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P Simeonova

Publications and source records attributed to P Simeonova.

9 recordsLinked to original sources
PubMed2001

Association of tumor necrosis factor-alpha and interleukin-1 gene polymorphisms with silicosis.

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.

Adult↗
PubMed2000

Overview of immunotoxicology and current applications to respiratory diseases.

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.

Animals↗
PubMed1998

Selected new developments in asbestos immunotoxicity.

Research over the past three decades has shown that the mammalian immune system can be altered by the occupational exposure of asbestos. Early clinical studies generally focused on systemic observations of immune alteration such as the number and function of peripheral lymphocytes and monocytes. More recently as the regulatory influence of local immunity in health and disease becomes more defined, immunologic changes occurring in the lung, the primary target organ of asbestos, have been significant areas of investigation. This review will focus on recent studies that examine the influence of asbestos on pulmonary immunity as well as the role of host immune competence in asbestos-related disease.

Animals↗
PubMed1997

Induction of early-immediate genes by tumor necrosis factor alpha contribute to liver repair following chemical-induced hepatotoxicity.

We and others have shown that tumor necrosis factor alpha (TNF-alpha) expression is increased in the livers of experimental animals following exposure to the chemical hepatotoxin, carbon tetrachloride (CCl4). Because TNF-alpha is involved in mediating inflammatory responses, its elevated expression is presumed to be associated with potentiating hepatotoxicity and/or aiding in liver repair processes. To study the role of TNF-alpha in chemical-induced hepatotoxicity, mice were administered neutralizing antibodies to TNF-alpha before administration of low, but hepatotoxic, doses of CCl4. Antibody treatment prevented CCl4-mediated increases in early-immediate gene expression associated with liver regeneration, including expression of c-jun and c-fos proto-oncogenes, as well as DNA binding of the activator protein-1 (AP-1) nuclear transcription factor. Hepatocyte proliferation following CCl4 treatment was also reduced in anti-TNF-alpha antibody-treated mice, as evidenced by a lack of proliferating cell nuclear antigen (PCNA) staining. Antibody treatment slightly delayed liver repair processes, as evidenced by extending the period in which plasma liver enzyme levels were increased and hepatocellular necrosis could be observed. Consistent with the above observations, injection of recombinant TNF-alpha into control mice induced rapid expression of c-jun and c-fos proto-oncogenes. Taken together, these results indicate that TNF-alpha positively modulates liver recovery following CCl4 exposure presumably by stimulating early-immediate genes involved in hepatic mitogenesis, a phenomenon also observed following partial hepatectomy.

Animals↗
PubMed1997

Antibodies to tumor necrosis factor alpha prevent increases in cell replication in liver due to the potent peroxisome proliferator, WY-14,643.

Several structurally dissimilar hypolipidemic drugs, plasticizers and halogenated hydrocarbons induce peroxisomes in hepatocytes, and cause hepatocellular adenoma and carcinoma in rats and mice. The mechanism by which these agents act is unknown, although recent studies have suggested a link between increased cell proliferation and hepatic cancer caused by peroxisome proliferators. Here, we demonstrate that neutralizing antibodies to tumor necrosis factor alpha (TNF alpha) block increases in protein kinase C and cell proliferation due to [4-chloro-6-(2,3-xylidino)-2-pyrimidinylthio]acetic acid (WY-14,643), a hypolipidemic drug and potent peroxisome proliferator that causes tumors. WY-14,643 moderately elevated the level of TNF alpha mRNA in the liver. TNF alpha was detected immunohistochemically exclusively in Kupffer cells. These results demonstrate that WY-14,643 acts as an indirect mitogen on hepatocytes via TNF alpha. We propose that the Kupffer cell, a major source of TNF alpha in the liver, is involved in the mechanism of the mitogenic effect of WY-14,643.

Animals↗
PubMed1994

Asbestos stimulates IL-8 production from human lung epithelial cells.

Studies have indicated that soluble products, including chemotactic factors, released by activated lung macrophages and fibroblasts are critical mediators in the pathogenesis of asbestos-induced pulmonary fibrosis. We provide evidence that mediators produced by lung epithelial cells in response to asbestos may also contribute to lung disease. In the present study, the carcinogenic and fibrogenic fibers, chrysotile and crocidolite asbestos, were shown to directly stimulate the human pulmonary type-II epithelial cell line, A549, and to a lesser degree primary human bronchial epithelial cells, to elicit the chemotactic cytokine IL-8 in the absence of endogenous stimuli such as IL-1 and TNF. That the membrane signaling events responsible for asbestos-induced IL-8 production are distinct from those responsible for IL-8 induction by cytokines was confirmed by using membrane-stabilizing agents and protein synthesis inhibitors. Stimulation was not observed with nonfibrogenic fibers, wollastonite and titanium dioxide, and was the direct result of asbestos-induced initiation of transcription. Asbestos failed to stimulate the release of TNF, IL-1 beta, or monocyte chemoattractant protein-1 in A549 or primary bronchial epithelial cells, indicating that cytokine secretion by asbestos is highly selective. However, a slight release of IL-1 alpha, probably preformed, was released in human bronchial epithelial cells. These data suggest that epithelial cells may, in addition to macrophages and fibroblasts, be an important effector cell in the immunopathogenesis of asbestos-associated diseases and in particular, in the neutrophilic infiltration that is commonly observed after asbestos exposure.

Asbestos, Serpentine↗
PubMedDate not supplied

Asbestos toxicity: an immunologic perspective.

Asbestos has long been associated with a number of life threatening pulmonary diseases, including asbestosis and mesothelioma. While the lung is the primary target organ for asbestos toxicity, a number of clinical and experimental studies over the past 30 years have shown that the immune system may also be altered by exposure to asbestos at occupationally relevant concentrations. Whereas early clinical studies generally focused on systemic observations of immune alteration, more recent studies have assessed the immunological changes occurring in the lung, the primary target organ of asbestos. This review will focus on the investigations that examine the influence of asbestos on systemic and local immunity, as well as the role that the immune system may play in asbestos-related disease.

Antibody Formation↗
PubMedDate not supplied

Acetaminophen-induced hepatotoxicity is associated with early changes in NF-kB and NF-IL6 DNA binding activity.

Nuclear transcription factors, such as NF-kB and NF-IL6, are believed to play an important role in regulating the expression of genes that encode for products involved in tissue damage and inflammation and, thus, may represent early biomarkers for chemical toxicities. In the present study changes in DNA binding activity of these factors were examined in livers of mice administered hepatotoxic doses of acetaminophen (APAP). NF-kB and NF-IL6 DNA binding occurred constitutively in control mouse liver. However, within 4 hr following administration of hepatotoxic doses of APAP, their binding activities were transiently lost and is in contrast to AP-1 transcription factor where activation occurs under similar conditions. These changes corresponded with increased release of inflammatory mediators (IL-6, serum amyloid A) and increased levels of enzymatic markers of hepatocyte damage. Similarly, treatment of mice with gadolinium chloride, an inhibitor of Kupffer cell activation and known to protect against APAP-induced hepatotoxicity, reduced the observed pathophysiological response in the liver while altering the APAP-associated changes in NF-kB DNA binding activity. NF-kB was found predominantly in parenchymal and endothelial cells and was composed primarily of relatively inactive p50 homodimer subunits in control liver. Taken together, these studies suggest that hepatotoxicity is associated with early and complex changes in DNA binding activities of specific transcription factors. In particular, NF-kB and NF-IL6 may serve as negative regulators of hepatocyte-derived inflammatory mediators and is analogous to that previously observed in certain other cell systems such as B lymphocytes.

Acetaminophen↗