RESUMEN
Experimental studies have reported that aerobic exercise after asthma induction reduces lung inflammation and remodeling. Nevertheless, no experimental study has analyzed whether regular/moderate aerobic training before the induction of allergic asthma may prevent these inflammatory and remodeling processes. For this purpose, BALB/c mice (n = 96) were assigned into non-trained and trained groups. Trained animals ran on a motorized treadmill at moderate intensity, 30 min/day, 3 times/week, for 8 weeks, and were further randomized into subgroups to undergo ovalbumin sensitization and challenge or receive saline using the same protocol. Aerobic training continued until the last challenge. Twenty-four hours after challenge, compared to non-trained animals, trained mice exhibited: (a) increased systolic output and left ventricular mass on echocardiography; (b) improved lung mechanics; (c) decreased smooth muscle actin expression and collagen fiber content in airways and lung parenchyma; (d) decreased transforming growth factor (TGF)-ß levels in bronchoalveolar lavage fluid (BALF) and blood; (e) increased interferon (IFN)-γ in BALF and interleukin (IL)-10 in blood; and (f) decreased IL-4 and IL-13 in BALF. In conclusion, regular/moderate aerobic training prior to allergic asthma induction reduced inflammation and remodeling, perhaps through increased IL-10 and IFN-γ in tandem with decreased Th2 cytokines.
Asunto(s)
Remodelación de las Vías Aéreas (Respiratorias) , Asma/inmunología , Citocinas/inmunología , Pulmón/inmunología , Condicionamiento Físico Animal , Animales , Asma/inducido químicamente , Líquido del Lavado Bronquioalveolar/inmunología , Inmunohistoquímica , Inflamación , Interferón gamma/inmunología , Interleucina-10/inmunología , Interleucina-13/inmunología , Interleucina-4/inmunología , Pulmón/patología , Pulmón/ultraestructura , Masculino , Ratones , Ratones Endogámicos BALB C , Microscopía Electrónica de Transmisión , Ovalbúmina/efectos adversos , Neumonía/inducido químicamente , Neumonía/inmunología , Neumonía/patología , Factor de Crecimiento Transformador beta/inmunologíaRESUMEN
BACKGROUND AND PURPOSE: Prostaglandin (PG) D(2) has emerged as a key mediator of allergic inflammatory pathologies and, particularly, PGD(2) induces leukotriene (LT) C(4) secretion from eosinophils. Here, we have characterized how PGD(2) signals to induce LTC(4) synthesis in eosinophils. EXPERIMENTAL APPROACH: Antagonists and agonists of DP(1) and DP(2) prostanoid receptors were used in a model of PGD(2) -induced eosinophilic inflammation in vivo and with PGD(2) -stimulated human eosinophils in vitro, to identify PGD(2) receptor(s) mediating LTC(4) secretion. The signalling pathways involved were also investigated. KEY RESULTS: In vivo and in vitro assays with receptor antagonists showed that PGD(2) -triggered cysteinyl-LT (cysLT) secretion depends on the activation of both DP(1) and DP(2) receptors. DP(1) and DP(2) receptor agonists elicited cysLTs production only after simultaneous activation of both receptors. In eosinophils, LTC(4) synthesis, but not LTC(4) transport/export, was activated by PGD(2) receptor stimulation, and lipid bodies (lipid droplets) were the intracellular compartments of DP(1) /DP(2) receptor-driven LTC(4) synthesis. Although not sufficient to trigger LTC(4) synthesis by itself, DP(1) receptor activation, signalling through protein kinase A, did activate the biogenesis of eosinophil lipid bodies, a process crucial for PGD(2) -induced LTC(4) synthesis. Similarly, concurrent DP(2) receptor activation used Pertussis toxin-sensitive and calcium-dependent signalling pathways to achieve effective PGD(2) -induced LTC(4) synthesis. CONCLUSIONS AND IMPLICATIONS: Based on pivotal roles of cysLTs in allergic inflammatory pathogenesis and the collaborative interaction between PGD(2) receptors described here, our data suggest that both DP(1) and DP(2) receptor antagonists might be attractive candidates for anti-allergic therapies.
Asunto(s)
Leucotrieno C4/biosíntesis , Prostaglandina D2/metabolismo , Receptores Inmunológicos/metabolismo , Receptores de Prostaglandina/metabolismo , Animales , Calcio/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Cisteína/metabolismo , Eosinófilos/metabolismo , Humanos , Leucotrienos/metabolismo , Masculino , Ratones , Toxina del Pertussis/farmacología , Antagonistas de Prostaglandina/farmacología , Receptores Inmunológicos/agonistas , Receptores Inmunológicos/antagonistas & inhibidores , Receptores de Prostaglandina/agonistas , Receptores de Prostaglandina/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacosRESUMEN
The absorption magnetic circular dichroism in EuTe was investigated as a function of the magnetic field at T = 2 K. In order to describe the optical spectra theoretically, we developed a model that takes into account the magnetic order of the lattice as a function of the magnetic field. The model allows us to calculate the absorption spectrum as a continuous function of the magnetic field intensity. The theory accounts for the strongly dichroic absorption seen at high fields, and for its continuous evolution towards the B = 0 spectrum, which is described by a much weaker and much broader absorption line. The drastic changes observed in the experimental spectra as a function of magnetic field are fully explained by the dependence of the Eu(2+) spin arrangement on the external magnetic field.
RESUMEN
BACKGROUND: Here we evaluate auto-antibody response against two potential antigenic determinants of genes highly expressed in low Gleason Score prostate cancer (PC) tumor samples, namely FLJ23438 and VAMP3. METHODS: RT-PCR assays were used to analyze mRNA expression profiles of FLJ23438 and VAMP3 transcripts. The auto-antibody response against FLJ23438 and VAMP3 recombinant proteins was tested by immunoblot assays using PC, benign prostate hyperplasia (BPH), healthy donors (HD), and other human cancers plasma samples. RESULTS: Our data showed that 37% (10/27) and 7.4% (2/27) of PC plasma samples presented auto-antibodies against FLJ23438 and VAMP3, respectively. Only 8.3% (1/12) of BPH plasma samples were reactive for both auto-antibodies, while none (0/12) of HD plasma samples tested were reactive. CONCLUSIONS: The prevalence of 37% of positive PC plasma samples for anti-FLJ23438 antibodies suggests that humoral immune response against this antigenic determinant could be a potential serum marker for this cancer.
Asunto(s)
Adenocarcinoma/inmunología , Autoanticuerpos/sangre , Biomarcadores de Tumor/inmunología , Neoplasias de la Próstata/inmunología , Proteína 3 de Membrana Asociada a Vesículas/inmunología , Adenocarcinoma/epidemiología , Adenocarcinoma/fisiopatología , Anciano , Antígenos/genética , Antígenos/inmunología , Biomarcadores de Tumor/sangre , Biomarcadores de Tumor/genética , Neoplasias de la Mama , Carcinoma de Células Escamosas , Línea Celular Tumoral , Neoplasias Colorrectales , Neoplasias Esofágicas , Regulación Neoplásica de la Expresión Génica , Humanos , Neoplasias Pulmonares , Masculino , Persona de Mediana Edad , Sistemas de Lectura Abierta/genética , Hiperplasia Prostática/epidemiología , Hiperplasia Prostática/inmunología , Hiperplasia Prostática/fisiopatología , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/fisiopatología , ARN Mensajero/genética , ARN Nuclear Pequeño/genética , ARN Nuclear Pequeño/inmunología , Proteínas Recombinantes/genética , Proteínas Recombinantes/inmunología , Estudios Seroepidemiológicos , Proteína 3 de Membrana Asociada a Vesículas/genéticaRESUMEN
Tissue eosinophilia prevention represents one of the primary targets to new anti-allergic therapies. As lipoxin A4 (LXA4) and aspirin-triggered 15-epi-LXA4 (ATL) are emerging as endogenous "stop signals" produced in distinct pathologies including some eosinophil-related pulmonary disorders, we evaluated the impact of in situ LXA4/ATL metabolically stable analogues on allergen-induced eosinophilic pleurisy in sensitized rats. LXA4/ATL analogues dramatically blocked allergic pleural eosinophil influx, while concurrently increasing circulating eosinophilia, inhibiting the earlier edema and neutrophilia associated with allergic reaction. The mechanisms underlying this LXA4/ATL-driven allergic eosinophilia blockade was independent of mast cell degranulation and involved LXA4/ATL inhibition of both IL-5 and eotaxin generation, as well as platelet activating factor action. These findings reveal LXA4/ATL as a novel class of endogenous anti-allergic mediators, capable of preventing local eosinophilia.
Asunto(s)
Alérgenos/inmunología , Antialérgicos/farmacología , Antiinflamatorios no Esteroideos/farmacología , Aspirina/administración & dosificación , Movimiento Celular/inmunología , Eosinófilos/inmunología , Ácidos Hidroxieicosatetraenoicos/farmacología , Lipoxinas , Animales , Antiinflamatorios no Esteroideos/administración & dosificación , Antiinflamatorios no Esteroideos/metabolismo , Inhibición de Migración Celular , Movimiento Celular/efectos de los fármacos , Relación Dosis-Respuesta Inmunológica , Eosinofilia/inmunología , Eosinofilia/patología , Eosinófilos/efectos de los fármacos , Femenino , Ácidos Hidroxieicosatetraenoicos/administración & dosificación , Ácidos Hidroxieicosatetraenoicos/metabolismo , Masculino , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Pleuresia/inmunología , Pleuresia/patología , Pleuresia/prevención & control , Ratas , Ratas WistarRESUMEN
In noninfected rats, challenge with allergen following local IgE sensitization induced a pleurisy marked by intense protein exudation that plateaued from 30 min to 4 h after challenge, reducing thereafter. Infection of rats with Angiostrongylus costaricensis induced a 5-fold increase in blood eosinophil numbers by 25 days postinfection, whereas the numbers of eosinophils in the pleural cavity ranged from normal to a weak increase. In infected rats, identically sensitized, challenge with Ag induced a much shorter duration of pleural edema with complete resolution by 4 h, but no change in the early edema response. In parallel, infection increased the number of eosinophils recovered from the pleural cavity at 4 h, but not at 30 min, following allergen challenge. Pretreatment with IL-5 (100 IU/kg, i.v.) also increased eosinophil numbers in blood and, after allergen challenge, shortened the duration of the pleural edema and increased pleural eosinophil numbers. There were increases in the levels of both PGE2 and lipoxin A4 (LXA4) in pleural exudate. Selective cyclooxygenase (COX)-2 inhibitors, NS-398, meloxicam, and SC-236, did not alter pleural eosinophilia, but reversed the curtailment of the edema in either infected or IL-5-pretreated rats. Pretreatment of noninfected animals with the PGE analogue, misoprostol, or two stable LXA4 analogues did not alter the magnitude of pleural exudation response, but clearly shortened its duration. These results indicate that the early resolution of allergic pleural edema observed during A. costaricensis infection coincided with a selective local eosinophilia and seemed to be mediated by COX-2-derived PGE2 and LXA4.
Asunto(s)
Angiostrongylus/inmunología , Dinoprostona/fisiología , Edema/terapia , Eosinofilia/enzimología , Ácidos Hidroxieicosatetraenoicos/fisiología , Hipersensibilidad/terapia , Isoenzimas/metabolismo , Lipoxinas , Prostaglandina-Endoperóxido Sintasas/metabolismo , Infecciones por Strongylida/enzimología , Administración Oral , Animales , Antiinflamatorios no Esteroideos/metabolismo , Antiinflamatorios no Esteroideos/farmacología , Antígenos Helmínticos/administración & dosificación , Corticosterona/sangre , Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa 2 , Inhibidores de la Ciclooxigenasa/administración & dosificación , Dinoprostona/metabolismo , Edema/enzimología , Edema/patología , Edema/fisiopatología , Eosinofilia/patología , Eosinofilia/fisiopatología , Exudados y Transudados/efectos de los fármacos , Exudados y Transudados/enzimología , Femenino , Ácidos Hidroxieicosatetraenoicos/metabolismo , Hipersensibilidad/enzimología , Hipersensibilidad/patología , Hipersensibilidad/fisiopatología , Inyecciones Intraperitoneales , Inyecciones Intravenosas , Interleucina-5/administración & dosificación , Isoenzimas/farmacología , Cinética , Leucotrieno C4/metabolismo , Masculino , Misoprostol/administración & dosificación , Derrame Pleural/enzimología , Derrame Pleural/metabolismo , Derrame Pleural/patología , Derrame Pleural/prevención & control , Pleuresia/enzimología , Pleuresia/patología , Pleuresia/fisiopatología , Prostaglandina-Endoperóxido Sintasas/farmacología , Ratas , Ratas Wistar , Infecciones por Strongylida/patología , Infecciones por Strongylida/fisiopatologíaRESUMEN
OBJECTIVE: To investigate the involvement of the fibrinogen-fibrin system in the acute reduction of the resident leukocyte population following pleural inflammation. METHODS: Sensitized and naive rats were injected intrapleurally (i.pl.) with antigen (ovalbumin) and platelet-activating factor (PAF) or bradykinin, respectively. Heparin (0.25 U/cavity), EDTA (80 microg/cavity) and hirudin (1 U/cavity) were injected locally 5 min before challenge, whereas fucoidin was injected intraperitoneally 30 min before stimulation. RESULTS: Antigen challenge led to a rapid reduction in the number of resident leukocytes 30 min post-challenge (from 7.7 +/- 0.4 x 10(6) cells/cavity to 2.3 +/- 0.2 x 106 cells/cavity, n = 6, p < 0.001). The pleural stimulation of naive rats with either PAF or bradykinin also led to a significant decrease in the pleural leukocyte population, which occurred in parallel with the formation of a fibrin meshwork containing captured cells, as attested by electron microscopy. Heparin prevented the drop in the total leukocyte numbers, without modifying either plasma leakage or histamine release at 30 min or the subsequent neutrophil and eosinophil infiltration noted 4 and 24 h post-challenge, respectively. Similarly, hirudin and EDTA prevented the antigen-induced leukocyte disappearance reaction. Heparin also impaired the drop in the pleural leukocyte numbers evoked by PAF and bradykinin. CONCLUSION: Our data show that the pleural resident cell disappearance phenomenon noted early after inflammatory provocation depends on the activation of the fibrinogen-fibrin system, and is not required for the subsequent leukocyte recruitment.
Asunto(s)
Coagulación Sanguínea/fisiología , Leucocitos/inmunología , Animales , Anticoagulantes/farmacología , Antitrombinas/farmacología , Tiempo de Sangría , Quelantes/farmacología , Ácido Edético/farmacología , Hirudinas/farmacología , Histamina/metabolismo , Recuento de Leucocitos , Leucocitos/fisiología , Masculino , Microscopía Electrónica , Pleuresia/inducido químicamente , Pleuresia/patología , Polisacáridos/farmacología , Ratas , Ratas Sprague-Dawley , Ratas Wistar , Estimulación QuímicaRESUMEN
In this study we examined the ability of the furofuran lignan yangambin to influence the local and systemic responses induced by antigen or PAF in actively sensitized or normal rats. Given intraperitoneally 1 h before stimulation, yangambin inhibited the pleural neutrophil and eosinophil infiltration evoked by the i.pl. injection of PAF or antigen into normal or 14 daysensitized rats whereas plasma exudation evoked by both stimuli was unaffected. The pleural neutrophil influx (6 h) after LTB4 stimulation was also significantly inhibited by yangambin. We also evidenced that the hemoconcentration, thrombocytopenia, and leucocytosis noted after i.v. PAF were all attenuated by yangambin. In actively sensitized rats, pretreatment with yangambin failed to modify the antigen-induced hemoconcentration and leucocytosis, but dose-dependently abrogated the thrombocytopenia noted 1 h post-stimulation. In vitro, the anaphylactic contraction of longitudinal jejunal segments to antigen challenge was significantly inhibited by yangambin (10(-5)-10(-4) M). Likewise, the contraction of jejunal segments from normal rats to PAF was markedly blocked by yangambin under conditions where the response to 5-hydroxytryptamine (5-HT) was not altered. In conclusion, our results show that antigen- and PAF-induced pleural neutrophil and eosinophil accumulation, but not exudation, is sensitive to treatment with yangambin. In addition, yangambin also suppressed the pleural neutrophil infiltration triggered by LTB4 as well as the blood thrombocytopenia and intestinal anaphylaxis elicited by antigen in rats. Thus, our findings indicate that yangambin shows an antagonistic action on receptors other than those of PAF, i.e., LTB4, and strongly suggest that it may be a useful drug in the treatment of some allergic inflammatory responses.
Asunto(s)
Antialérgicos , Eosinófilos/fisiología , Furanos/farmacología , Lignanos/farmacología , Neutrófilos/fisiología , Factor de Activación Plaquetaria/antagonistas & inhibidores , Animales , Eosinófilos/efectos de los fármacos , Femenino , Leucocitosis/inducido químicamente , Leucocitosis/prevención & control , Masculino , Neutrófilos/efectos de los fármacos , Extractos Vegetales , Factor de Activación Plaquetaria/toxicidad , Pleuresia/inducido químicamente , Pleuresia/inmunología , Pleuresia/prevención & control , Ratas , Ratas Wistar , Trombocitopenia/inducido químicamente , Trombocitopenia/prevención & controlRESUMEN
Previous studies have evidenced for the existence of interactive regulatory mechanisms between insulin and steroid hormones in different systems. In this study, we have investigated whether endogenous corticosteroids could be implicated in the hyporeactivity to antigen challenge observed in sensitized diabetic rats. Alloxinated rats showed a long-lasting increase in the blood glucose levels and a reduction in the number of pleural mast cells at 48 and 72 hr, but not at 24 hr after alloxan administration. In parallel, they also showed a significant elevation in the plasma levels of corticosterone together with an increase in the adrenal/body weight ratio. Antigen-evoked eosinophil accumulation appeared significantly reduced in rats pretreated with dexamethasone as well as in those rendered diabetic 72 hr after alloxan. In the same way, naive animals treated with dexamethasone also responded with a significant decrease in the number of pleural mast cells. Interestingly, when sensitized diabetic rats were pretreated with the steroid antagonist RU 38486 a reversion of the reduction in the allergen-induced eosinophil accumulation was noted. We conclude that the down-regulation of the allergic inflammatory response in diabetic rats is close-related to reduction in mast cell numbers and over expression of endogenous corticosteroids.
Asunto(s)
Corticoesteroides/fisiología , Diabetes Mellitus Experimental , Eosinofilia/inducido químicamente , Pleura/inmunología , Pleuresia/inmunología , Corticoesteroides/análisis , Glándulas Suprarrenales , Aloxano , Análisis de Varianza , Animales , Dexametasona , Masculino , Mastocitos , Ovalbúmina , Radioinmunoensayo , Ratas , Ratas WistarRESUMEN
Alloxan damages insulin-producing cells and has been used as an inducer of experimental diabetes in several animal species. In this study, administration of alloxan (40 mg/kg, i.v.) to rats was followed by a selective and time-dependent reduction in the number of pleural mast cells (50 +/- 2.2%, p < 0.01; mean +/- SEM), while mononuclear cell and eosinophil counts were not altered. As compared to naive rats, the reduction in mast cell numbers was first noted 48 h following alloxan administration and remained unaltered for at least 60 days. It is noteworthy, that the depletion in the mast cell population was not accompanied by alterations in the total amount of histamine stored per cell. Sensitized rats turned diabetic by alloxan treatment performed 72 h before challenge showed a less pronounced antigen-induced mast cell degranulation compared to nondiabetic rats. Moreover, rats injected with alloxan 72 and 48 but not 24 h before challenge, reacted to allergenic challenge with 50% reduction in the number of eosinophils recruited to the pleural cavity within 24 h. We found that the less pronounced eosinophil accumulation did not relate to an intrinsic cell locomotor abnormality since eosinophils from diabetic rats presented similar chemotactic responses to LTB4 and PAF in vitro as compared to matching controls. Insulin (3 IU/rat) restored basal levels of mast cells and reversed the subsequent inhibition of allergen-induced pleural eosinophilia, suggesting a causative relationship between these phenomena. Treatment with insulin also significantly increased the number of mast cells in the pleural cavity of naive rats (from 637 +/- 57 to 978 +/- 79 x 10(3) cells/cavity, p < 0.001). Consistently, previous depletion of mast cells by means of local treatment with compound 48/80 significantly reduced the antigen-induced eosinophil recruitment in sensitized animals. We conclude that the reduction in the pleural mast cell population noted in alloxan-treated rats could be directly implicated in the diminished pleural eosinophil influx following allergen challenge. This hyporesponsiveness is independent of an intrinsic abnormality of cell chemotaxis, but can be imitated by local mast cell depletion.
Asunto(s)
Diabetes Mellitus Experimental/complicaciones , Diabetes Mellitus Experimental/inmunología , Eosinofilia/inmunología , Mastocitos/inmunología , Pleura/inmunología , Pleuresia/inmunología , Aloxano , Animales , Recuento de Células , Quimiotaxis , Eosinofilia/etiología , Insulina/farmacología , Insulina/uso terapéutico , Masculino , Neutrófilos/inmunología , Pleura/química , Pleura/citología , Pleuresia/etiología , Ratas , Ratas WistarRESUMEN
Previous studies demonstrated that the selective inhibition of phosphodiesterase type IV suppresses antigen-induced eosinophil infiltration and also downregulates certain eosinophil functions assessed in vitro. In the current study, we compared the effect of selective inhibitors of phosphodiesterase IV with the effect of phosphodiesterase III and V inhibitors, focusing on eosinophil chemotaxis stimulated by platelet-activating factor (PAF) and leukotriene B4 in a modified Boyden chamber. The effect of beta 2-adrenoceptor agonists and forskolin as well as the analogue N6-2'-O-dibutyryladenosine 3':5'-cyclic monophosphate (Bt2 cyclic AMP) was also determined. For this purpose eosinophils were obtained by lavage of the peritoneal cavity of normal Wistar rats and purified on Percoll gradients to 85-95% purity. Our results showed that PAF and leukotriene B4 (0.001-10 microM) elicited a concentration-dependent increase in eosinophil migration with maximal responses observed at 1 microM and 0.1 microM respectively. Pre-incubation with the type IV phosphodiesterase inhibitor, rolipram (1-100 microM), suppressed the chemotactic response triggered by PAF and leukotriene B4, in association with elevation of eosinophil cyclic AMP, whereas the compounds milrinone and SK&F 94836 (type III selective) as well as zaprinast (type V selective) were ineffective. The beta 2-adrenoceptor agonists salbutamol and salmeterol (1-100 microM) did not alter the intracellular levels of cyclic AMP and also failed to inhibit the eosinophil response. Moreover, incubation of eosinophils with the adenylate cyclase activator forskolin (1-100 microM), while inducing a discrete increase in cyclic AMP, markedly inhibited PAF- and leukotriene B4-induced eosinophil chemotaxis. Eosinophils treated with a combination of individually inactive amounts of forskolin plus rolipram significantly inhibited the eosinophil migration elicited by PAF and leukotriene B4, but did not change cyclic AMP baseline levels. Though only at the highest concentration tested (100 microM), the analogue Bt2 cyclic AMP abolished the eosinophil chemotaxis. Thus we conclude that the direct inhibitory effect of phosphodiesterase IV inhibitors on eosinophil chemotaxis may account for their suppressive activity on tissue eosinophil accumulation following antigen challenge.
Asunto(s)
Quimiotaxis de Leucocito/efectos de los fármacos , Eosinófilos/inmunología , Inhibidores de Fosfodiesterasa/farmacología , Agonistas Adrenérgicos beta/farmacología , Animales , Bucladesina/farmacología , Colforsina/farmacología , AMP Cíclico/análisis , Isoenzimas/antagonistas & inhibidores , Leucotrieno B4/farmacología , Factor de Activación Plaquetaria/farmacología , Agregación Plaquetaria/efectos de los fármacos , Pirrolidinonas/farmacología , Ratas , Ratas Wistar , RolipramRESUMEN
The local effect of salbutamol and N6,2'-O-dibutyryl adenosine 3':5'-cyclic monophosphate (Bt2 cyclic AMP) on the rat pleural inflammation caused by allergen was investigated. Antigen (ovalbumin, 12 micrograms/cavity) intrathoracically administered to immunized rats led to a marked pleural protein extravasation and leukocyte infiltration, as attested by the quantification of protein and enumeration of leukocytes recovered from the pleural cavity. Salbutamol (10-40 micrograms/cavity) and the cell-permeable cyclic AMP analogue, Bt2 cyclic AMP (20-160 micrograms/cavity), injected 1 h and 5 min before the antigen, respectively, inhibited the exudation occurring within 30 min, and neutrophil and eosinophil accumulation occurring 4 and 24 h, respectively. The late eosinophilia was also markedly attenuated by salbutamol administered 10 min post-challenge, when mast cells had already been degranulated. Pretreatment with the beta-adrenoceptor antagonist propranolol (1 mg/kg, i.v.) failed to modify the inhibitory effect of Bt2 cyclic AMP, but abolished the blockade caused by salbutamol of leukocyte infiltration under conditions where the salbutamol anti-exudatory activity was impaired to about 80%. In another set of experiments, salbutamol (20 and 40 micrograms/cavity) markedly inhibited the exudation caused by histamine and 5-hydroxytryptamine (5-HT) which, though to a lesser extent, was also sensitive to Bt2 cyclic AMP (80 micrograms/cavity). As observed with allergic pleurisy, propranolol impaired the inhibition by salbutamol of histamine- and 5-HT-induced exudation, whereas the Bt2 cyclic AMP inhibition was not affected. We conclude that salbutamol and Bt2 cyclic AMP share the ability to inhibit pleural exudation and leukocyte recruitment caused by allergen in immunized rats, suggesting that the anti-inflammatory effect of salbutamol may be mediated by a cyclic AMP signaling pathway, probably via beta 2-adrenoceptor activation.
Asunto(s)
Agonistas Adrenérgicos beta/farmacología , Albuterol/farmacología , Antígenos/inmunología , Bucladesina/farmacología , Quimiotaxis de Leucocito/efectos de los fármacos , Pleuresia/prevención & control , Antagonistas Adrenérgicos beta/farmacología , Animales , AMP Cíclico/metabolismo , Femenino , Hipersensibilidad/prevención & control , Masculino , Pleuresia/etiología , Pleuresia/metabolismo , Propranolol/farmacología , Ratas , Ratas Wistar , Transducción de SeñalRESUMEN
The efficacy of cetirizine in comparison with meclizine, another piperazine H1 receptor antagonist, in rat pleurisy caused by allergen or autacoid was investigated. Sensitization was achieved by subcutaneous injection of a mixture of ovalbumin and aluminium hydroxide. Fourteen days later, the animals were challenged with an intrathoracic injection of ovalbumin (12 micrograms/cavity), which caused drastic mast cell degranulation, followed by pleural oedema and leucocyte influx. Cetirizine and meclizine (2.5-30 mg/kg i.p.), 1 h before challenge, inhibited the exudatory response evoked by antigen, under conditions where neutrophil and eosinophil accumulation was affected only by the former. When administered intrathoracically 22 h after allergen, i.e. using a curative approach, cetirizine (15 micrograms/cavity) drastically reduced the pleural eosinophilia noted 24 h post-challenge, indicating that this drug can reverse an already established eosinophilia. Cetirizine (15 mg/kg i.p.) also restored, to about 39% (P < 0.001), the number of uninjured mast cells recovered from the pleural cavity following allergen stimulation. In normal rats, cetirizine (5-15 micrograms/cavity) completely inhibited the pleural exudation elicited by histamine and only partially the exudation caused by 5-hydroxytryptamine or bradykinin, but was quite inactive against platelet-activating factor. We conclude that the pleural exudation triggered by allergen, vasoactive amines or bradykinin is clearly sensitive to cetirizine. In addition, the ability of the drug to interfere with pleural neutrophil or eosinophil mobilization and mast cell degranulation seems not to be associated with its ability to block the histamine H1 receptor.
Asunto(s)
Cetirizina/uso terapéutico , Antagonistas de los Receptores Histamínicos H1/uso terapéutico , Pleuresia/tratamiento farmacológico , Animales , Antígenos/inmunología , Bradiquinina/farmacología , Gránulos Citoplasmáticos/efectos de los fármacos , Femenino , Histamina/farmacología , Recuento de Leucocitos , Masculino , Mastocitos/efectos de los fármacos , Meclizina/farmacología , Ovalbúmina/inmunología , Factor de Activación Plaquetaria/farmacología , Pleuresia/inmunología , Ratas , Ratas Wistar , Serotonina/farmacologíaRESUMEN
The intrathoracic injection of ovalbumin (12 micrograms/cavity) into actively sensitized rats led to a long-lasting eosinophil recruitment, which appeared 24 h after stimulation. In this study, pharmacological antagonists were used in order to evaluate the potential involvement of arachidonic acid metabolites and PAF-acether in the pleural eosinophil accumulation by antigen. Administration of the cyclooxygenase inhibitor indomethacin (2 mg/kg, i.p.), 1 h before the antigen challenge, failed to modify the 24-hour eosinophilia. In contrast, the dual cyclooxygenase and lipoxygenase inhibitor BW 755C and the more selective inhibitor BW A4C (5 and 10 micrograms/cavity, i.t.), injected 1 h before the antigen, were effective. Similarly, the PAF-acether antagonists BN 52021 and WEB 2086 (20 mg/kg, i.p.) abrogated the eosinophil accumulation, which was also sensitive to the topical treatment with the glucocorticoid dexamethasone (5 and 10 micrograms/cavity). Our findings suggest that the antigen-induced eosinophil mobilization is dependent on lipoxygenase derivatives and PAF-acether, but not on prostaglandins.