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Abstract Diethyldithiophosphate (DEDTP) is a metabolite produced by the degradation of organophosphorus pesticides and a dialkylphosphate that is chemically synthesized with widespread commercial use. DEDTP is a stable compound, and most studies considered it harmless. However, some studies found adverse effects in vitro , including toxicity in different human cell types. However, there are no in vivo studies characterizing the toxicological effects of DEDTP. Therefore, we investigated the genotoxicity and immunotoxicity of DEDTP in a murine model. We used C57BL/6J and Balb/c mice (6–8-weeks-old) exposed to DEDTP i.p. We established that the medium lethal dose (LD 50) of DEDTP was 0.537 g/kg. DEDTP was genotoxic in vivo because it increased the frequency of micronuclei in polychromatic erythrocytes in peripheral blood at 0.05 g/kg. DEDTP showed immunotoxic effects on T and Natural Killer cells and immunomodulatory effects on macrophages, especially M2 type that increased 1000% after 20 days of exposure to 0.01 g/kg. These effects modified the response to a tumoural challenge. DEDTP exposure increased tumour size and reduced the response of lymphocytes to tumoural antigen stimulation. We conclude that exposure to DEDTP produced genotoxic and immunomodulatory effects at environmentally relevant concentrations, which affected the growth of tumours in vivo. These results suggest that DEDTP might reduce the quality of life in exposed individuals, and it exhibits genotoxicity and immunotoxicity despite its stability. Graphical abstract Unlabelled Image Highlights • DEDTP induces MN in PCE. • DEDTP is immunotoxic for T and NK cells. • DEDTP increases M2 macrophages. • DEDTP reduces the number of tumours but increases tumour size. [ABSTRACT FROM AUTHOR]

Recurrent airway obstruction (RAO), also known as heaves, is an allergic respiratory condition that develops in horses following an exposure to aeroallergens in hay and straw. This is manifested by airway hyperreactivity, inflammation, bronchoconstriction, as well as a leukocyte and platelet infiltration into the airways. Platelet activation and an increase in circulating platelet-leukocyte aggregates may lead to airway remodeling. The aim of this study was to explore the effect of seven-day antigen challenge on dynamics of platelet indices and CD41/61 and CD62 P expression on platelets in horses with RAO. Ten RAO-affected horses and ten healthy horses were included in this study. All horses were exposed to 7 days hay and straw challenge. Blood samples were collected prior to the challenge (Pre-challenge) and 1, 2, 3, 7 and 14 days after the initiating the antigen challenge. Blood samples were obtained to determine the platelet count (PLT), mean platelet volume (MPV) and platelet large cell ratio (P-LCR). Expression of CD62 P and CD41/61 was detected by flow cytometry on activated platelets. Antigen challenge resulted in a significant gradual decrease of PLT in RAO horses, but not in controls. MPV and P-LCR in control and RAO-affected horses remained unchanged after antigen challenge. The expression of CD62 P and CD41/61 in RAO horses was significantly higher compared to control horses. The antigen challenge resulted in an increase expression of CD62 P and CD41/61 on the platelets of RAO-affected horses, while did not lead to significant changes in the control group. An increased expression of CD62 P and CD41/61 indicates platelet activation what may contribute to the formation of platelet aggregates in their respiratory system. [ABSTRACT FROM AUTHOR]

The definition of late-phase response (LPR) associated with nasal allergy is not as clear as that associated with asthma. Furthermore, LPR and immediate-phase response often act in concert to produce confounding symptoms due to repeated attacks over a short period of time. We examined the nasal airway resistance (NAR), allergic symptoms, eosinophil cationic protein and histamine concentration in nasal surface tissue 30 min before, and 10 min, 1, 3, 5, 7 and 9 h after a house dust (HD) nasal challenge test was performed twice on 10 patients with HD perennial nasal allergy. Nasal airway resistance readings after the HD nasal challenge test were classified into three types based on changes in NAR: type I (short-lasting, five cases); type II (prolonged, eight cases); and type III (biphasic, six cases). Delayed increases in NAR were not observed in type I patients with weak responses to nasal challenge. In type II patients, baseline NAR was elevated and numerous basophilic metachromatic cells (BC) were present in the epithelial layer. In type III patients, baseline NAR was not as elevated as it was in type II patients, but marked responses to challenge were noted. In all three types of changes in NAR, eosinophil leukocyte increased at late phase. Moreover, there was no correlation of change in NAR with an increase in the number of eosinophil leukocyte and BC at the epithelial layer in all three types, which suggests that further study is required to confirm the exact role of eosinophils and basophilic cells in LPR.

Background: Although neurogenic inflammation of the airways via activation of C-fibers is thought to be important in the pathogenesis of asthma, the mechanisms regulating C-fiber activity remain uncertain. Objective: The influence of a cannabinoid receptor agonist, WIN 55,212-2, on C-fiber activation in guinea pig airways was investigated, as was the mechanism by which cannabinoids regulate antigen-induced airway inflammation. Methods: The inhibitory effect of WIN 55,212-2 on antigen-induced plasma extravasation was assessed in guinea pig tracheal tissues by photometric measurement of extravasated Evans blue dye after extraction with formamide. Results: Pretreatment with WIN 55,212-2 (0.001, 0.01 or 0.1 mg/kg) significantly and dose-dependently reduced tracheal plasma extravasation induced by inhaling a 5% ovalbumin solution for 2 min after pretreatment with a neutral endopeptidedase inhibitor (phosphoramidon at 2.5 mg/kg i.v.). A cannabinoid CB2 receptor antagonist (SR144528) blunted the inhibitory effect of WIN 55,212-2, while a cannabinoid CB1 antagonist (SR141716A) did not. Pretreatment with a neurokinin-1 receptor antagonist (FK888) significantly reduced ovalbumin-induced extravasation of Evans blue dye. Pretreatment with the combination of WIN 55,212-2 and FK888 reduced antigen-induced plasma extravasation more markedly than FK888 alone. Conclusions: These findings suggest that WIN 55,212-2 inhibits C-fiber activation via the cannabinoid CB2 receptor and thus suppresses antigen-induced inflammation in guinea pig airways. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The mechanisms of eosinophil activation in perennial allergic rhinitis (AR) are not fully understood but may be mediated by a series of inflammatory mediators, including locally produced specific antibodies. The aim of this study was to evaluate the role of locally produced allergen-specific antibodies in the nasal lavage fluid during the recruitment of inflammatory cells in AR. Thirteen patients with AR and a positive nasal provocation test (NPT) with Dermatophagoides pteronyssinus and 10 asymptomatic subjects, sensitized to D. pteronyssinus but who had a negative NPT were enrolled. Nasal lavage fluids were collected before and at 10, 30, and 60 minutes and 3, 6, and 24 hours after the NPT. Inflammatory cells were counted, and eosinophil cationic protein (ECP) and specific immunoglobulin E (IgE), IgG, and IgA antibodies were measured by enzyme-linked immunosorbent assay. After NPT, six subjects showed early responses and seven subjects showed dual responses. The eosinophil count and ECP level in lavage fluid were significantly increased after NPT in patients with positive NPTs, and these values were significantly higher than in the negative group. The specific IgA level in lavage fluid was increased after NPT in the positive group, and significant differences were noted for both the early and the late positive responses. Significant correlations were found between specific IgA and ECP levels in lavage fluid during early and late responses. Eosinophil recruitment occurred during both early and late responses after allergen exposure in perennial AR. Locally produced allergen-specific IgA (but not IgE or IgG) may be involved in eosinophil activation in both early and late responses. [ABSTRACT FROM AUTHOR]

Abstract: Argemone platyceras is used in Mexico as a remedy for cough, bronchitis and pneumonia. The present study was performed to investigate the pharmacological anti-asthmatic properties of Argemone platyceras on airways and to identify its active principles. Methanol extracts of leaves and flowers, subsequent organic and aqueous extraction phases, and silica gel chromatography fractions were assayed on the carbachol-induced response, and/or on ovalbumin antigenic challenge, and on leukotriene D4-induced response of tracheae from sensitized and non-sensitized guinea-pigs. Methanol extracts, ethyl-acetate phase, and its fractions 6 and 7 inhibited the carbachol-induced contractile response. Isoquercitrin and rutin were the main compounds found in fractions 6 and 7 respectively. Isoquercitrin (fraction 6) abolished the response to ovalbumin, and decreased the contractile response to leukotriene D4. Because of its effect on carbachol-induced contractile response, on the late-phase response to ovalbumin, and on leukotriene D4-induced contractile response, isoquercitrin might be highly useful in treatment of asthma. [Copyright &y& Elsevier]

Background: Angiotensin II is a putative mediator in asthma, but the effect of topical administration of type 1 angiotensin II (AT1) receptor antagonists on allergic airway reactions is not known. Objective: To investigate the effect of intranasal administration of CV-11974, an AT1 receptor antagonist, and of PD123319, a type 2 angiotensin II (AT2) receptor antagonist, on antigen-induced airway reactions in guinea pigs. Methods: Thirty minutes after intranasal topical administration of CV-11974 (0.1 or 1.0 mg/ml) or PD123319 (10 mg/ml) into the airways, the animals were given an antigen challenge. Airway hyperresponsiveness and bronchoalveolar lavage fluid were analyzed 24 h after the antigen challenge. Results: Although these compounds did not inhibit antigen-induced early-phase bronchoconstriction or late-phase airway eosinophilia, intranasal administration of CV-11974 (but not PD123319) inhibited antigen-induced airway hyperresponsiveness in a dose-dependent manner 24 h after the antigen challenge. Conclusion: Intranasal administration of an AT1 receptor antagonist reduces antigen-induced airway hyperresponsiveness.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We examined the effect of endobronchial (EB) or whole-lung (WL) challenge with ragweed or Timothy grass extract on alveolar macrophage (AM) activation. Expression of 17 constitutive activation markers on AM was examined by flow cytometry. Late-phase bronchial obstruction was greater after WL challenge, while changes in bronchoalveolar lavage cytology (eosinophil accumulation) were greater after EB challenge. After EB challenge, levels of 10 of 17 markers (CD11a, CD11b, CD14, CD18, CD23, CD32, CD63, CD64, HLA-class I, and HLA-DR) were significantly increased (by 33–234%, P < 0.05). Six markers (CD16, CD29, CD33, CD35, CD44, CD71, and HLA-DQ) remained unchanged. Levels of seven markers following EB challenge (CD14, CD16, CD18, CD29, CD32, HLA-class I, and HLA DQ) correlated with airway sensitivity to methacholine. WL challenge only increased expression of HLA-class I. The different results obtained with the two challenge methods probably depend on higher local concentrations of allergen in the EB challenge. We suggest that activation of AM occurs following EB challenge with antigen in asthmatics. [Copyright &y& Elsevier]

T cells using the γδ T cell receptor (TCR) are abundant in mucosal and epidermal tissues in mice. Most studies of mucosal γδ T cells, however, have examined cells from the intestinal mucosa, whereas little is known about the presence or function of γδ T cells in the oral cavity. To better understand the involvement of oral γδ T cells in immunity, we have characterized TCR variable γ-gene usage in the buccal epithelium from normal mice, and from mice challenged locally with a non-replicating antigen (bovine serum albumin [BSA]) or by influenza-virus infection as a replicating antigen. Our findings demonstrate a restricted use of Vγ genes by buccal γδ T cells, consisting primarily of Vγ1.2, Vγ3, and Vγ5, with minimal use of Vγ2 and Vγ4 genes. Of particular interest, 3–4 days post-antigen challenge with BSA, there was a precipitous drop in the level of expression of Vγ1.2, Vγ3, and Vγ5 genes, and to a lesser extent for the Vγ2 gene, whereas Vγ4 gene expression increased between days 1 and 2 post-priming. In influenza-infected mice, a similar pattern was observed for the Vγ2 and Vγ5 genes, but not other Vγ genes. The immune-modulating effects of oral antigen exposure on buccal γδ T cells suggest that these cells are functionally involved in the local immune response to both replicating and non-replicating antigens in oral mucosal surfaces. [Copyright &y& Elsevier]

BackgroundChronic mast cell-mediated inflammation may contribute significantly towards the extensive tissue remodelling that is a feature of lungworm infection in ruminants. Understanding the factors that control tissue remodelling is a necessary step toward effective management and treatment of conditions that feature such pathology. ObjectiveWe sought to define in a novel ovine model system, the cellular, immune and mast cell phenotypic events that occur following local lung challenge with a recombinant protein antigen, DvA-1, derived from the ruminant lungworm nematode, Dictyocaulus viviparus. MethodsTwo spatially disparate lung segments in systemically sensitized sheep were challenged on three occasions with DvA-1 (3xDVA) and two further segments were challenged with saline (3xSAL). Two months after the third challenge, one of the two segments previously repeatedly challenged with DvA-1 was challenged again with DvA-1 (3xDVA:DVA) whilst the other was challenged with saline (3xDVA:SAL). A similar protocol was followed with the saline challenged segments (3xSAL:SAL and 3xSAL:DVA). Bronchoalveolar lavage fluid (BALF) (n = 16) and tissue (n = 3) were collected after the last challenge. ResultsCellular changes 24 h after the fourth challenge were characterized by an increase in the absolute numbers of neutrophils and eosinophils in BALF from 3xDVA:DVA and 3xSAL:DVA segments. Local antibody production was implied through increased levels of antibody in both 3xDVA:DVA and 3xDVA:SAL segments, with the latter being unaffected by inflammation. Levels of active transforming growth factor beta-1 (TGF-β1) were significantly increased in 3xDVA:SAL segments and a trend towards an increase was apparent in 3xDVA:DVA segments. Total TGF-β1 levels were significantly correlated with eosinophil counts in all except the 3xDVA:SAL segments. Such changes in the bronchoalveolar space were complemented by increased ratios of sheep mast cell... [ABSTRACT FROM AUTHOR]

In order to establish an experimental model for the study of immunological reactions to exogenic immunogens in the upper and lower respiratory system NMRI mice were subjected to inhalation of the mitogenic and inflammatory response inducing lectin concanavalin A (Con A) and bovine serum albumin (BSA). Immunological reactions were induced in the upper respiratory tract and in the lungs. Serologically, the course of the antibody titre was measured by radio-immunoassay over several weeks. Germinal centre reactions in the nose and paranasal sinus equivalents were the morphological correlate. The lungs showed an increase in the number of macrophages and a thickening of the alveolocapillary membrane, but no germinal centre reactions were observed. These morphological and serological results may indicate a priming of the immune response in the upper respiratory tract leading to a subsequent production of antibodies in the lung. [ABSTRACT FROM AUTHOR]

We studied the effect of the inhaled leukotriene D4 antagonist, L-648,051, on antigen-induced bronchoconstriction and nonspecific bronchial reactivity Ten males with mild atopic asthma completed a double-blind, randomized, two-period, placebo-controlled cross-over study For a 7-day period patients inhaled either placebo or 6 mg of L-648,051 four times daily Bronchial reactivity to methacholine was measured at base line (day 1) and after 6 days, treatment (day 7). On day 8, after inhaling 6 mg of the antagonist (or placebo), the patients were challenged by inhaled antigen, they received an additional 6 mg of the antagonist (or placebo) 3 h later. Pulmonary function (forced expiratory volume in 1 s, FEV1) was measured serially through an 8-h post-antigen challenge Nonspecific airway reactivity was again measured on day 9 Compared to placebo, L-648,051 treatment dmimished the methacholine reactivity, on both day 7 (NS) and on day 9 (P<0.05) In addition, the immediate and late bronchial responses to antigen challenge on day 8 were attenualed in the patients when treated with L-648,051 In the immediate phase (0-3 h postchallenge), the airway response was significantly reduced at all recordings between 20 min and 1h postchallenge In tile late phase (3-8 h postchallenge), the pulmonary response was also reduced However, the reduction was statistically significant only at the 5-h recording The results suggest that sulfidopeptide Icukotnenes are of unportance for nonspecific airway reactivity, and that leukotriene D4 is a significant mediator in tile immediate asthmatic reaction. [ABSTRACT FROM AUTHOR]

We examined the ability of the inhaled leukotriene D4 antagonist (L-648,051) to inhibit antigen-induced asthmatic responses. Twelve patients with stable exogenous asthma participated in two separate double-blind, placebo-controlled, cross-over trials. The ability of the antagonist to reverse or inhibit antigen-induced bronchoconstrictor response was examined; both the immediate and the late phases were studied. In the reversal study, patients inhaled 800 μg of L-648,051 during the immediate phase (15 min after antigen challenge) and again during in the late phase (7 h after antigen challenge). In the prevention study, the same dose (800 μg) of L-648,051 was inhaled before the expected immediate reaction (5 min before antigen challenge) as well as before the expected late reaction (2.5 h after antigen challenge). The LTD4 antagonist was not effective in reversing the airway response to inhaled antigen, as measured by airway resistance (Rt), forced expiratory volume in 1 s (FEV1) or forced vital capacity (FVC). When the antagonist was given prior to antigen challenge, a slight reduction in Rt was observed during the immediate phase, but not during the late phase. Some improvement in FEV1 and FVC during the immediate phase was also observed, but these changes did not reach statistical significance. These results suggest that LTD4 plays a role in the immediate phase of antigen-induced asthma. [ABSTRACT FROM AUTHOR]

We investigated the effects of a novel platelet-activating factor (PAF) receptor antagonist, CIS-19 [cis-2-(3, 4-dimethoxyphenyl)-6-isopropoxy-7-methoxy-1-(N-methylformamido)-1, 2, 3, 4-tetrahydronaphthalene], on PAF-, histamine-, substance P- and antigen-induced bronchoconstriction and microvascular leakage, as well as PAF- and antigen-induced bronchial hyperreactivity to methacholine in urethane-anesthetized guinea-pigs. Administration of CIS-19 (0.5–5 mg/kg, i.v.) inhibited the increase in lung resistance induced by PAF (30 ng/kg, i.v.) in a dose-dependent manner, but failed to inhibit the increase induced by histamine (30 μg/kg, i.v.) or substance P (6.5 μg/kg, i.v.). CIS-19 (5 mg/kg, i.v.) did not inhibit the increase in lung resistance induced by ovalbumin (2 mg/kg, i.v.) in actively sensitized guinea-pigs. PAF (30 ng/kg, i.v.)-induced microvascular leakage, measured by the extravasation of Evans blue dye, was dose-dependently inhibited by CIS-19 (0.5–5 mg/kg, i.v.) in the trachea, main bronchi and intrapulmonary airways, but it did not affect histamine (30 μg/kg, i.v.)- or substance P (6.5 μg/kg, i.v.)-induced microvascular leakage at all airway levels. CIS-19 (2.5 and 5 mg/kg) did not affect ovalbumin (2 mg/kg, i.v.)-induced microvascular leakage in all airway levels in actively sensitized guinea-pigs. CIS-19 (2.5 and 5 mg/kg, i.v.) significantly inhibited PAF-induced enhancement of the bronchial response to methacholine, but had no effect on ovalbumin (0.05 mg/kg, i.v.)-induced bronchial hyperreactivity in actively sensitized guinea-pigs. It is concluded that CIS-19 is a potent PAF receptor antagonist which inhibits PAF- but not antigen-induced bronchoconstriction, microvascular leakage and bronchial hyperreactivity. These results suggest that PAF plays little or no role in early airway responses following antigen challenge. [ABSTRACT FROM AUTHOR]

In 14 nonsmokers with extrinsic bronchial asthma, static lung volumes, FEV 1.0, specific conductance, and maximal expiratory flow rates breathing air and a 80% He-20% O mixture were measured before and after antigen-induced bronchoconstriction. In 9 of these subjects, nitrogen washout curves after a VC breath of oxygen were obtained with determination of the slope of phase III, the height of phase IV and the closing capacity. Two subjects were retested once and three times, respectively, with different antigens. Density dependence of the maximal expiratory flow (ΔV > 20%) was found in 78% pre- and 39% postprovocation. In the He responders after challenge, the height of phase IV increased, while in nonresponders after challenge the height of phase IV decreased. The results suggest that the major site of flow limitation in acute antigen-induced asthmatic attacks might be inter- and intra-individually located predominantly in central or peripheral airways depending on the host's reaction to the antigen used for challenge. [ABSTRACT FROM AUTHOR]

The goal of these studies was to characterize the role played by antigen challenge in 2,3,7,8-tetrachlorodibenzo- p-dioxin (TCDD)-induced immunosuppression. The effects of single exposure to TCDD (4.2, 14, and 42 μg/kg) in B6C3F1 mice on the reverse plaque assay (RPA; no sensitization) and the sheep red blood cell (SRBC) antibody response were compared. While the RPA was suppressed in a dose-dependent fashion with significance at the two highest doses, a much more dramatic effect was noted with the primary anti-SRBC response: a suppression was noted at the lowest dose, which was comparable to that observed with the highest dose in the RPA. Subsequent studies compared the RPA in B6C3F1 ( Ah-high responder) and DBA/2 ( Ah-low responder) mice after both single and repeated exposure to identical cumulative doses of TCDD (4.2, 14, and 42 μg/kg). The repeated exposures consisted of 14 consecutive daily treatments of 0.3, 1.0, and 3.0 μg/kg. The results indicated only a slight difference in the effects of TCDD in the two strains after single exposure, and even less difference after repeated exposure. Moreover, administering TCDD on different days relative to the SRBC challenge indicated a suppression in both strains when given 1, 2, or 3 days before antigen challenge, on the day of antigen challenge, or 1 or 2 days after antigen challenge. The only day of administration where the suppression was attenuated was 3 days after antigen challenge. These results confirm an important relationship between antigen challenge and TCDD exposure on immunosuppression. [ABSTRACT FROM AUTHOR]