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Biomedical subjects

J F Regal

Publications and source records attributed to J F Regal.

At least 19 recordsLinked to original sources
PubMed2001

Trimellitic anhydride-induced eosinophilia in a mouse model of occupational asthma.

Trimellitic anhydride (TMA) is a low-molecular-weight chemical known to cause occupational asthma. The present study was designed to determine if TMA elicited eosinophil infiltration into lungs of sensitized mice similar to previous studies with the protein allergen ovalbumin (OA). BALB/c mice were sensitized intradermally with 0.1 ml of 3% TMA or 0.3% OA in corn oil followed by intratracheal instillation with TMA conjugated to mouse serum albumin (TMA-MSA; 30 or 400 microg) or OA (30 microg). Nonsensitized mice received corn oil vehicle intradermally and MSA (30 microg) intratracheally. The allergic response was elicited 3 weeks later by intratracheal instillation of 30 or 400 microg TMA-MSA, OA, or control MSA. Cellular infiltration into bronchoalveolar lavage fluid (BAL) was determined 72 h later. Eosinophil peroxidase (EPO) and myeloperoxidase (MPO) activity in lung homogenates was used as an estimate of numbers of eosinophils and neutrophils, respectively, in lung tissue. In TMA-sensitized mice, TMA-MSA challenge significantly increased numbers of eosinophils in BAL and EPO in lung, indicating an increase in number of eosinophils in the airway and tissue. In nonsensitized mice, TMA-MSA challenge also caused a small but significant increase in eosinophils in BAL compared to MSA control. Total IgE in both plasma and BAL was significantly higher in TMA-sensitized compared to nonsensitized mice. The eosinophil infiltration in TMA-sensitized mice was similar in magnitude to the response in OA-sensitized mice. These studies are the first to demonstrate TMA-induced eosinophilia in mouse lung and to provide a model for comparing mechanisms and mediators responsible for the substantial eosinophilia induced by TMA and OA.

Allergens↗
PubMed2001

Trimellitic anhydride-induced allergic response in the guinea pig lung involves antibody-dependent and -independent complement system activation.

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.

Allergens↗
PubMed2000

Minor role of the C3a receptor in systemic anaphylaxis in the guinea pig.

Previously, Regal et al. [Regal, J.F., Fraser, D.G., Toth, C.A., 1993. Role of the complement system in antigen-induced bronchoconstriction and changes in blood pressure in the guinea pig. J. Pharmacol. Exp. Ther. 267, 979-988] demonstrated that preventing complement system activation resulted in inhibition of anaphylaxis in the guinea pig, and that the C-terminal 21 amino acids of guinea pig C3a (C3a-peptide) mimic the symptoms of anaphylactic shock in the guinea pig [Regal, J.F., 1997. Role of the complement system in pulmonary disorders. Immunopharmacology 38, 17-25]. To determine if C3a is an essential mediator of systemic anaphylaxis, the anaphylactic response to ovalbumin (OA) was assessed in guinea pigs genetically deficient in the C3a receptor (C3aR-) compared to their control strain of animals which were C3a receptor positive (C3aR+). In addition, the response to another control strain of animals, Hartley guinea pigs, was determined. Sensitized guinea pigs were anesthetized, and bronchoconstriction and changes in blood pressure were monitored in response to intravenous (i.v.) injection of either C3a-peptide, recombinant human C5a (rHuC5a) or OA. Both Hartley guinea pigs and C3aR+ animals responded similarly to C3a-peptide and rHuC5a. C3aR- animals, however, were unresponsive to C3a-peptide and responded normally to rHuC5a, confirming their functional deficiency of the C3a receptor. In response to OA, C3aR+ animals and Hartley guinea pigs responded with a severe bronchoconstriction, an initial transient hypotension, followed by an increase in blood pressure and a delayed prolonged hypotensive response. In contrast, in C3aR- animals, the increased blood pressure response to OA was significantly prolonged, the delayed hypotensive response was blunted, and the bronchoconstriction was delayed compared to the C3aR+ animals. The difference in the anaphylactic response could not be explained by differing amounts of OA-specific IgG1 antibody or C3a generated during the anaphylactic response. Thus, these data suggest that C3a plays a minor role in the hypotension of systemic anaphylaxis and investigation of a role for other products of complement system activation, either alone or in combination with C3a, is clearly warranted.

Anaphylaxis↗
PubMed2000

Dietary phytoestrogens have anti-inflammatory activity in a guinea pig model of asthma.

Phytoestrogens are a normal constituent of soy protein and have been shown to have anti-inflammatory activity in various in vitro and in vivo models. The present study was designed to determine if a diet enriched in the phytoestrogen isoflavones, genistin and daidzin, would alter the antigen-induced cellular infiltration, particularly eosinophilia, characteristic of a guinea pig model of asthma. Throughout the duration of the study, guinea pigs were maintained on a control diet (standard guinea pig chow) or the same diet enriched in isoflavones. The animals were placed on the diet 2 weeks prior to active sensitization with ovalbumin (OA). Three weeks after sensitization, animals were challenged with OA aerosol. The cellular infiltration into the lung and protein and red blood cells (RBC) in the bronchoalveolar lavage fluid (BAL) were determined 17 hr later. In animals maintained on the control diet, OA aerosol challenge resulted in the expected increase in eosinophils in both the BAL and the lung tissue, an increase in neutrophils in the BAL, and an increase in protein and the number of RBC in the BAL. In contrast, in animals maintained on the isoflavone diet, the OA-induced eosinophilia in the lung tissue was significantly attenuated. In addition, OA challenge caused a greater increase in BAL protein in animals maintained on the isoflavone diet compared with animals on the control diet. Our results indicated that a diet enriched in isoflavones results in reduced antigen-induced eosinophilia in the lung in the guinea pig model of asthma. However, this beneficial anti-inflammatory effect of dietary phytoestrogens is accompanied by a potentially detrimental increase in antigen-induced leakage of protein into the airspace.

Aerosols↗
PubMed1998

The role of IgG1 and IgG2 in trimellitic anhydride-induced allergic response in the guinea pig lung.

Trimellitic anhydride (TMA) is a small molecular weight chemical used in the paint and plastics industry that can cause asthma-like symptoms in humans. Guinea pigs sensitized intradermally with TMA will respond to antigen challenge with asthma-like symptoms, including an immediate bronchoconstriction and a delayed cellular infiltration into the lung, particularly eosinophil infiltration. Sensitized guinea pigs produce TMA-specific IgG1, which is thought to be important in asthmatic reactions in this animal model; however, they also produce TMA-specific IgG2 antibody. The purpose of the present study was to determine the role of IgG1 and IgG2 in the TMA-induced immediate bronchoconstriction and delayed cellular infiltration in the guinea pig. Guinea pigs were passively sensitized by intratracheal instillation of TMA-specific IgG2, an antibody preparation enriched with TMA-specific IgG1, or a combination of the two. The allergic response was induced by intratracheal instillation of TMA conjugated to guinea pig serum albumin (TMA-GPSA). A significantly greater bronchoconstrictor response was observed in animals sensitized with a combination of the IgG2 and IgG1 preparation compared to those sensitized with IgG2 or the IgG1 preparation alone. Cellular infiltration was quantified 24 h after antigen challenge by differential cell counts of bronchoalveolar lavage (BAL) cells as well as by using eosinophil peroxidase (EPO) and myeloperoxidase (MPO) activity as a measure of the numbers of eosinophils and neutrophils, respectively. In the BAL, passively sensitizing with IgG2 alone resulted in an increase in both TMA-induced MPO and EPO activity. In contrast, in the lung, passively sensitizing with a partially purified preparation of TMA-specific IgG1 alone resulted in a significant increase in TMA-induced EPO activity. Passively sensitizing with IgG2 in conjunction with the IgG1 preparation resulted in an enhanced cellular infiltration and lung injury over that seen with either antibody preparation alone. These data demonstrate an augmentation of IgG1-mediated responses by the addition of IgG2 and suggest a significant role for both subclasses of IgG antibodies in this guinea pig model of TMA-induced occupational asthma.

Aged↗
PubMed1997

Role of the complement system in pulmonary disorders.

Immune injury in the lung is classically divided into types I-IV hypersensitivity, with the complement system being involved in types II and III hypersensitivity. Anaphylaxis and asthma are generally considered prototypes of type I hypersensitivity and hypersensitivity pneumonitis as an example of type III hypersensitivity in the lung. However, in asthma, for example, increasing evidence indicates that in addition to mast cells, T lymphocytes play an important role. Therefore, considering asthma as strictly a type I mediated reaction is too simplistic. This report will review the evidence regarding the involvement of the complement system and complement activation products in anaphylaxis, asthma and immune complex disease in various experimental models of pulmonary disease. Identification of the mediators responsible for the symptoms may suggest rational targets for the continued development of effective therapy to combat immune injury in the lung.

Anaphylatoxins↗
PubMed1996

Systemic complement system depletion does not inhibit cellular accumulation in antihistamine pretreated allergic guinea pig lung.

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.

Adjuvants, Immunologic↗
PubMed1995

Trimellitic anhydride-induced allergic response in the lung: role of the complement system in cellular changes.

Trimellitic anhydride (TMA) is a small molecular weight industrial compound that will cause asthma-like symptoms in humans. Some of these TMA-induced symptoms can be reproduced in the guinea pig. In the guinea pig model of TMA-induced asthma, intratracheal instillation of TMA coupled to guinea pig serum albumin causes an immediate bronchoconstriction and increase in airway microvascular leakage with concomitant decrease in circulating platelets and white blood cells and subsequent cellular infiltration of mononuclear cells, neutrophils and eosinophils into the bronchoalveolar lavage fluid. In addition, in the lung tissue an increase in eosinophil peroxidase activity (a measure of eosinophil numbers) occurs. The purpose of this study was to determine whether complement system activation was essential for any of these TMA-induced events. Guinea pigs pretreated with cobra venom factor (CVF) had significantly reduced amounts of complement component C3 in the lavage fluid 24 hours after TMA conjugated to guinea pig serum albumin challenge indicating that the CVF treatment was successful in depleting complement proteins. Pretreatment with CVF did not affect the immediate TMA-induced bronchoconstriction nor the TMA-induced microvascular leakage. In animals depleted of the complement system by pretreatment with CVF the TMA-induced increase in mononuclear cells, total white blood cells, red blood cells, and EPO activity in the bronchoalveolar lavage was significantly reduced. Thus, our results suggest that in the guinea pig, the complement system is an important source of mediators for cellular infiltration into the lung after exposure to this acid anhydride and that inhibiting complement activation may be useful in preventing the inflammatory cell infiltration in TMA-induced asthma.

Allergens↗
PubMed1993

Enhancement of antigen-induced bronchoconstriction after intravascular complement activation with cobra venom factor. Reversal by granulocyte depletion.

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.

Animals↗
PubMed1993

Role of the complement system in antigen-induced bronchoconstriction and changes in blood pressure in the guinea pig.

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.

Animals↗
PubMed1991

Reduced anaphylactic responsiveness of strain 2 guinea pigs.

Strain 2 guinea pigs have been shown to have diminished anaphylactic responsiveness. In the present study, experiments were conducted comparing various characteristics of the anaphylaxis-resistant Strain 2 guinea pigs to those of an outbred anaphylaxis-prone Dunkin-Hartley strain. To bypass the possibility that differences in antibody titers accounted for the difference in anaphylactic reactivity, both strains of guinea pig were passively sensitized with the same amount of IgG antibody to ovalbumin. Measures of anaphylactic responsiveness to subsequent antigen challenge with ovalbumin included (i) systemically induced respiratory responses; (ii) isolated cardiac responses; and (iii) cutaneous responses. In all cases, using an amount of antibody sufficient to sensitize Dunkin-Hartley guinea pigs, the anaphylactic responses of the Strain 2 guinea pigs were either nonexistent or significantly less than those of the Dunkin-Hartley strain. To further determine which factors might be responsible for this difference, tissue histamine content, histamine releasability, and histamine responsiveness of the two strains were measured. The results of these studies indicated that the respiratory hyporesponsiveness of the Strain 2 guinea pigs may be due to a low pulmonary histamine content combined with reduced pulmonary responsiveness to histamine. However, since the cardiac histamine content and the responsiveness of the Strain 2 guinea pigs were not different from those of the Dunkin-Hartley strain, these factors cannot contribute to the reduced Strain 2 cardiac anaphylactic responsiveness. Compound 48/80 released equal quantities of histamine from the isolated hearts of the Strain 2 and the Dunkin-Hartley animals, but antigen challenge evoked histamine release only from the isolated Dunkin-Hartley hearts. We conclude that the cardiac anaphylactic hyporesponsiveness of the Strain 2 guinea pigs may be due to an inability of antigen to evoke release of anaphylactic mediators such as histamine.

Anaphylaxis↗
PubMed1991

Recombinant human C5a-induced bronchoconstriction in the guinea pig: inhibition by an H1 antagonist after depletion of circulating granulocytes and platelets.

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)

Animals↗
PubMed1990

Recombinant human C5a-induced bronchoconstriction in the guinea-pig: a histamine independent mechanism.

Recombinant human C5a (rHuC5a), produced by a synthetic gene expressed in Escherichia coli, causes a decrease in dynamic lung compliance and an increase in pulmonary resistance when injected intravenously in anesthetized mechanically ventilated guinea pigs over a dose range of 5-20 micrograms/kg. Intravenous injection of rHuC5a also caused an immediate decrease in mean arterial blood pressure followed by a transient increase. The purpose of this study was to determine the mediators responsible for these effects. To assess the role of histamine, plasma levels of histamine were monitored and the effects of the H1 antagonist pyrilamine were assessed. rHuC5a caused a significant increase in plasma histamine. However, the H1 antagonist did not alter the maximum or the time course of the bronchoconstrictor response indicating that histamine did not play a major role. The LTD4 antagonist L-649,923 did not inhibit the rHuC5a-induced bronchoconstriction whereas the cyclo-oxygenase inhibitor indomethacin did. Thus, to assess the role of cyclo-oxygenase products, plasma levels of thromboxane (TX) B2, prostaglandin (PG) D2 and PGF2 alpha were monitored after injection of rHuC5a. In addition, guinea pigs were treated with either the TX synthetase inhibitor U-63557A or with the TX receptor antagonist SQ 29,548. rHuC5a challenge caused an increase in plasma concentrations of TXB2, PGD2 and PGF2 alpha which peaked before the maximum of the bronchoconstriction. SQ 29,548 significantly inhibited the maximum of the bronchoconstrictor response, whereas U-63557A did not inhibit the maximum but did inhibit the time course of the response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Enhancement of antigen-induced bronchoconstriction in the guinea pig after intravascular complement activation with cobra venom factor.

The purpose of the present studies was to begin to test the hypothesis that the complement system is important for antigen-induced bronchoconstriction in the guinea pig. The effect of the complement-depleting agent cobra venom factor (CVF) on antigen-induced bronchoconstriction in guinea pigs passively sensitized with IgG or IgE antibody to ovalbumin was determined. Intravenous injection of CVF significantly reduced total hemolytic complement activity (CH50), caused a transient decrease in dynamic lung compliance, an increase in pulmonary resistance, and a decrease in circulating white blood cells with a sustained decrease in platelets. Antigen-induced bronchoconstriction was not inhibited in either IgG- or IgE-sensitized guinea pigs depleted of complement. Thus, a role for the complement system as a contributing factor in antigen-induced bronchoconstriction was not supported. On the contrary, our studies revealed an enhanced antigen-induced bronchoconstriction in guinea pigs depleted of complement with CVF. Our studies were then directed towards characterizing the enhanced response to begin to determine the mechanism responsible. The enhanced antigen-induced bronchoconstriction occurred in both IgG- and IgE-sensitized guinea pigs and was most apparent at lower antigen doses. The enhanced response still occurred in animals treated for 5 min with a dose of CVF (10 U) which caused no demonstrable decrease in CH50, a 30% level of conversion of C3, and a normal response to C5a. These data suggested that the enhanced response was not related to the level of C5a responsiveness of the animal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Immunologic↗
PubMed1989

The role of C5a in hypersensitivity reactions in the lung.

What role the complement system in general, and C5a in particular play in hypersensitivity reactions in the lung is unknown. A review of the available studies indicates that C5a can mimic hypersensitivity reactions in the lung by virtue of its ability to cause cell infiltration and edema in the lung, cause a short lived airway hyperreactivity and cause bronchoconstriction. Its ability to cause contraction of isolated airways and in vivo bronchoconstriction in the guinea-pig is due to the release of histamine and arachidonate metabolites, mediator systems similar to those evoked by antigen-antibody reactions in the guinea-pig lung. To begin to determine if C5a generation with complement system activation was an important contributor to antigen-induced bronchoconstriction, the response to antigen was assessed in animals depleted of complement by cobra venom factor and unresponsive to C5a. Unexpectedly, these animals responded to antigen with a much greater bronchoconstriction than did animals with an intact complement system. This suggested that an intact complement system was somehow important in limiting allergic bronchoconstriction or conversely that allergic bronchoconstriction might be heightened when preceded by complement system activation. Thus, the data implicates C5a and/or complement system activation as a modulator of antigen-induced bronchoconstriction rather than directly contributing to the bronchoconstrictor component of hypersensitivity reactions in the lung.

Animals↗
PubMed1989

Role of adenosine in hypoxic alterations of anaphylaxis of isolated guinea pig hearts.

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.

Adenosine↗
PubMed1988

C5a-induced bronchoconstriction: absence of a role of circulating white blood cells and platelets.

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.

Airway Resistance↗