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Early onset preeclampsia is characterized by hypertension, reduced placental perfusion, intrauterine growth restriction and increased activation of complement, part of innate immunity. We reported that inhibition of complement activation... more
Early onset preeclampsia is characterized by hypertension, reduced placental perfusion, intrauterine growth restriction and increased activation of complement, part of innate immunity. We reported that inhibition of complement activation attenuated reduced uterine perfusion pressure (RUPP)-induced hypertension in the pregnant rat. Although recent studies in pregnant mice indicate injection of autoantibodies to angiotensin II Type 1 receptor (AT1-AA) activate complement and increase blood pressure, the sequence of events following placental ischemia remains unknown. Thus, we hypothesized AT1-AA interaction with its antigen was responsible for complement activation critical to placental ischemia-induced hypertension. The AT1 antagonist losartan prevents AT1-AA interaction with the AT1 receptor. Thus, we determined the effect of losartan on complement activation following placental ischemia in rat. Dams received drinking water with or without 30 mg/kg/day losartan on gestation day (GD)13-19. On GD14, rats underwent Sham surgery or RUPP surgery with placement of clips on abdominal aorta and uterine arteries to decrease placental perfusion. On GD19, mean arterial pressure (MAP) via arterial catheter and serum C3a as an indicator of complement activation were measured. As expected, RUPP surgery increased complement activation (C3a) and MAP and decreased fetal weight compared to Sham. Importantly, losartan treatment did not significantly change RUPP-induced increase in C3a. These data indicate AT1-AA interaction with the AT1 receptor does not mediate complement activation and its subsequent involvement in hypertension following placental ischemia.
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Previous studies suggest that high levels of adenosine may enhance histamine release and contribute to atrioventricular (AV) nodal conduction arrhythmias during anaphylaxis of isolated guinea pig hearts. To determine whether elevations in... more
Previous studies suggest that high levels of adenosine may enhance histamine release and contribute to atrioventricular (AV) nodal conduction arrhythmias during anaphylaxis of isolated guinea pig hearts. To determine whether elevations in endogenous adenosine evoked by hypoxic conditions have similar effects, isolated hearts of guinea pigs passively sensitized by intracardiac injection were perfused with solutions equilibrated with 95% O2 (normoxia) or 30% O2 (hypoxia). When compared with normoxia, hypoxia before antigen challenge increased adenosine release, decreased vascular resistance, and prolonged P-R intervals, whereas hypoxia during anaphylaxis potentiated the increase in adenosine release, attenuated the increases in vascular resistance and atrial rate, and increased the occurrence of conduction arrhythmias without altering the antigen-induced release of either histamine or thromboxane. Addition of the adenosine receptor antagonist 8-(4-sulfophenyl)theophylline (SP-T) to the hypoxic perfusate significantly decreased antigen-induced release of histamine and thromboxane. These data indicate that 1) hypoxia-induced depression of antigen-induced mediator release may be counteracted by the stimulatory effect of the increased adenosine induced by hypoxia, and 2) under hypoxic conditions, adenosine's negative dromotropic, chronotropic, and vasodilatory effects may influence the anaphylactic reaction.
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Cleavage of the complement protein C5 by activation of the complement system yields a low molecular weight fragment C5a. Knowledge of the alterations in blood pressure induced by C5a as well as the mediators responsible for the blood... more
Cleavage of the complement protein C5 by activation of the complement system yields a low molecular weight fragment C5a. Knowledge of the alterations in blood pressure induced by C5a as well as the mediators responsible for the blood pressure changes may provide information concerning the potential role of C5a in the adverse hemodynamic responses associated with complement activation. The purpose of this study was to characterize changes in mean arterial pressure in the guinea pig after intravenous challenge with a combination of guinea pig C5a plus C5a(des-Arg) (C5a/C5a(des-Arg)) and determine the mediators responsible for the transient increase in blood pressure which was observed. Mean arterial pressure was monitored in mechanically ventilated pentobarbital-anesthetized guinea pigs. Intravenous injection of C5a/C5a(des-Arg) consistently caused a marked but transient rise in blood pressure. A transient hypotensive response was also seen with injection of markedly higher doses of guinea pig C5a/C5a(des-Arg). Various pharmacological antagonists were used to determine the mediators responsible for the increase in blood pressure induced by guinea pig C5a/C5a(des-Arg). We found that the LTD4 antagonist L-649,923 did not inhibit the transient rise in blood pressure. However, the cyclooxygenase inhibitor indomethacin inhibited the C5a/C5a(des-Arg)-induced pressor response as did the thromboxane synthetase inhibitor U-63557A and the thromboxane receptor antagonist SQ 29,548. In addition, the C5a/C5a(des-Arg)-induced pressor response was not inhibited by the H1 antagonist pyrilamine, but was inhibited in part by the alpha-adrenergic antagonist phentolamine. Also, the response was reduced in animals depleted of circulating platelets or white blood cells. Thus, the results of our studies suggest that intravenously injected guinea pig C5a/C5a(des-Arg) causes release of the vasoconstrictor thromboxane, most likely from circulating white blood cells or platelets, resulting in a transient rise in blood pressure in the guinea pig. In addition, release of catecholamines may contribute to the pressor response observed.
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Research Interests: Cardiology and Medicine
Recombinant human C5a (rHuC5a) causes an intense bronchoconstriction very quickly after i.v. injection into the guinea pig. In addition, it causes a biphasic blood pressure response characterized by a small hypotensive phase followed by a... more
Recombinant human C5a (rHuC5a) causes an intense bronchoconstriction very quickly after i.v. injection into the guinea pig. In addition, it causes a biphasic blood pressure response characterized by a small hypotensive phase followed by a larger transient hypertensive phase. The overall goal was to determine the role of circulating cells in the bronchoconstriction and changes in blood pressure induced by rHuC5a. Intravenous injection of rHuC5a causes a transient granulocytopenia and thrombocytopenia, suggesting that these cells may be important targets of C5a action. However, the magnitude of granulocytopenia does not directly correlate with the magnitude of the bronchoconstriction, suggesting no direct connection between the events. Our studies continued to determine if depletion of circulating granulocytes and/or platelets altered the magnitude of, or the participation of histamine in, C5a-induced bronchoconstriction in the guinea pig. Selective depletion of circulating granulocytes, circulating platelets or both with specific antisera did not alter the severity, time of onset or duration of the rHuC5a-induced bronchoconstriction. The rHuC5a-induced hypertensive blood pressure response was significantly reduced only in guinea pigs depleted of just granulocytes. After depletion of both circulating granulocytes and platelets, histamine plays an important role in mediating the rHuC5a-induced bronchoconstriction as evidenced by the effectiveness of an H1 antagonist in inhibiting the response. This is in contrast to the ineffectiveness of the same H1 antagonist in inhibiting rHuC5a-induced bronchoconstriction in guinea pigs with normal numbers of circulating granulocytes and platelets or guinea pigs depleted of granulocytes only or platelets only.(ABSTRACT TRUNCATED AT 250 WORDS)
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Research Interests: Engineering, Gerontology, Computational Biology, Biology, China, and 15 moreFutures Studies, Carbon Market, England, Biological Sciences, Humans, Emissions Trading, Female, Academic achievement, Genome, Biological evolution, Clinical Sciences, BMJ, Circulation, Bates, and Cardiovascular medicine and haematology
Chemicals and proteins can cause hypersensitivity reactions in the respiratory tract via multiple mechanisms. Hypersensitivity responses require a latent period and develop in two stages: An induction or sensitization phase and an... more
Chemicals and proteins can cause hypersensitivity reactions in the respiratory tract via multiple mechanisms. Hypersensitivity responses require a latent period and develop in two stages: An induction or sensitization phase and an elicitation or effector phase with appearance of symptoms. Often, the hypersensitivity reaction to a given allergen involves a combination of both humoral (Types I–III) and cell mediated (Type IV) components leading to disease. This chapter will focus on hypersensitivity reactions in the respiratory tract that are most often encountered by toxicologists including allergic rhinitis, allergic asthma, anaphylaxis, and hypersensitivity pneumonitis. In addition, chronic beryllium disease will be presented as an example of a Th1-mediated hypersensitivity reaction. Current knowledge of mechanisms will be presented as well as animal models used in research in hypersensitivity reactions in the respiratory tract.
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The complement cleavage product, C5a, causes a bronchoconstriction in the guinea pig as evidenced by a decrease in dynamic lung compliance and an increase in pulmonary resistance. Previous studies had demonstrated that the antihistamine... more
The complement cleavage product, C5a, causes a bronchoconstriction in the guinea pig as evidenced by a decrease in dynamic lung compliance and an increase in pulmonary resistance. Previous studies had demonstrated that the antihistamine pyrilamine and the cyclooxygenase inhibitor indomethacin inhibited the C5a-induced bronchoconstriction but the leukotriene (LT)D4 antagonist L-649,923 did not. As an extension of those studies, the purpose of the present study was to determine the contribution of specific cyclooxygenase products and/or LTB4 in mediating C5a-induced bronchoconstriction. To assess the role of the various potential mediators, plasma levels of thromboxane (TX)B2, prostaglandin (PG)D2 and PGF2 alpha were monitored. In addition, guinea pigs were treated either with the TX synthetase inhibitor U-63557A, treated with the TX receptor antagonist SQ 29,548 or made tachyphylactic to the bronchoconstrictor actions of LTB4. C5a challenge caused an increase in plasma concentrations of TXB2, which peaked before the maximum of the bronchoconstriction. However, no significant increase in plasma concentrations of PGD2 or PGF2 alpha was seen. Both U-63557A at 80 mg/kg and SQ 29,548 significantly inhibited the C5a-induced bronchoconstriction, whereas 10 mg/kg of U-63557A did not. The inability of 10 mg/kg of U-63557A to inhibit the response could be explained by both incomplete inhibition of TX synthesis as well as possibly by the increased plasma concentrations of the potent bronchoconstrictor PGD2, which occurred with C5a challenge in the presence of U-63557A. In animals tachyphylactic to LTB4, the maximum of the C5a-induced bronchoconstriction was no different from control.(ABSTRACT TRUNCATED AT 250 WORDS)
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Our previous studies with C5a, a cleavage product of the fifth component of complement, have shown that the antihistamine diphenhydramine and the cyclo-oxygenase inhibitor aspirin do not inhibit the C5a-induced contraction of isolated... more
Our previous studies with C5a, a cleavage product of the fifth component of complement, have shown that the antihistamine diphenhydramine and the cyclo-oxygenase inhibitor aspirin do not inhibit the C5a-induced contraction of isolated guinea pig trachea (Regal, Eastman & Pickering, 1980; Regal & Pickering, 1981). We investigated the effect of cyclo-oxygenase inhibitors in the presence of diphenhydramine to determine if cyclo-oxygenase products were contributing to the contraction beyond any effect they might have on histamine release. A combination of a cyclo-oxygenase inhibitor and diphenhydramine caused a delay in onset and decrease in magnitude and duration of the C5a-induced contraction. Indomethacin itself also caused a slight inhibition. In contrast, a combination of aspirin and diphenhydramine did not inhibit the initial portion of antigen-induced tracheal contraction any more than diphenhydramine alone and enhanced the later portion just as aspirin alone. Cross tachyphylaxis experiments demonstrated that antigen pretreatment significantly inhibited a subsequent C5a-induced tracheal contraction, though C5a pretreatment did not affect a subsequent antigen-induced contraction. Thus, cyclo-oxygenase products do contribute to C5a-induced tracheal contraction, and histamine participation in the presence of cyclo-oxygenase inhibitors is suggested. Our studies demonstrate the dissimilarities of C5a and antigen-induced contraction as regards inhibition by aspirin plus diphenhydramine, yet suggest common pathways leading to the contractile response as evidenced by cross tachyphylaxis experiments.
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Our previous studies have demonstrated that activation of the C system with cobra venom factor (CVF) in a passively sensitized guinea pig results in an enhanced bronchoconstrictor response to Ag but not to other constrictor agents. Thus,... more
Our previous studies have demonstrated that activation of the C system with cobra venom factor (CVF) in a passively sensitized guinea pig results in an enhanced bronchoconstrictor response to Ag but not to other constrictor agents. Thus, our immediate goal was to determine the mechanism of the CVF-induced enhancement of the Ag-induced bronchoconstriction. Isolated airways from sensitized guinea pigs that had been treated with CVF responded normally to Ag. Because such a system lacks the normal circulating cell populations, we hypothesized that the CVF-induced enhancement of the Ag-induced bronchoconstriction was dependent on the presence of circulating white blood cells or platelets. Guinea pigs were depleted of circulating granulocytes, platelets, or both using specific antisera and the effect on the CVF-induced enhancement of the Ag-induced bronchoconstriction was determined. We found that CVF treatment did not result in an enhanced Ag-induced bronchoconstriction in guinea pigs depleted of either granulocytes or both granulocytes and platelets. However, the enhanced response was still apparent in guinea pigs depleted of just platelets. We investigated the effects of CVF itself and found that CVF treatment did not alter the number, or percentages, of different cell populations in the bronchoalveolar lavage, did not alter the protein or albumin content of the lavage fluid or the wet:dry ratio of the lung. In addition, CVF did not cause an increase in airway microvascular permeability as assessed by leakage of Evans blue. However, CVF did substantially increase granulocytes sequestered in the lung as measured by increased myeloperoxidase content. Thus, C activation by CVF results in an increase in neutrophils in the lung and an enhanced Ag-induced bronchoconstriction dependent on the presence of circulating granulocytes. These studies suggest that C activation and/or retention of granulocytes in the lung may be important in determining the severity of an Ag-induced bronchoconstriction.
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Cleavage of the complement protein C5 by activation of the complement system yields a low molecular weight fragment, C5a, historically referred to as anaphylatoxin. Among the biological activities of C5a is the ability to contrast... more
Cleavage of the complement protein C5 by activation of the complement system yields a low molecular weight fragment, C5a, historically referred to as anaphylatoxin. Among the biological activities of C5a is the ability to contrast isolated smooth muscle. This report is concerned with initial studies identifying mediators responsible for C5a-induced contraction of isolated guinea-pig aortic rings. C5a, purified from yeast-activated guinea-pig serum, caused a concentration-related contraction of the isolated guinea-pig aorta. The H1 antagonist diphenhydramine partially inhibited the response of the aorta to C5a, indicating that released histamine was, at least in part, responsible for the contraction. 5,8,11,14-Eicosatetraynoate, an inhibitor of both the lipoxygenase and cyclooxygenase pathway of arachidonate metabolism, inhibited the C5a-induced aortic contraction to an even greater extent than diphenhydramine, suggesting that products of arachidonate metabolism also play a role in the contraction. The cyclooxygenase inhibitors aspirin and indomethacin did not inhibit the C5a-induced aortic contraction, yet a combination of aspirin and diphenhydramine or indomethacin and diphenhydramine completely inhibited the aortic response to C5a. The presence of aspirin did not affect the ability of diphenhydramine to inhibit the response of the aorta to exogenous histamine, thus suggesting that cyclooxygenase products were not affecting the reactivity of histamine at the target smooth muscle. These studies indicate that both histamine and cyclooxygenase products are mediators responsible for C5a-induced aortic contraction.
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Trimellitic anhydride (TMA) is one of many low molecular weight compounds known to cause occupational asthma. In our previous studies the TMA-induced allergic response in guinea pigs was attenuated by depletion of complement.... more
Trimellitic anhydride (TMA) is one of many low molecular weight compounds known to cause occupational asthma. In our previous studies the TMA-induced allergic response in guinea pigs was attenuated by depletion of complement. Specifically, the leakage of red blood cells and infiltration of inflammatory cells into the lung after TMA challenge was significantly reduced. Thus, we hypothesize that in the presence of specific antibody, TMA activates the complement system and complement activation products play a role in mediating inflammatory cell infiltration into the lung and lung hemorrhage. Guinea pigs were sensitized by intradermal injection of TMA in corn oil. An increase in the complement activation product C3a was detected in bronchoalveolar lavage, but not in plasma, of both sensitized and nonsensitized guinea pigs after intratracheal challenge with TMA conjugated to GPSA (TMA-GPSA). In vitro experiments demonstrated that TMA-GPSA caused complement activation by antibody-dependent as well as antibody-independent pathways. In sensitized animals, TMA-GPSA challenge caused significant increases in eosinophils, neutrophils, and macrophages in lung, along with increases in red blood cells and protein in the airspace. The infiltration of eosinophils was unique in that the magnitude of the GPSA/TMA-GPSA effect was significantly different between nonsensitized and sensitized animals. C3a concentrations in BAL correlated with all measures of cell infiltration in sensitized animals, but not in nonsensitized animals. These data indicate that complement activation in the absence of antibody is not sufficient for the complete allergic response to occur. Both sensitization and the complement system are required for TMA-induced eosinophilia.
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Systemic anaphylaxis involves life-threatening bronchoconstriction and a serious hypotensive response often complicated by cardiac arrhythmias. The purpose of the present study was to determine whether complement system activation is... more
Systemic anaphylaxis involves life-threatening bronchoconstriction and a serious hypotensive response often complicated by cardiac arrhythmias. The purpose of the present study was to determine whether complement system activation is essential to the bronchoconstriction and the changes in blood pressure seen in guinea pig models of anaphylaxis. The soluble complement receptor 1 (sCR1; BRL 55730) was used to inhibit activation of the classical and alternative pathways of complement in the guinea pig, and to determine whether this inhibition prevents bronchoconstriction and changes in blood pressure induced by i.v. antigen injection in guinea pigs that are either passively or actively sensitized to the antigen ovalbumin. sCR1 at 15 mg/kg did not affect significantly either the antigen-induced bronchoconstriction or the changes in blood pressure in a guinea pig passively sensitized with immunoglobulin G antibody to ovalbumin. However, it shortened the duration of the antigen-induced increase in blood pressure and inhibited the antigen-induced decrease in circulating platelets in an actively sensitized guinea pig. Continued studies using a cumulative dose of sCR1 of 105 mg/kg administered over a 24-hr period demonstrated that sCR1 attenuated the bronchoconstrictor response and the decrease in circulating platelets and prevented the hypotension induced by antigen in an actively sensitized guinea pig. At a cumulative dose of 105 mg/kg, sCR1 did not inhibit the bronchoconstrictor or blood pressure response to either histamine or bradykinin, indicating that its attenuation of cardiovascular and respiratory reactivity is specific for complement-related processes. The anaphylactic response was accompanied by complement activation as evidenced by cleavage of the C3 molecule. In the presence of sCR1, no C3 cleavage products were detectable in the plasma. Our studies demonstrate that complement activation is an essential step in the antigen-induced bronchoconstriction and the changes in blood pressure in an actively sensitized guinea pig model of anaphylaxis. Continued studies of the differing mechanisms and mediators of anaphylaxis are of importance, and the complement system clearly warrants consideration as a source of those mediators.
Research Interests: Immunology, Complement activation, Medicine, Complement System, Histamine, and 15 moreAntibodies, Anaphylaxis, Blood Pressure, Pubmed, Animals, Male, Immunization, Solubility, Guinea Pig, Bovine Serum Albumin, Recombinant Proteins, Antigens, Bradykinin, Guinea pigs, and Pharmacology and pharmaceutical sciences
Research Interests: Medicine, Occupational Asthma, Blood Pressure, Animals, Male, and 15 moreHeart rate, Allergens, Sensitization, Inhalation, Occupational Exposure, Guinea Pig, Airway Obstruction, Dust, Bovine Serum Albumin, Eosinophilia, Serum albumin, Airway resistance, Erythrocyte Count, Guinea pigs, and Pharmacology and pharmaceutical sciences
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C5a, a peptide derived from the fifth component of complement, has been shown to cause significant prolonged smooth muscle contraction in isolated guinea pig trachea. This contraction was not affected by the antihistamine... more
C5a, a peptide derived from the fifth component of complement, has been shown to cause significant prolonged smooth muscle contraction in isolated guinea pig trachea. This contraction was not affected by the antihistamine diphenyhydramine. To assess further the potential role that C5a may play in allergic bronchospasm, we investigated the role of products of arachidonate metabolism in the C5a-induced tracheal contraction. 5,8,11,14-Eicosatetraynoic acid, an inhibitor of lipoxygenase and cyclooxygenase, virtually eliminated the tracheal contraction induced by C5a. The prostaglandin synthesis inhibitor, acetylsalicylate, did not inhibit the C5a-induced tracheal contraction and enhanced the tracheal response to acetylcholine. FPL 55712, an antagonist of slow reacting substance of anaphylaxis (SRS-A), almost completely inhibited the tracheal response to C5a and at higher concentrations employed, FPL 55712 also inhibited the tracheal response to exogenous prostaglandin F 2 alpha. These studies indicate that C5a-induced tracheal contraction is mediated by a product or products of arachidonate metabolism, and is, at least in part, mediated by SRS-A.
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Research Interests: Endocrinology, Oxidative Stress, Medicine, Pregnancy, Humans, and 15 moreInternal Medicine, Hypertension, Placenta, Ischemia, Preeclampsia, Blood Pressure, Female, Animals, Clinical Sciences, Rats, Pre Eclampsia, Vascular endothelial growth factor receptor, Pravastatin, Cardiovascular medicine and haematology, and placental growth factor
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Gestational hypertension with or without low birth weight is associated with increased risk for Type 2 diabetes in offspring. Pancreatic beta cell mass is set very early in life and can influence whether an individual develops Type 2... more
Gestational hypertension with or without low birth weight is associated with increased risk for Type 2 diabetes in offspring. Pancreatic beta cell mass is set very early in life and can influence whether an individual develops Type 2 diabetes. We previously demonstrated that postnatal day (PD)13 female offspring of rats subjected to chronic placental ischemia-induced hypertension had significantly reduced beta cell area. Previous studies in humans have noted increased circulating C3 in Type 2 diabetics, as well as an important role for intracellular complement C3 in maintaining integrity of the beta cell in the islet. Thus, we hypothesized that decreased C3 in islets is associated with reductions in beta cell area in rat offspring following placental insufficiency. The rat Reduced Uterine Perfusion Pressure (RUPP) model was used to mechanically induce placental insufficiency in the dam by placing silver clips on abdominal aorta and uterine arteries on gestation day 14 of a 21-day gestation, resulting in hypertension in the dam. Pancreatic islets and acinar were isolated by collagenase perfusion and hand picking from PD13 female offspring of RUPP and Sham dams. The concentration of C3 in serum, isolated islets and acinar was determined by ELISA. C3 was significantly increased in serum of female RUPP compared to female Sham offspring. In contrast, C3 in islets was significantly decreased in RUPP female offspring compared to Sham with no significant differences detected in acinar C3 concentrations. Thus, these data suggest that decreased C3 in islets of PD13 offspring may contribute to reduction of beta cell area and long-term susceptibility for Type 2 diabetes.
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Research Interests: New Guinea and Guinea Pig
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Immunotoxicity can take the form of an enhanced immune response or hypersensitivity. Asthma is one possible consequence of hypersensitivity in the lung, with characteristics that include reversible airway obstruction, eosinophil... more
Immunotoxicity can take the form of an enhanced immune response or hypersensitivity. Asthma is one possible consequence of hypersensitivity in the lung, with characteristics that include reversible airway obstruction, eosinophil infiltration into the lung, and airway hyperresponsiveness to agonists such as methacholine. In toxicology, two primary areas of investigation prompt the measurement of the asthmatic response in an animal: (1) identification of chemicals or proteins that cause asthma, i.e., respiratory allergens, and (2) identification of exposures that will exacerbate existing asthma. An ovalbumin-induced asthma model can be used to identify exposures that exacerbate existing asthma. A protocol for the sensitization and challenge of mice with ovalbumin is described; it leads to the asthma symptoms of airway hyperresponsiveness and eosinophil infiltration. Assessment of airway hyperresponsiveness to methacholine uses whole body plethysmography in conscious unrestrained mice. Bronchoalveolar lavage of the mouse determines the extent of cellular infiltration into the airspace. Removal of lung lobes and assay of eosinophil peroxidase and myeloperoxidase provides a measure of the numbers of eosinophils and neutrophils, respectively, in the lung. Depending on the experimental goals, bronchoalveolar lavage fluid and lung tissue can also be used for isolation of RNA, and measurement of cytokines, chemokines, antibodies, and inflammatory mediators.
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Guinea-pig antibody to ovalbumin was separated into two pools using Protein A Sepharose. The antibody pool retained by the Protein A Sepharose [immunoglobulin (Ig) G pool] was heat stable and persisted in skin sites of the guinea pig less... more
Guinea-pig antibody to ovalbumin was separated into two pools using Protein A Sepharose. The antibody pool retained by the Protein A Sepharose [immunoglobulin (Ig) G pool] was heat stable and persisted in skin sites of the guinea pig less than 7 days. The antibody pool which did not bind to Protein A Sepharose (IgE pool) was heat labile and persisted in guinea-pig skin at least 10 days. Both antibody pools were capable of mediating contraction of isolated guinea-pig tracheal and lung parenchymal strips using airway strips passively sensitized in vivo or in vitro. Although the majority of the skin sensitizing ability of the IgE pool was destroyed by heating at 56 degrees C for 4 hr, its ability to mediate airway contraction was only partially inhibited. Experiments examining [125I]Protein A binding of the antibody pools indicated that the contractions seen in airways sensitized with IgE pool was not due to contamination with IgG. These studies provide a system for examining antagonism of and mediators responsible for IgG-vs. IgE-mediated airway contraction and for evaluating the apparently heat stable properties of IgE.
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The present study was designed to determine if depletion of the complement system in the circulation with cobra venom factor (CVF) prevented the cellular infiltration in a guinea pig model of asthma. Guinea pigs were sensitized with... more
The present study was designed to determine if depletion of the complement system in the circulation with cobra venom factor (CVF) prevented the cellular infiltration in a guinea pig model of asthma. Guinea pigs were sensitized with ovalbumin (OA) alone or OA with complete Freund's adjuvant. Animals were pretreated with CVF and challenged with OA aerosol for 15 min in the presence of the antihistamine pyrilamine. Either 6 or 20 h later, bronchoalveolar lavage (BAL) was collected and the numbers of white blood cells and red blood cells and amount of protein were determined. In addition, eosinophil peroxidase and myeloperoxidase activity of the lavage and lung homogenate was measured as an indicator of eosinophil and neutrophil infiltration. Aerosol OA challenge caused cellular infiltration in the lung and BAL. CVF treatment did not inhibit the OA-induced cellular infiltration but resulted in an enhanced accumulation of eosinophils 6 h after OA and increased protein in the lavage at 20 h after OA compared to animals not treated with CVF and challenged with OA. Total hemolytic complement activity in the serum was reduced by more than 98% and local complement activity (C3 in the BAL) by more than 95% by CVF treatment. However, after OA challenge in CVF-treated animals, the C3 content of the BAL was not different from control. Thus, leakage of plasma proteins or local synthesis of C3 induced by OA was sufficient to maintain C3 at normal levels in the BAL despite drastic reductions in C3 in the circulation (> 98%) by CVF treatment. Our studies indicate that the systemic complement system is not essential for the cellular infiltration in this guinea pig model of asthma. Complement in local compartments may have an important role in inflammatory events in the lung. In addition, complement system depletion and/or activation may be an important determinant of the severity of a subsequent allergic reaction.
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... Springer-Verlag 1985 Immunotoxicity of Immunotherapeutic Agents Arthur G. Johnson and Jean Regal ... J Exp Med 150:15 20. Dimartino MH, Walz DT (1977) Inhibition of lysosomal enzyme release from rat leukocytes by auranofin.... more
... Springer-Verlag 1985 Immunotoxicity of Immunotherapeutic Agents Arthur G. Johnson and Jean Regal ... J Exp Med 150:15 20. Dimartino MH, Walz DT (1977) Inhibition of lysosomal enzyme release from rat leukocytes by auranofin. Inflammation 2:131 21. ...
Research Interests: Immunology, Immunotoxicology, Medicine, Drug, Humans, and 15 moreGold, Immunity, Immunosuppression, Immunotherapy, Clinical Sciences, Immune system, Lipopolysaccharides, Graft Rejection, Cyclophosphamide, Action Selection, Levamisole, Glucocorticoids, Azathioprine, Adverse effect, and inosine pranobex
C5a causes an intense bronchoconstriction when injected intravenously into the guinea pig. The present study was designed to determine if circulating white blood cells or platelets were important target cells for the induction of... more
C5a causes an intense bronchoconstriction when injected intravenously into the guinea pig. The present study was designed to determine if circulating white blood cells or platelets were important target cells for the induction of bronchoconstriction on intravenous injection of C5a. To accomplish this, we examined the effect of C5a on numbers of circulating cells as well as the effect of depletion of various circulating cell populations on C5a-induced bronchoconstriction. Intravenous injection of C5a caused a precipitous drop in circulating granulocytes which preceded the maximum bronchoconstrictor response. The levels of circulating platelets and mononuclear cells were unchanged by intravenous injection of C5a. Depletion of either white blood cells or platelets did not significantly alter either the maximum bronchoconstrictor response to C5a or the time course of the response. Thus, these studies suggest that C5a-induced bronchoconstriction in the guinea pig is not dependent on an interaction of C5a with circulating white blood cells or platelets.
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Research Interests: Immunology, Asthma, Medicine, Female, Animals, and 15 moreMale, Allergens, Lung, Eosinophils, Dose Response Relationship, Guinea Pig, Age Factors, Pulmonary Function, Primary Prevention, AIRWAY HYPERRESPONSIVENESS, Airway Inflammation, Experimental Group, Bronchial Hyperresponsiveness, Methacholine, and Guinea pigs
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Immunotoxicity can manifest as an exaggerated immune response to a normally innocuous substance and lead to hypersensitivity or allergic reactions in the lung. Allergens are encountered environmentally or in the workplace and can be low-... more
Immunotoxicity can manifest as an exaggerated immune response to a normally innocuous substance and lead to hypersensitivity or allergic reactions in the lung. Allergens are encountered environmentally or in the workplace and can be low- and high-molecular-weight substances. Allergic asthma and allergic rhinitis are examples of allergic reactions in the lung with immediate, late and chronic phases contributing to respiratory tract pathology. Mechanistically, allergic asthma and rhinitis reflect a combination of antibody and cell-mediated immune reactions involving IgE antibody to allergen in the early stages and Th2 cell involvement as the disease progresses to late-phase reactions and chronic allergic inflammation. Multiple cell types and mediators are involved in the inflammatory response in the lung. Mechanistic differences leading to the asthma/rhinitis phenotype have been noted with different allergens, primarily low-molecular-weight substances. Xenobiotics that are not allergens themselves may enhance the immune response to allergens or exacerbate pre-existing asthma and airway hyper-responsiveness. The complexity of the allergic response in terms of humoral and cell-mediated immunity, as well as potential differences in mechanisms depending on the allergen, present a very challenging scenario for the toxicologist to predict the exposures that will result in allergic rhinitis or asthma. Keywords: asthma; allergy; lung; rhinitis; hypersensitivity; immunotoxicology
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Previous studies had suggested that histamine and products of arachidonate metabolism were mediators of the bronchoconstriction induced in guinea pigs by the complement cleavage product C5a. The present study was conducted to further... more
Previous studies had suggested that histamine and products of arachidonate metabolism were mediators of the bronchoconstriction induced in guinea pigs by the complement cleavage product C5a. The present study was conducted to further define the arachidonate metabolite(s) involved. Tracheal airflow and transpulmonary pressure were measured in anesthetized and artificially ventilated guinea pigs and pulmonary resistance and dynamic lung compliance were calculated as a measure of bronchoconstriction. The effect of the peptido-leukotriene antagonist L-649,923 and the thromboxane synthetase inhibitor U-63557A on the C5a-induced bronchoconstriction was determined. Also, the response to C5a was evaluated in animals made tachyphylactic to the bronchoconstrictor actions of LTB4. C5a-induced bronchoconstriction was not altered in animals treated with L-649,923 or made tachyphylactic to LTB4 suggesting that LTB4 and peptido-leukotrienes are not major mediators of the response. C5a challenge caused a significant increase in plasma thromboxane B2 levels which was prevented in part by the thromboxane synthetase inhibitor U-63557A. In addition, C5a-induced bronchoconstriction was significantly inhibited by U-63557A. Thus, these studies suggest that thromboxane is the arachidonate metabolite at least in part responsible for C5a-induced bronchoconstriction.