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ABSTRACT: Warfarin is a Vitamin K (VK) antagonist that affects Vitamin K-dependent (VKD) processes, including blood coagulation, as well as processes unrelated to hemostasis such as bone growth, calcification, and growth of some cell types. In addition, warfarin exerts influence on some non-VKD-related activities, including anti-tumor and immunomodulating activity. With respect to the latter, both immune stimulating and suppressive effects have been noted in different experimental systems. To explore the in vivo immunomodulatory potential of warfarin on one type of activity (i.e., cytokine production) in two different immune cell populations (i.e., mononuclear or polymorphonuclear cells), effects of subchronic oral warfarin intake in rats on pro-inflammatory cytokine (i.e., TNFα, IL-6) production by peripheral blood mononuclear and polymorphonuclear cells (granulocytes) was examined. Differential effects of warfarin intake on TNFα and IL-6 were noted, depending on the type of peripheral blood leukocytes and on the cytokine examined. Specifically, a lack of effect on TNFα and a priming of IL-6 production by mononuclear cells along with a decrease in TNFα and a lack of effect on IL-6 in polymorphonuclear cells were seen in warfarin-exposed hosts. The cell- and cytokine-dependent effects from subchronic oral warfarin intake on peripheral blood leukocytes demonstrated in this study could, possibly, differentially affect reactions mediated by these cells. Ultimately, the observed effects in rats might have implications for those humans who are on long-term/prolonged warfarin therapy.
Journal of Immunotoxicology 07/2012; · 1.44 Impact Factor
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ABSTRACT: Topical application of dinitrochlorobenzene (DNCB) is employed in the immunotherapy of skin diseases. Activation of T-cell mediated immune responses (Th1/type1) is the supposed mechanism of the clinical effect of DNCB, but there are no data concerning innate/inflammatory mechanisms. In this study, the effect of repeated topical DNCB application on peripheral blood polymorphonuclear (PMN) leukocytes has been examined in two rat strains which differ in the propensity to mount Th1/type1 or Th2/type2 responses. The dynamics of changes in PMN numbers and effector activities (respiratory burst, nitric oxide production and myeloperoxidase content), as well as in adhesion and TNF-α production following the rat skin sensitization with low (0.4%) and high (4%) DNCB doses were measured. Both priming and activation of PMNs were observed following skin sensitization with DNCB, with dose-dependent as well as time-dependent differences in some PMN activities. Obtained data might be relevant for understanding the immune mechanisms of topical DNCB therapy.
Environmental toxicology and pharmacology. 03/2012; 33(2):168-80.
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ABSTRACT: Warfarin affects mainly vitamin K dependent (VKD) processes, but the effects on some non-VKD-related activities such as tumor growth inhibition and mononuclear cell-mediated immune reactions were shown as well. In this study, the effect of subchronic (30 days) oral warfarin (0.35 mg/l and 3.5mg/l) intake on peripheral blood granulocytes in rats was investigated. Increase in prothrombin and partial thromboplastin time at high warfarin dose reflected its basic activity. Priming effect for respiratory burst was noted at both warfarin doses, while only high warfarin dose resulted in priming for adhesion, the rise in intracellular myeloperoxidase content/release and stimulation of nitric oxide production. Differential effects of high warfarin dose were noted on granulocyte cytokines IL-6 (lack of the effect), TNF-α (decreased release and mRNA expression) and IL-12 (increase in mRNA for IL-12 subunits p35 and p40). Changes in granulocytes seems not to rely on mitogen activated kinases p38 and ERK. Warfarin intake was associated with an increase in circulating IL-6, fibrinogen and haptoglobin and with changes in the activity of erythrocyte antioxidant enzymes superoxide dismutase and catalase. The effects of oral warfarin intake on peripheral blood granulocytes demonstrated in this study might be relevant for oral anticoagulant therapy strategies in humans.
Food and chemical toxicology: an international journal published for the British Industrial Biological Research Association 02/2012; 50(5):1499-507. · 2.99 Impact Factor
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ABSTRACT: We recently demonstrated that macrophage migration inhibitory factor deficient (MIF (- / -)) mice exhibited a higher susceptibility to lethal systemic Aspergillus fumigatus infections than genetically matched, wild-type (WT) C57BL/6 mice, and displayed altered cytokine profiles in the spleen when challenged by sublethal infections. In this report we focused on the potential involvement of MIF in the response of mice to sublethal systemic A. fumigatus infections in tissues other than spleen. Impaired fungal clearance from lungs, kidneys, liver and brain in MIF (- / -) mice was noted and was associated with histologically-evident differences in signs of inflammation in these organs. Higher values of some indicators of pathologic changes in urine parameters (increases in bilirubin, glucose and ketones), as well as a greater degree of brain tissue damage, pointed to multiple organs being affected in MIF (- / -) mice. Analysis of the lung response revealed differences in the composition of infiltrated cells between MIF-sufficient and MIF-deficient mice. MPO activity and reactive oxygen species production were impaired, as well as production of IL-17 and IFN-γ in MIF (- / -) mice as compared to WT counterparts. Lower systemic IL-1β and IL-6 levels in infected MIF (- / -) mice coincided with reduced blood neutrophil counts and organ infiltration. Collectively, this study identifies MIF as a resistance factor that orchestrates events in several non-lymphoid areas which provide a milieu that accomplishes anti-fungal A. fumigatus defense.
Medical mycology: official publication of the International Society for Human and Animal Mycology 01/2012; 50(5):476-87. · 2.13 Impact Factor
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ABSTRACT: Contact hypersensitivity reaction (CHS) is a T-cell-mediated skin inflammatory reaction to cutaneous exposure to small sensitizing chemicals, haptens. While the significance of local inflammatory skin response to the hapten application in CHS induction and expression is known, there is paucity of data concerning systemic inflammation in CHS. In this study, changes in cellular (peripheral blood granulocytes) and humoral (plasma tumor necrosis factor (TNF)-α levels) components of inflammation during sensitization of rats with two consecutive applications of dinitrochlorobenzene (DNCB) were examined. The impact of sensitization on these parameters was determined by employing low (0.4%) and high (4%) hapten doses and by examining the dynamics (i.e. one and three days following the last application of DNCB) of these changes. Dose-dependent increase in relative numbers and priming (for respiratory burst and adhesion) effect of skin sensitization with DNCB on peripheral blood neutrophils in rats were noted. No changes in circulating TNF-α levels were observed following the sensitization. The increase in lung myeloperoxidase content and histologically evident presence of neutrophils was observed in lungs of the sensitized rats. The changes in granulocyte priming for adhesion might have accounted for the observed increase in lung neutrophil content in the sensitized rats.
Cutaneous and Ocular Toxicology 07/2011; 31(1):7-13. · 0.91 Impact Factor
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ABSTRACT: To evaluate the effects of epicutaneous application of anticoagulant warfarin, by examining the presence of tissue injury and immune/inflammatory activity in exposed skin.
Rats were exposed to warfarin by applying 10 μg of warfarin-sodium to 10-12 cm(2) skin (range 0.8-1 μg per 1 cm(2)) for 3 consecutive days. Tissue injury was evaluated by lipid peroxidation, histomorphological changes and signs of reparative activity in skin. T cell infiltration and selected aspects of epidermal cell activity were examined as indicators of immune/inflammatory skin response to warfarin application.
Repeated warfarin application exerted no effect on skin metabolic viability, but resulted in tissue injury (increased malondialdehyde, MDA, production, evident histo-morphological changes in epidermis and dermis depicting cell injury and death). Increased numbers of proliferating cell nuclear antigen (PCNA(+)) cells indicated reparative processes in injured skin. Infiltration of CD3(+) cells (T lymphocytes) along with the increased production of tumor necrosis factor-a (TNF-a) by epidermal cells from warfarin-treated skin and their co-stimulatory effect in an in vitro T-cell activation assay demonstrated immunomodulatory effects of epicutaneous warfarin.
Presented data have documented tissue damage associated with immune/inflammatory activity in skin exposed to warfarin. Observed effects are relevant to immunotoxic potential of this anticoagulant in settings of external exposure.
Biomedical and Environmental Sciences 04/2011; 24(2):180-9. · 1.35 Impact Factor
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ABSTRACT: Contact hypersensitivity (CHS) is a T-cell-mediated skin inflammatory reaction to cutaneous exposure to small sensitizing chemicals, haptens. Majority of CHS studies were conducted in mice and there is paucity of data in other experimental animals. In the present study, characteristics of contact hypersensitivity reaction to dinitrochlorobenzene (DNCB) were determined in Th1-prone Dark Agouti (DA) rats by evaluating sensitization phase as a function of time-dependent changes in draining lymph nodes (DLN). Apart from basic indices of DLN activity (cellularity and proliferation), the production of cytokines relevant for CHS induction, interleukin-6 (IL-6), interferon-γ (IFN-γ), interleukin-17 (IL-17) and interleukin-4 (IL-4) was analyzed. Anti-inflammatory cytokine interleukin-10 (IL-10) production by DLN cells was determined as well. Highest production of IL-6, IFN-γ and IL-17 in sensitized animals was observed at day 3 after DNCB application, with a decrease at day 5. Increased messages for IFN-γ and IL-17 were noted at this time point. In contrast to inflammatory cytokines, anti-inflammatory cytokine interleukin-4 (IL-4) was undetectable during the entire sensitization phase. Differential pattern (IL-6 and IFN-γ) and level (IFN-γ and IL-17) of inflammatory cytokine production was noted in sensitized Th2-prone Albino Oxford (AO) rats. Similarly to DA rats, no changes in IL-4 were noted in AO rats. Strain-dependent differences in inflammatory cytokine production seem to be based on anti-inflammatory cytokine interleukin-10 (IL-10). Production of IFN-γ concomitantly with undetectable IL-4 in both strains classify rat CHS to DNCB as Th1/type 1 reaction. Detection of IL-17 in sensitized DLN cells points to the involvement of T(IL-17) cells in rat contact hypersensitivity.
Immunobiology 12/2010; 216(7):763-70. · 3.20 Impact Factor
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ABSTRACT: To examine the presence of gender differences in pulmonary inflammation evoked by acute systemic cadmium administration in rats.
Presence of basic indicators of lung inflammation (inflammatory cytokine lung content, leukocyte infiltration and activity of cells recovered from lungs by enzyme digestion) was analyzed and compared in animals of the two sexes.
Intraperitoneal administration of cadmium (1.0 mg/kg) resulted in higher cadmium content in lungs of female rats. Higher tumor necrosis factor (TNF) content was noted in lung homogenates of male rats, while interleukin-6 (IL-6) content was slightly, but significantly greater in lungs of female rats. Increased leukocyte infiltration was observed in lungs of male rats, mainly due to neutrophils. Increased responsiveness to phorbol myristate acetate (PMA) stimulation was noted in cells recovered from lungs of male rats. Rise in intracellular content of myeloperoxidase (MPO) was noted in lung cells from cadmium-treated rats of both sexes, but higher in cells from male rats.
Presented data documented a more intense pulmonary inflammatory response to systemic cadmium administration in males, with higher IL-6 levels in lungs of female individuals. These sex differences in proinflamatory activity of cadmium in lungs should be taken into consideration in studying the remote toxicity of this heavy metal.
Biomedical and Environmental Sciences 08/2010; 23(4):293-9. · 1.35 Impact Factor
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ABSTRACT: The nematode Calodium hepaticum and the cestode Taenia taeniaeformis are zoonotic helminths primarly found in the liver of common wild rats. Most reports on these helminth species with cosmopolitan distribution are from Asia, and there is paucity of data for Europe. Wild Norway rats (Rattus norvegicus) from urban and suburban habitats of the Belgrade area were examined for the presence of Calodium hepaticum and Taenia taeniaeformis larvae liver infections. The presence of visible cysts and a histomorphology of parasite-related inflammatory liver responses were sought as signs of infection. The total prevalence of infection was 10.9% (C. hepaticum) and 29.9% (T. taeniaeformis), with no differences between the sexes. No difference in the annual prevalence of both helminth species was noted. Data obtained in this study provide new information relevant to wild Norway rats as sources of C. hepaticum and T. taeniaeformis liver infection in this geographic area, and, in a wider context, in Europe. .
Archives of Biological Sciences. 01/2010;
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ABSTRACT: Pulmonary inflammation is a biological response to cadmium entering the body via the respiratory route. Systemic administration of this metal revealed the lungs as a significant site of its disposition. In this study, the presence of basic indicators of lung inflammation (leukocyte infiltration and activity of cells recovered from lungs by enzyme digestion) was analyzed in the rat model of acute systemic cadmium intoxication. Intraperitoneal administration of both cadmium doses (0.5mg/kg and 1.0mg/kg) resulted in increased numbers of neutrophils. Signs of spontaneous activation of lung cells including the capacity of reduction of nitroblue tetrazolium (NBT), increase in myeloperoxidase (MPO) intracellular content and increase in interleukin-6 (IL-6) production were noted at both cadmium doses. Increased lung cell responsiveness to stimulation in vitro was noted at the higher cadmium dose. The presence of pulmonary inflammatory parameters in rats administered intraperitoneally with cadmium revealed the lungs as remote inflammatory targets of this metal.
Environmental toxicology and pharmacology. 09/2009; 28(2):225-31.
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ABSTRACT: Basic parameters of spleen immune activity (spleen weight, histomorphology of splenic compartments, and mitogen-induced splenocyte proliferative capacity in vitro) were evaluated in adult individuals of wild Norway rats from urban habitats and compared to the same data obtained in laboratory rat strains. A wider range of relative spleen mass and differential histomorphological characteristics, together with differences in the level and pattern of responsiveness of splenocytes to exogenous stimulation, were noted in spleens of wild Norway rats. Evidence of both enhanced and low-level immune-relevant spleen activity in wild rats demonstrates the complexity of changes in spleen immune activity in rats from natural populations.
Archives of Biological Sciences. 01/2009;
