-
[show abstract]
[hide abstract]
ABSTRACT: Abstract Allergic contact dermatitis (ACD) is a common skin inflammatory disease that develops in hosts sensitized with contact allergens. Elucidation of dose-response relationships represents one of the approaches in studying the type of ACD in humans/animal models, termed as contact hyper-sensitivity reaction (CHS). Such studies have demonstrated that the intensity of sensitization determines the response to elicitation with a contact allergen, but underlying mechanisms are unclear. The aim of this study is to explore the impact of the sensitization on contact hypersensitivity to dinitrochlorobenzene (DNCB) in rats by measuring the incidence and intensity of a challenge response in hosts sensitized with two different doses (i.e. low and high) of this hapten. Assumptions concerning the contribution from the magnitude of sensitization doses were drawn on the basis of effects from the two doses on the measured reaction parameters. Ear swelling and activity of lymph nodes that drain challenged skin (cdLN), including cellularity, proliferation, and effector cytokine IFNγ and IL-17 production was measured in rats sensitized with 0.4% or 4% DNCB and challenged with a non-irritant (0.13%) dose. Sensitization with 4% DNCB resulted in a greater proportion of rats who responded more intensely (than unsensitized challenged rats) to challenge in terms of ear swelling and increases in cdLN activity (except for IFNγ). The intensity of cdLN responses was higher in these hosts as well. Among the high-dose-sensitized rats, greater cellularity/proliferation of cells from lymph nodes (sdLN) that drain the high-dose-sensitized skin, as well as higher IL-17 production, was noted compared to what was seen in rats that received low-dose sensitization. In contrast, unchanged spontaneous and even decreased hapten-stimulated IFNγ production after the high DNCB dose was observed. Based on the data, it seems the impact of magnitude of sensitization dose on CHS might be related to the rise in the proportion of rats that responded to challenge with an increase of dLN activity. Coincidental higher production of IL-17 by dLN cells from the high-dose-sensitized rats and following challenge of these hosts underscored the significance of IL-17 for a CHS to DNCB.
Journal of Immunotoxicology 04/2013; · 1.44 Impact Factor
-
Journal of the Serbian Chemical Society 02/2013; · 0.88 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Using a nonlethal systemic Aspergillus fumigatus infection, we have recently shown that similarly efficient elimination of fungus from spleens of prototypic Th1 (C57BL/6) and prototypic Th2 (BALB/c) mice is associated with differential immune responses. In light of these data and given the disseminated character of infection, the aim of the present study is to explore whether there are also strain-dependent differences in antifungal responses in peripheral tissues of infected mice. Although similar efficiency of conidia removal was noted in liver and kidneys of both strains, BALB/c mice seemed more prone to tissue injury. Compared with other nonlymphoid organs, lungs proved immunologically the most responsive in systemic aspergillosis. Lower numbers of neutrophils and macrophages in the lungs of infected BALB/c mice, delayed and lower (compared with C57BL/6 mice) expression of their oxidative activity, along with late IFN-γ and upregulated IL-4 production by lung cells might be responsible for slower elimination of A. fumigatus from the lungs of this mouse strain. The data obtained imply that lungs should be viewed as mandatory organ in evaluation of immune-mediated antifungal potential of drugs in models of systemic/disseminated infection and that strain differences noted in tissue responses should be taken into account in these settings.
Apmis 09/2012; · 1.99 Impact Factor
-
[show abstract]
[hide abstract]
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
-
[show abstract]
[hide abstract]
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.
-
[show abstract]
[hide abstract]
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
-
[show abstract]
[hide abstract]
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
-
[show abstract]
[hide abstract]
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
-
[show abstract]
[hide abstract]
ABSTRACT: To assess the role of synanthropic rodents in the epidemiology of urban toxoplasmosis, Toxoplasma gondii infection was examined in 144 rats (Rattus norvegicus) and 12 mice (Mus musculus) captured using live animal traps in three locations in Belgrade city characterized by poor housing and degraded environment. In rats, specific IgG antibodies were detected by modified agglutination test in 22 (27.5%) of the 80 blood samples available. Toxoplasma brain cysts were microscopically detected in 11 (7.6%), and Toxoplasma DNA by real-time polymerase chain reaction was demonstrated in 15 (10.4%) animals. Of these, both cysts and Toxoplasma DNA were detected in five (3.5%) rats. In mice, cysts were observed in 3 (25%), but Toxoplasma DNA was detected in even 10 (83.3%) animals, including all 3 with morphologically recognized cysts. Being a link in the chain of Toxoplasma infection, the existence of urban rodent reservoirs of infection represents a public health risk.
Vector borne and zoonotic diseases (Larchmont, N.Y.) 10/2010; 11(8):1209-11. · 2.61 Impact Factor
-
[show abstract]
[hide abstract]
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
-
[show abstract]
[hide abstract]
ABSTRACT: In this study, we investigated splenic and lung cell responses to nonlethal systemic Aspergillus fumigatus infection in mice. Apart from basic indices of spleen and lung cell activity, IL-17 expression by cells from both tissues was determined and compared to the expression of IFN-gamma and IL-4. Progressive decrease in tissue fungal burden correlated with increased spleen and lung cell activity. Increased IL-17 message was noted in spleen cells at all time points (3, 7 and 15 days post-infection; p.i.), while a modest increase in IFN-gamma mRNA expression was noted at day 3 p.i. Increased cytokine production at days 3 and 7 (IL-17) and throughout the experimental period (IFN-gamma) was found. In contrast, spleen cell IL-4 expression was considerably lower during infection, resulting in high IFN-gamma/IL-4 and IL-17/IL-4 ratios in the spleen. Pro-inflammatory cytokine response was observed in the lungs as well, but primarily as the result of increased production of IFN-gamma by lung cells in response to challenge with conidia and the absence of change in IL-4 response. Increased activity of cells from both tissues, as well as the pattern of cytokine production, created an optimal pro-inflammatory milieu for fungal eradication.
Medical mycology: official publication of the International Society for Human and Animal Mycology 08/2010; 48(5):735-43. · 2.13 Impact Factor
-
[show abstract]
[hide abstract]
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.
-
[show abstract]
[hide abstract]
ABSTRACT: To examine the presence of gender differences in pro-inflammatory potential of cadmium in rats by comparing systemic inflammatory response to acute cadmium intoxication in animals of the two sexes.
Basic aspects of this response were evaluated, including plasma levels of inflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) and of major rat acute phase protein alpha 2-macroglobulin (alpha2-M), as soluble indicators of inflammation, and the number and activity of peripheral blood leukocytes, as cellular indicators of inflammation.
Differential increases of IL-6 and alpha2-M (higher in males than in females) in peripheral blood cell counts and types (leukocytosis and shift in the ratio of granulocytes to lymphocytes more pronounced in males vs females) and in levels of neutrophil priming (higher in males vs females) were noted.
The data document a more intense inflammatory response to cadmium administration in males. The sex differences in inflammatory effects of cadmium might be taken into consideration in studying the toxicity of this heavy metal.
Biomedical and Environmental Sciences 03/2009; 22(1):1-7. · 1.35 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Percutaneous toxicity of anticoagulant rodenticides is usually manifested by coagulopathy and/or fatal outcome. There are, however, virtually no data on other biological effects of this class of pesticides that gain access into the organism via skin. In this study, percutaneous toxicity of epicutaneously applied warfarin was evaluated by measuring changes in peripheral blood granulocytes in rats. Application of 10 mug (0.05 mg/kg) or 100 mug (0.5 mg/kg) of warfarin (WF) for 3 consecutive days resulted in an increase in prothrombin time, documenting the access of warfarin to systemic circulation. Application of warfarin led to an increase in relative numbers of granulocytes at higher dose, whereas both doses resulted in increased metabolical viability, evaluated by 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2H-tetrazolium bromide (MTT) reduction assay. Higher warfarin dose resulted in both granulocyte activation and priming (evaluated by cytochemical nitroblue tetrazolium, NBT, reduction assay of respiratory burst), whereas only a tendency toward activation was noted at lower WF dose. Soluble mediators from the circulation seem responsible for the observed effects, as exogenous plasma from WF-treated animals stimulated NBT reduction by isologous or naïve granulocytes. Data presented in this study are relevant for the recognition of biological effects, other than those affecting hemostasis, of anticoagulant rodenticides that gain access to systemic circulation through the skin.
Cutaneous and Ocular Toxicology 02/2008; 27(1):29-40. · 0.91 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Dermatotoxic effects of epicutaneous application of a first generation anticoagulant, warfarin (WF), were examined in rats. Selected parameters of skin activity were determined 24 hours following warfarin application by histomorphological and immunohistochemical analysis and by assessing some aspects of immunomodulatory potential of warfarin in skin. Increased number of mast cells, with degranulation at higher doses of warfarin was noted in warfarin treated skin. Mast cell presence coincided with changes in blood vessels and fibroblast appearance suggesting mast cell activity in warfarin treated skin. Signs of nuclear hypertrophy and anysonucleosys were noted by analysis of PCNA(+) cells in epidermis following warfarin application. Histomorphological changes were accompanied by immunemodulating activity in warfarin treated skin. This was judged by slightly increased numbers of CD3(+) cells in epidermis and superficial dermis and by production of organ cultured full thickness skin explants of factors with costimulatory activity in T-cell activation/proliferation assay. Presented data demonstrates the potential of warfarin to modulate local skin activity in rats.
Cutaneous and Ocular Toxicology 02/2007; 26(1):1-13. · 0.91 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Dermatotoxic effects of epicutaneous application of a first-generation anticoagulant, warfarin (WF) were examined in rats. Selected parameters of skin activity were determined 24h following warfarin application, including metabolic viability of skin explants, some aspects of oxidative activity in skin tissue homogenates and inflammatory/immune relevant activity of epidermal cells from warfarin-treated skin. No changes in skin metabolic viability (MTT reduction) were noted ex vivo following WF application, suggesting the absence of immediate toxicity for skin. In contrast, increased formation of malondialdehyde (MDA), with a decrease in protein and non-protein thiols in homogenates of warfarin-treated skin was demonstrated, pointing to prooxidant activity in warfarin-treated skin. Increased costimulatory activity of epidermal cells isolated from warfarin-exposed skin in Con-A-stimulated T-cell activation/proliferation assay was noted, reflecting proinflammatory and immune-modulating capacity of warfarin for epidermis. No evident differences in skin histology between control and warfarin-treated skin were found at that time point, while striking changes in tissue integrity, cellularity and appearance 72 h following WF application were noted. The observed histological picture probably reflects a regenerative/inflammatory program related to oxidant/inflammation-type warfarin-evoked injury to the skin. Presented data demonstrate the potential of epicutaneously applied warfarin to modulate local skin activity in rats.
Toxicology 10/2005; 212(2-3):206-18. · 3.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The immunotoxicity of epicutaneously administered anticoagulant rodenticide warfarin (WF) was examined in this work by using experimental contact hypersensitivity (CHS) reaction to hapten dinitrochlorobenzene (DNCB). WF (0.05 and 0.5 mg/kg) administration 24 h before the induction of CHS does not change expression of CHS evaluated by ear swelling assay. Regional draining lymph node response during sensitization phase was characterized by decreased cellularity but increased spontaneous and IL-2 stimulated proliferation of draining lymph node cells (DLC). No changes in IL-2 production and in numbers of CD25(+) cells were noted and even decreased proliferative index (ratio of IL-2 stimulated to unstimulated DLC proliferation) was detected. Increase in granulocyte activity (MTT reduction and adhesion to plastic) was noted following application of WF solely with further increase following subsequent application of DNCB, when granulocyte activation (NBT reduction) was noted also. Access of WF into general circulation might be responsible for observed changes, what was supported by ex vivo changes in DLC and granulocyte functions assessed before initiation of sensitization and by in vitro effect of exogenous WF as well. Differential effects of WF on lymphocytes and granulocytes noted in this study highlight the need for simultaneous testing of both cell type activity what might constitute a more integrated approach in immunotoxicity studies.
Toxicology 07/2003; 188(1):83-100. · 3.68 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Studies of systemic and pulmonary Aspergillus fumigatus infection demonstrated differential susceptibility of inbred mice of various genetic background to lethal outcome, with an opposite pattern of Th1 cytokine interferon-γ (IFN-γ) and Th2 cytokine interleukin-4 (IL-4) in susceptible vs resistant mice. We have shown recently reciprocal IFN-γ and IL-4 expression in spleens of Th1-prone C57BL/6 mice in sublethal systemic aspergillosis. In this study, resistance to systemic (i.v.) A. fumigatus infection was investigated in Th2-prone BALB/c mice by survival rate at different fungal inocula, efficiency of reduction of visceral organ and spleen fungal burden at sublethal conidia dose and splenic immune response to this dose and compared to C57BL/6 mice. No strain differences in survival were noted at three A. fumigatus doses, with similar extent and dynamics of fungal eradication from all organs following sublethal conidia dose injection. Progressive decrease in spleen fungal burden was associated with different dynamics and quality of changes in spleen activity of BALB/c and C57BL/6 mice. Increased spleen mass and cellularity was noted in both strains, with higher values in BALB/c mice at some time points what might be ascribed to peripheral blood cell recruitment, as well as hematopoietic activity and red pulp upgrowth. Infection tipped the balance towards pro-inflammatory antifungal splenic response by a highly increasing IFN-γ and without changing the IL-4 expression in BALB/c mice, in contrast to down-regulating anti-inflammatory (IL-4) and a moderately increasing IFN-γ response in C57BL/6 mice. Jointly, stimulation of IL-17 expression noted in both strains provided an optimal inflammatory milieu in the spleen of infected mice that might have contributed to efficient removal of conidia.
Immunobiology 216(1-2):234-42. · 3.20 Impact Factor
