increased in dexamethasone-treated mice and that rMuIL-6 treatment reduced its expression, indicating that IL-6 may influence dermal matrix formation and, specifically, collagen synthesis. These results demonstrate that IL-6 can restore abnormal wound repair that occurs in immunodeficiency and suggest its use as a potential therapy.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Imunossupressores/administração & dosagem , Interleucina-6/administração & dosagem , Pele/efeitos dos fármacos , Pele/imunologia , Cicatrização/efeitos dos fármacos , Cicatrização/imunologia , Animais , Citocinas/biossíntese , Dexametasona/administração & dosagem , Dexametasona/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Injeções Subcutâneas , Masculino , Metaloproteinase 10 da Matriz , Metaloendopeptidases/biossíntese , Camundongos , Camundongos Endogâmicos C57BL , Pele/enzimologiaRESUMO
BACKGROUND: Nearly 9 million individuals are exposed to agents in the workplace associated with asthma, and isocyanates represent the most common cause of occupationally induced asthma. OBJECTIVES: Nonetheless, the immunological mechanisms responsible for isocyanate-induced asthma are not clear. A murine model for toluene diisocyanate (TDI) asthma is described and employed to examine inflammatory and immune components that may be involved in the disease. METHODS: Groups (n = 6) of C57BL/6J and athymic mice were sensitized by subcutaneous injection (20 microl on day 1, 5 microl on days 4 and 11), and 7 days later challenged by inhalation (100 p.p.b., days 20, 22 and 24) with TDI. Twenty-four hours following the last challenge the tracheae and lungs were examined for histological changes as well as for the expression of Th1, Th2 and pro-inflammatory cytokines. Mice were also examined for airway reactivity to methacholine challenge and for specific and total IgE and IgG antibodies. RESULTS: TDI sensitization resulted in increased reactivity to methacholine challenge as well as a significant inflammatory response in the trachea and nares of wild-type mice, but not in the athymic mice nor in the lungs of the C57BL/6J mice. Airway inflammation was characterized by inflammatory cell influx, goblet cell metaplasia and epithelial damage. Histological changes in the trachea were accompanied by increased mRNA expression of interleukin (IL)-4, tumour necrosis factor alpha, lymphotoxin beta, lymphotactin and Rantes, as well as TDI-specific IgG antibodies and elevated levels of total IgE. IgE-specific antibodies were not detected with this exposure regimen but were produced when the TDI concentrations were increased. CONCLUSIONS: These studies provide a unique murine model for occupational asthma that generates both inflammatory and immune mediators similar to those occurring in TDI-induced asthma in humans.
Assuntos
Hiper-Reatividade Brônquica/imunologia , Modelos Animais de Doenças , Mediadores da Inflamação/imunologia , Tolueno 2,4-Di-Isocianato/imunologia , Animais , Asma/induzido quimicamente , Asma/imunologia , Brônquios/imunologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos NusRESUMO
The liver, which is the major organ responsible for the metabolism of drugs and toxic chemicals, is also the primary target organ for many toxic chemicals. Increasing evidence has indicated that inflammatory processes are intimately involved in chemical-induced hepatotoxic processes, and like other inflammatory diseases, such as autoimmunity, are responsible for producing mediators that can effect liver damage or repair. This review will summarize our current understanding of how inflammatory processes influence hepatic pathology and repair following exposure to established hepatotoxic chemicals including carbon tetrachloride, an industrial chemical, and acetaminophen, a widely used analgesic.
Assuntos
Inflamação/fisiopatologia , Fígado/efeitos dos fármacos , Animais , Humanos , Camundongos , Antígeno Nuclear de Célula em Proliferação/análise , Receptores do Fator de Necrose Tumoral/fisiologia , Fator de Necrose Tumoral alfa/fisiologiaRESUMO
The article highlighted in this issue is "Endotoxin enhancement of ozone-induced mucous cell metaplasia is neutrophil-dependent in rat nasal epithelium," by James G. Wagner, Steven J. Van Dyken, Jon A. Hotchkiss, and Jack R. Harkema (pp. 338-347).
Assuntos
Oxidantes Fotoquímicos/efeitos adversos , Ozônio/efeitos adversos , Mucosa Respiratória/efeitos dos fármacos , Poluentes Atmosféricos/efeitos adversos , Animais , Humanos , Exposição por Inalação , Metaplasia/induzido quimicamente , Metaplasia/patologia , Mucosa Respiratória/patologiaRESUMO
Because of the potential of arsenic for causing cancer in humans, and of the fact of widespread environmental and occupational exposure, deriving acceptable human-limit values has been of major concern to industry as well as to regulatory agencies. Based upon epidemiological evidence and mechanistic studies, it has been argued that a non-linear dose-response model at low-level exposures is more appropriate for calculating risk than the more commonly employed linear-response models. In the present studies, dose-response relationships and recovery studies employing a cancer precursor marker, i.e., activating protein (AP)-1 DNA-binding activity, were examined in bladders of mice exposed to arsenic in drinking water and compared to histopathological changes and arsenic tissue levels in the same tissue. While AP-1 is a functionally pleomorphic transcription factor regulating diverse gene activities, numerous studies have indicated that activation of the MAP kinase pathway and subsequently increased AP-1 binding activities, is a precursor for arsenic-induced cancers of internal organs as well as the skin. We observed previously that within 8 weeks of exposure AP-1 activation occurs in urinary bladder tissue of mice exposed to arsenic in the drinking water. In the present studies, C57BL/6 mice were exposed to sodium arsenite at various concentrations in the drinking water for 8 consecutive weeks. Minimal but observable AP-1 activity occurred in bladder tissue at exposure levels below which histopathological changes or arsenic tissue accumulation was detected. Marked AP-1 DNA-binding activity only occurred at exposure levels of sodium arsenite above 20 microg/ml, where histopathological changes and accumulation of arsenic in the urinary bladder epithelium occurred. Although the experimental design did not allow statistical modeling of the entire dose-response curve, the general shape of the dose-response curve is not inconsistent with the previously proposed hypothesis that arsenic-induced cancer follows a non-linear dose-response model.
Assuntos
Arsênio/toxicidade , Carcinógenos Ambientais/toxicidade , Epitélio/metabolismo , Fator de Transcrição AP-1/biossíntese , Bexiga Urinária/efeitos dos fármacos , Bexiga Urinária/metabolismo , Animais , Arsênio/farmacocinética , Carcinógenos Ambientais/farmacocinética , Dano ao DNA , Proteínas de Ligação a DNA , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Ingestão de Líquidos , Epitélio/efeitos dos fármacos , Epitélio/patologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Medição de Risco , Distribuição Tecidual , Bexiga Urinária/patologiaRESUMO
Silicosis, an interstitial lung disease prevalent among miners, sand blasters, and quarry workers, is manifested as a chronic inflammatory response leading to severe pulmonary fibrotic changes. Proinflammatory cytokines, such as TNFalpha and IL-1, produced in the lung by type II epithelial cells and alveolar macrophages, have been strongly implicated in the formation of these lesions. Recently, a number of single nucleotide polymorphisms (SNPs), which quantitatively affect mRNA synthesis, have been identified in the TNFalpha promoter and IL-1 gene cluster and their frequency is associated with certain chronic inflammatory diseases. To assess the role of these SNPs in silicosis, we examined their frequency in 325 ex-miners with moderate and severe silicosis and 164 miners with no lung disease. The odds ratio of disease for carriers of the minor variant, TNFalpha (-238), was markedly higher for severe silicosis (4.0) and significantly lower for moderate silicosis (0.52). Regardless of disease severity, the odds ratios of disease for carriers of the IL-1RA (+2018) or TNFalpha (-308) variants were elevated. There were no significant consistent differences in the distribution of the IL-1alpha (+4845) or IL-1beta (+3953) variants with respect to disease status. In addition, several significant gene-gene and gene-gene-environment interactions were observed. Different associations between moderate cases and controls versus severe cases and controls were also observed in a number of these multigene comparisons. These studies suggest that gene-environment interactions involving cytokine polymorphisms play a significant role in silicosis by modifying the extent of and susceptibility to disease.
Assuntos
Predisposição Genética para Doença , Interleucina-1/genética , Polimorfismo de Nucleotídeo Único , Silicose/genética , Fator de Necrose Tumoral alfa/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Minas de Carvão , DNA/análise , Primers do DNA/química , Genótipo , Humanos , Pulmão/química , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Razão de Chances , Reação em Cadeia da Polimerase , Polimorfismo de Fragmento de Restrição , Silicose/epidemiologia , Silicose/patologia , Fumar , Estados Unidos/epidemiologiaRESUMO
BACKGROUND: Silicosis is characterized by fibrosing nodular lesions that eventually develop into progressive pulmonary fibrosis. Pro-inflammatory cytokines, such as interleukin-1 (IL-1), play a key role in the development of silicosis by regulating mediators which are responsible for lung injury, inflammation, and potentially fibrosis. To study whether functional single nucleotide polymorphisms (SNPs) located in the regulatory elements of genes coding for the IL-1alpha, IL-1beta, and IL-1 receptor antagonist (RA) cytokines are associated with silicosis, we examined 318 Caucasian cases confirmed histopathologically with pulmonary silicosis and 163 controls without any apparent inflammation or other pulmonary disease. METHODS: Genotyping was carried out by polymerase chain reaction-restriction fragment length polymorphism technique. RESULTS: The proportion of the IL-1RA (+ 2018) allele 2 genotype was increased in miners with silicosis (0.27) compared to controls (0.16). The odds of being a case were 2.15 (CI = 1.4-3.3) times higher for subjects with at least one copy of allele 2. No statistically significant differences in the allelic frequencies or genotype distributions for IL-1alpha (+ 4845) or IL-1beta (+ 3953) were found between the control and disease groups. CONCLUSIONS: This is the first report showing an association between the IL-1RA (+ 2018) polymorphism and silicosis, and suggests that this polymorphism may confer increased risk for the development of the disease.
Assuntos
Minas de Carvão , Interleucina-1/genética , Polimorfismo Genético/genética , Silicose/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Frequência do Gene , Humanos , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Silicose/patologia , Fatores de TempoRESUMO
During the past decade there has been significant progress made in understanding how environmental agents, drugs, certain chemicals present in the diet, and occupational agents affect the immune system of animals and humans. Polycyclic aromatic hydrocarbons (PAHs) are an important class of environmentally prevalent xenobiotics that exert complex effects on the immune system. These agents, typified by benzo(a)pyrene (BaP), have been shown to alter antigen and mitogen receptor signaling pathways, leading to suppression of humoral and cell-mediated immunity, and at high exposure levels to activation of genes involved in apoptosis in lymphoid cells. Interestingly, at low exposure levels, PAHs may actually augment cell signaling pathways, resulting in immune enhancement or an adjuvant effect. While the biochemical targets and mechanisms responsible for immune modulation are still under investigation, several themes are evolving. PAHs, principally through their cytochrome-P450-derived metabolites, activate oxidative and electrophilic signaling pathways in lymphoid and nonlymphoid cells, including myeloid, epithelial, and other cells. Although PAHs affect signaling pathways in nonlymphoid cells leading to complex interactions between antigen-specific and nonspecific immune and inflammatory responses, this brief review focuses on the mechanisms of signaling by environmentally prevalent PAHs in human lymphocytes. Understanding the mechanisms by which xenobiotics alter adaptive and nonadaptive immune responses may shed light on the etiology of environmental and occupational immune diseases.
Assuntos
Poluentes Ambientais/análise , Linfócitos/imunologia , Hidrocarbonetos Policíclicos Aromáticos/análise , Animais , Poluentes Ambientais/toxicidade , Humanos , Linfócitos/citologia , Hidrocarbonetos Policíclicos Aromáticos/toxicidade , Transdução de SinaisRESUMO
It has been postulated that an inflammatory response after cutaneous wounding is a prerequisite for healing, and inflammatory cytokines, such as interleukin-6 (IL-6), might be intimately involved in this process. IL-6-deficient transgenic mice (IL-6 KO) displayed significantly delayed cutaneous wound healing compared with wild-type control animals, requiring up to threefold longer to heal. This was characterized by minimal epithelial bridge formation, decreased inflammation, and granulation tissue formation. Using electrophoretic mobility shift assays of wound tissue from IL-6 KO mice, decreased AP-1 transcription factor activation was shown compared with wild-type mice 16 h after wounding. In situ hybridization of wound tissue from wild-type mice revealed IL-6 mRNA expression primarily in the epidermis at the leading edge of the wound. Delayed wound healing in IL-6 KO mice was reversed with a single dose of recombinant murine IL-6 or intradermal injection of an expression plasmid containing the full-length murine IL-6 cDNA. Treatment with rmIL-6 also reconstituted wound healing in dexamethasone-treated immunosuppressed mice. The results of this study may indicate a potential use for IL-6 therapeutically where cutaneous wound healing is impaired.
Assuntos
Interleucina-6/deficiência , Pele/imunologia , Cicatrização/imunologia , Animais , Proteínas Estimuladoras de Ligação a CCAAT/genética , Proteínas de Ligação a DNA/genética , Dexametasona/farmacologia , Terapia Genética/métodos , Glucocorticoides/farmacologia , Terapia de Imunossupressão , Interleucina-6/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT3 , Transativadores/genética , Fator de Transcrição AP-1/genéticaRESUMO
Only recently have toxicologists come to understand the role of inflammation, and TNFalpha specifically, in classical toxicological processes. This relationship appears fairly complex, as inflammation and proliferation may well be only one facet of a time- and dose-dependent continuum of toxicological and repair processes. Not surprisingly, considerable efforts are being undertaken using our newly found understanding of molecular control to develop specific and safe chemical, biological, and molecular regulators of TNFalpha for potential therapeutic use. Their effectiveness in controlling environmental or occupational diseases has yet to be established.
Assuntos
Doença Hepática Induzida por Substâncias e Drogas/metabolismo , Doença Hepática Induzida por Substâncias e Drogas/patologia , Inflamação/induzido quimicamente , Fígado/patologia , Fator de Necrose Tumoral alfa/metabolismo , Animais , Tetracloreto de Carbono/toxicidade , Divisão Celular , Células Cultivadas , Regulação da Expressão Gênica/efeitos dos fármacos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Necrose , Antígeno Nuclear de Célula em Proliferação/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores do Fator de Necrose Tumoral/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologiaRESUMO
Environmental and occupational exposure to arsenic is associated with increased risk of skin, urinary bladder, and respiratory tract cancers. The mechanisms responsible for arsenic carcinogenesis have not been established. Arsenic does not act through classic genotoxic and mutagenic mechanisms, as do other metals such as cadmium or chromium. Increasing evidence indicates that arsenic acts at the level of tumor promotion by modulating the signaling pathways responsible for cell growth.
Assuntos
Arsênio/toxicidade , Carcinógenos/toxicidade , Neoplasias/induzido quimicamente , Neoplasias/genética , Animais , Humanos , Neoplasias Pulmonares/induzido quimicamente , Neoplasias Pulmonares/genética , Neoplasias Cutâneas/induzido quimicamente , Neoplasias Cutâneas/genética , Neoplasias da Bexiga Urinária/induzido quimicamente , Neoplasias da Bexiga Urinária/genéticaRESUMO
Immunotoxicology has been defined as the study of adverse effects on the immune system resulting directly from environmental, occupational, or therapeutic exposure to chemicals (including drugs), biological materials and, in certain instances, physiological factors, collectively referred to as agents. It encompasses immunosuppression, allergy, autoimmunity and inflammation.
Assuntos
Imunotoxinas/imunologia , Pulmão/imunologia , Hipersensibilidade Respiratória/imunologia , Animais , Humanos , Hipersensibilidade Respiratória/diagnóstico , Medição de RiscoRESUMO
Although the mechanism of action has not yet been defined, epidemiological studies have demonstrated an association between elevated arsenic levels in drinking water and the incidence of urinary bladder transitional cell carcinomas. In the current studies, we demonstrate that mice exposed to 0.01% sodium arsenite in drinking water develop hyperplasia of the bladder urothelium within 4 weeks of exposure. This was accompanied by the accumulation of inorganic trivalent arsenic, and to a lesser extent dimethylarsinic acid, in bladder tissue, as well as a persistent increase in DNA binding of the activating protein (AP)-1 transcription factor. AP-1 transactivation by arsenic also occurred in bladders of transgenic mice containing an AP-1 luciferase reporter. Consistent with these in vivo observations, arsenite increased cell proliferation and AP-1 DNA binding in a human bladder epithelial cell line. Gene expression studies using RNase protection assays, reverse transcription-PCR, and cDNA microarrays indicated that arsenite alters the expression of a number of genes associated with cell growth, such as c-fos, c-jun, and EGR-1, as well as cell arrest, such as GADD153 and GADD45. The proliferation-enhancing effect of arsenic on uroepithelial cells likely contributes to its ability to cause cancer.
Assuntos
Arsenitos/farmacocinética , Arsenitos/toxicidade , Proteínas Estimuladoras de Ligação a CCAAT , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas Imediatamente Precoces , Compostos de Sódio/farmacocinética , Compostos de Sódio/toxicidade , Fator de Transcrição AP-1/metabolismo , Bexiga Urinária/efeitos dos fármacos , Urotélio/efeitos dos fármacos , Animais , Arseniatos/farmacocinética , Divisão Celular/efeitos dos fármacos , Cruzamentos Genéticos , Dano ao DNA , Proteínas de Ligação a DNA/genética , Proteína 1 de Resposta de Crescimento Precoce , Feminino , Genes fos , Genes jun , Humanos , Hiperplasia , Peptídeos e Proteínas de Sinalização Intracelular , Luciferases/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Proteínas/genética , Acetato de Tetradecanoilforbol/toxicidade , Distribuição Tecidual , Fator de Transcrição AP-1/genética , Fator de Transcrição CHOP , Fatores de Transcrição/genética , Ativação Transcricional , Bexiga Urinária/metabolismo , Bexiga Urinária/patologia , Urotélio/metabolismo , Urotélio/patologia , Proteínas GADD45RESUMO
A structure-activity relationship (SAR) model has been developed to discriminate skin irritant from nonirritant esters. The model is based on the physicochemical properties of 42 esters that were tested in humans for skin irritation. Nineteen physicochemical parameters that represent transport, electronic, and steric properties were calculated for each chemical. Best subsets regression analysis indicated candidate models for further analysis. Regression analyses identified significant models (p < 0.05) that had variables that were also significant (p < 0.05). These candidate models were evaluated using linear discriminant analysis to determine if the irritant esters could be discriminated from nonirritant esters. The stability of the model was evident from the consistency of parameters among ten submodels generated using multiple random sampling of the database. The sensitivity of the ten models, evaluated by "leave-one-out" cross-validation, ranged from 0. 846 to 0.923, with a mean of 0.885 +/- 0.025 (95% CI). The specificity ranged from 0.615 to 0.923, with a mean of 0.738 +/- 0.06 (CI). Compared with nonirritant esters, irritant esters had lower density, lower water solubility, lower sum of partial positive charges, higher Hansen hydrogen bonding parameter, and higher Hansen dispersion parameter. The results indicate that physicochemical features of esters contribute to their ability to cause skin irritation in humans, and that chemical partitioning into the epidermis and intermolecular reactions are likely important components of the response. This model is applicable for prediction of human irritation of esters yet untested.