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1.
Br J Anaesth ; 116(2): 277-81, 2016 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-26787798

RESUMEN

BACKGROUND: Local anaesthetics are commonly delivered to the epidural space by either intermittent bolus or continuous infusion. While these methods have been investigated in terms of analgesia and total dose administered, they have not been compared in terms of their effect on the spread of injectate within the epidural space. This animal study compared the spread of dye delivered to the epidural space in a porcine model by either bolus or infusion. METHODS: After ethical approval, epidural catheters were placed at three vertebral levels in seven anaesthetized pigs. Aqueous dye (1 ml) was injected into the catheter as a bolus, or as an infusion over 30 min. Animals were euthanized at the end of the study and necropsy performed immediately to quantify the extent of dye spread. RESULTS: In seven animals, 20 catheters were successfully placed in the epidural space. The mean (sd) extent of dye spread was 8.9 (2.6) cm in the infusion group compared with 15.2 (2.7) cm in the bolus group (P<0.001). Segmental spread was significantly greater in the bolus group compared with the infusion group (P<0.01). CONCLUSION: In the porcine epidural model, spread of one ml of epidural dye solution is more extensive after a single bolus compared with short term infusion.


Asunto(s)
Colorantes/farmacocinética , Infusiones Parenterales/métodos , Inyecciones Espinales/métodos , Animales , Espacio Epidural , Inyecciones Epidurales , Modelos Animales , Porcinos
2.
Clin Exp Allergy ; 41(6): 801-10, 2011 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-21255140

RESUMEN

Background Secreted phospholipase A(2) (sPLA(2) ) may be important mediators of asthma, but the specific sPLA(2) s involved in asthma are not known. Objective To evaluate sPLA(2) group IIA, V, and X proteins (sPLA(2) -IIA, sPLA(2) -V, and sPLA(2) -X) in bronchoalveolar lavage (BAL) fluid, BAL cells, and airway epithelial cells of subjects with and without asthma, and examine the relationship between the levels of specific sPLA(2) enzymes and airway inflammation, asthma severity, and lung function. Methods The expression of sPLA(2) -IIA, sPLA(2) -V, and sPLA(2) -X in BAL cells and epithelial brushings was assessed by qPCR. The levels of these sPLA(2) proteins and sPLA(2) activity with and without group II and group X-specific inhibitors were measured in BAL fluid from 18 controls and 39 asthmatics. Results The airway epithelium expressed sPLA(2) -X at higher levels than either sPLA(2) -IIA or sPLA(2) -V, whereas BAL cells expressed sPLA(2) -IIA and sPLA(2) -X at similar levels. The majority of sPLA(2) activity in BAL fluid was attributed to either sPLA(2) -IIA or sPLA(2) -X. After 10-fold concentration of BAL fluid, the levels of sPLA(2) -X normalized to total protein were increased in asthma and were associated with lung function, the concentration of induced sputum neutrophils, and prostaglandin E(2) . The levels of sPLA(2) -IIA were elevated in asthma when normalized to total protein, but were not related to lung function, markers of airway inflammation or eicosanoid formation. Conclusions and Clinical Relevance These data indicate that sPLA(2) -IIA and sPLA(2) -X are the major sPLA(2) s in human airways, and suggest a link between the levels of sPLA(2) -X in the airways and several features of asthma.


Asunto(s)
Asma/enzimología , Fosfolipasas A2 Grupo II/metabolismo , Fosfolipasas A2 Grupo X/metabolismo , Sistema Respiratorio/enzimología , Adulto , Asma/inmunología , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , Activación Enzimática/inmunología , Femenino , Regulación Enzimológica de la Expresión Génica/inmunología , Humanos , Masculino , Persona de Mediana Edad , Mucosa Respiratoria/metabolismo , Sistema Respiratorio/inmunología , Infecciones del Sistema Respiratorio/enzimología , Infecciones del Sistema Respiratorio/inmunología
3.
Clin Exp Allergy ; 38(12): 1959-68, 2008 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-19037968

RESUMEN

BACKGROUND: Increased levels of serum IgE are associated with greater asthma prevalence and disease severity. IgE depletion using an anti-IgE monoclonal antibody has met with success in the treatment of moderate-to-severe and severe persistent allergic asthma. OBJECTIVE: To test whether B cell-targeted therapy is a more effective treatment for airway hyperresponsiveness (AHR) in a murine model compared with IgE-depletion. METHODS: We delivered soluble mTACI-Ig, a receptor for the B cell survival factors BLyS (B Lymphocyte Stimulator) and APRIL (A PRoliferation-Inducing Ligand), or anti-IgE to allergen-sensitized mice before airway challenge with allergen. RESULTS: mTACI-Ig treatment reduced circulating mature B cell levels in the blood, while anti-IgE treatment had no effect on B cell counts. Both mTACI-Ig and anti-IgE decreased the levels of total and allergen-specific IgE in the serum. Histopathologic analysis of lungs showed a reduction in disease severity scores for both treatment groups, but results were more pronounced in mTACI-Ig-treated mice. Neutrophil and eosinophil numbers in the bronchoalveolar lavage (BAL) were significantly reduced following mTACI-Ig treatment, but not after anti-IgE delivery. BLyS and APRIL blockade also resulted in a significant decrease in IL-4 and eotaxin mRNA and IL-4 and KC protein levels in total lung homogenates and BAL fluid, respectively. Finally, mTACI-Ig treatment was more effective than anti-IgE treatment in reducing AHR to inhaled antigen. CONCLUSIONS: Our data demonstrate that delivery of mTACI-Ig is a more effective treatment than anti-IgE mAb in a murine model of AHR.


Asunto(s)
Asma/prevención & control , Proteínas Recombinantes de Fusión/uso terapéutico , Alérgenos/efectos adversos , Animales , Anticuerpos Monoclonales/administración & dosificación , Anticuerpos Monoclonales/uso terapéutico , Asma/sangre , Asma/etiología , Asma/inmunología , Factor Activador de Células B/genética , Linfocitos B/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Quimiocinas/genética , Quimiocinas/metabolismo , Modelos Animales de Enfermedad , Eosinófilos/inmunología , Inmunoglobulina E/sangre , Inmunoglobulina E/inmunología , Inflamación/patología , Inyecciones Intraperitoneales , Interleucina-4/genética , Interleucina-4/metabolismo , Pulmón/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Neutrófilos/inmunología , Ovalbúmina/efectos adversos , ARN Mensajero/genética , Proteínas Recombinantes de Fusión/administración & dosificación , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética
4.
Allergy ; 63(8): 953-61, 2008 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-18691297

RESUMEN

Exercise-induced (EI) hypersensitivity disorders are significant problems for both recreational and competitive athletes. These include EI-asthma, EI-bronchoconstriction, EI-rhinitis, EI-anaphylaxis and EI-urticaria. A group of experts from the European Academy of Allergology and Clinical Immunology and the American Academy of Allergy Asthma and Immunology met to discuss the pathogenesis of these disorders and how to diagnose and treat them, and then to develop a consensus report. Key words (exercise with asthma, bronchoconstriction, rhinitis, urticaria or anaphylaxis) were used to search Medline, the Cochrane database and related websites through February 2008 to obtain pertinent information which, along with personal reference databases and institutional experience with these disorders, were used to develop this report. The goal is to provide physicians with guidance in the diagnosis, understanding and management of EI-hypersensitivity disorders to enable their patients to safely return to exercise-related activities.


Asunto(s)
Ejercicio Físico , Hipersensibilidad/etiología , Anafilaxia/etiología , Asma Inducida por Ejercicio/etiología , Humanos , Hipersensibilidad/diagnóstico , Hipersensibilidad/terapia , Rinitis/etiología , Síndrome , Urticaria/etiología
5.
Eur Respir J ; 24(1): 107-15, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15293612

RESUMEN

Lung expression of the extracellular matrix protein, laminin, and its receptor, laminin-1 receptor, were examined in a mouse model of asthma with airway remodelling. Ovalbumin (OVA) was administered to BALB/c mice, intraperitoneally on days 0 and 14, and intranasally periodically between days 14 and 75. The mice developed airway eosinophil and mononuclear inflammatory cell infiltration and fibrosis. On day 76, a marked increase in total laminin was seen in the airways of OVA-treated mice compared to controls by Western blot analysis. The increased laminin expression was detected immunocytochemically in the thickened subepithelial basement membrane and around airways and blood vessels. The OVA-treated mice showed increased expression of the alpha1, beta1, and gamma1 chains of the laminin-1 isoform in monocytes, macrophages and eosinophils infiltrating the airways. Laminin-1 receptor expression was increased in inflammatory and endothelial cells in the lungs of OVA-treated mice compared to controls. Treatment of OVA-sensitised/challenged mice with dexamethasone reduced airway expression of laminin and laminin-1 receptor in OVA-treated mice but not airway hyperresponsiveness to methacholine. Laminin deposition may be an important component of the airway remodelling observed in chronic allergic lung inflammation and is a process modulated by corticosteroids.


Asunto(s)
Asma/inmunología , Hiperreactividad Bronquial/inmunología , Dexametasona/farmacología , Eosinofilia/tratamiento farmacológico , Receptores de Laminina/inmunología , Receptores de Laminina/metabolismo , Resistencia de las Vías Respiratorias/efectos de los fármacos , Animales , Asma/metabolismo , Biomarcadores/análisis , Biopsia con Aguja , Western Blotting , Hiperreactividad Bronquial/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Eosinofilia/diagnóstico , Femenino , Inmunohistoquímica , Ratones , Ratones Endogámicos BALB C , Factores de Riesgo , Sensibilidad y Especificidad
6.
J Immunol ; 165(8): 4640-8, 2000 Oct 15.
Artículo en Inglés | MEDLINE | ID: mdl-11035107

RESUMEN

Leukotrienes are important mediators of the eosinophilic influx and mucus hypersecretion in the lungs in a murine model of asthma. We used in situ PCR in this model of human asthma to detect lung mRNA for 5-lipoxygenase (5-LO) and 5-LO-activating protein (FLAP), key proteins necessary for leukotriene synthesis. Lung tissue was obtained on day 28 from mice treated with i.p. (days 0 and 14) and intranasal (days 14, 25, 26, and 27) OVA or saline. After fixation, the tissue sections underwent protease- and RNase-free DNase digestion, before in situ RT-PCR using target-specific cDNA amplification. 5-LO and FLAP-specific mRNA was visualized by a digoxigenin detection system, and positive cells were analyzed by morphometry. 5-LO and FLAP-specific mRNA and protein were associated primarily with eosinophils and alveolar macrophages in the airways and pulmonary blood vessels in OVA-sensitized/challenged mice. 5-LO and FLAP protein expression increased on a per-cell basis in alveolar macrophages of OVA-treated mice compared with saline controls. Pulmonary blood vessel endothelial cells were also positive for 5-LO, FLAP mRNA, and protein. 5-LO inhibition significantly decreased 5-LO and FLAP-specific mRNA and protein expression in the lung inflammatory cells and endothelial cells. These studies demonstrate a marked increase in key 5-LO pathway proteins in the allergic lung inflammatory response and an important immunomodulatory effect of leukotriene blockade to decrease 5-LO and FLAP gene expression.


Asunto(s)
Araquidonato 5-Lipooxigenasa/genética , Proteínas Portadoras/genética , Antagonistas de Leucotrieno , Inhibidores de la Lipooxigenasa , Pulmón/enzimología , Pulmón/patología , Proteínas de la Membrana/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Proteínas Activadoras de la 5-Lipooxigenasa , Animales , Araquidonato 5-Lipooxigenasa/biosíntesis , Asma/enzimología , Asma/metabolismo , Asma/patología , Proteínas Portadoras/biosíntesis , Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Endotelio Vascular/patología , Femenino , Humanos , Inyecciones Intraperitoneales , Pulmón/metabolismo , Macrófagos Alveolares/enzimología , Macrófagos Alveolares/metabolismo , Proteínas de la Membrana/biosíntesis , Ratones , Ratones Endogámicos BALB C , Especificidad de Órganos/genética , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , ARN Mensajero/biosíntesis , ARN Mensajero/metabolismo
7.
Am J Respir Crit Care Med ; 162(2 Pt 1): 523-7, 2000 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-10934081

RESUMEN

Platelet-activating factor (PAF) is a potent lipid mediator associated with key features of asthma such as airway constriction, eosinophil infiltration, edema, and mucus accumulation. Regulation of PAF occurs primarily through degradation to biologically inactive lyso-PAF by cellular and secreted PAF-acetylhydrolase (PAF-AH). We evaluated the effect of human recombinant PAF-AH (rPAF-AH) on the dual phase asthmatic response in atopic subjects with mild asthma. Effects on induced sputum cell counts and differentials, eosinophilic cationic protein (ECP), and tryptase were evaluated. Enrolled subjects demonstrated a positive skin test and a dual asthmatic response to allergen inhalation challenge. Fourteen subjects received rPAF-AH (1 mg/kg) or placebo intravenously in a randomized, double blind, placebo-controlled, two-period crossover study. Treatment with rPAF-AH did not significantly reduce either the early- or late-asthmatic response. Sputum eosinophil cell counts were not affected by treatment, but there was a trend toward a reduction in sputum neutrophils. No significant change in sputum ECP and tryptase was observed between rPAF-AH and placebo. Thus, at the dose studied, the unique anti-PAF agent rPAF-AH demonstrated no significant effect on the allergen-induced dual-phase asthmatic response.


Asunto(s)
Asma/tratamiento farmacológico , Fosfolipasas A/uso terapéutico , Factor de Activación Plaquetaria/metabolismo , 1-Alquil-2-acetilglicerofosfocolina Esterasa , Alérgenos , Asma/etiología , Asma/fisiopatología , Estudios Cruzados , Método Doble Ciego , Humanos , Inyecciones Intravenosas , Fosfolipasas A/administración & dosificación , Fosfolipasas A/farmacología , Proteínas Recombinantes/administración & dosificación , Proteínas Recombinantes/farmacología , Proteínas Recombinantes/uso terapéutico
8.
J Immunol ; 164(6): 3360-7, 2000 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-10706731

RESUMEN

Numerous in vitro and in vivo studies in both animal models and human asthmatics have implicated platelet-activating factor (PAF) as an important inflammatory mediator in asthma. In a murine asthma model, we examined the anti-inflammatory activities of recombinant human PAF-acetylhydrolase (rPAF-AH), which converts PAF to biologically inactive lyso-PAF. In this model, mice sensitized to OVA by i.p. and intranasal (i.n.) routes are challenged with the allergen by i.n. administration. The OVA challenge elicits an eosinophil infiltration into the lungs with widespread mucus occlusion of the airways and results in bronchial hyperreactivity. The administration of rPAF-AH had a marked effect on late-phase pulmonary inflammation, which included a significant reduction in airway eosinophil infiltration, mucus hypersecretion, and airway hyperreactivity in response to methacholine challenge. These studies demonstrate that elevating plasma levels of PAF-AH through the administration of rPAF-AH is effective in blocking the late-phase pulmonary inflammation that occurs in this murine allergen-challenge asthma model. These results suggest that rPAF-AH may have therapeutic effects in patients with allergic airway inflammation.


Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Asma/prevención & control , Hiperreactividad Bronquial/prevención & control , Pulmón/patología , Fosfolipasas A/farmacología , Proteínas Recombinantes/farmacología , 1-Alquil-2-acetilglicerofosfocolina Esterasa , Alérgenos/administración & dosificación , Alérgenos/inmunología , Animales , Asma/enzimología , Asma/inmunología , Asma/patología , Hiperreactividad Bronquial/enzimología , Hiperreactividad Bronquial/inmunología , Hiperreactividad Bronquial/patología , Líquido del Lavado Bronquioalveolar/química , Movimiento Celular/efectos de los fármacos , Movimiento Celular/inmunología , Modelos Animales de Enfermedad , Eosinófilos/efectos de los fármacos , Eosinófilos/inmunología , Femenino , Humanos , Interleucina-5/metabolismo , Pulmón/efectos de los fármacos , Pulmón/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Cloruro de Metacolina/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Moco/efectos de los fármacos , Moco/metabolismo , Fosfolipasas A/sangre , Fosfolipasas A/inmunología , Factor de Activación Plaquetaria/inmunología , Proteínas Recombinantes/sangre , Proteínas Recombinantes/inmunología
9.
J Immunol ; 164(2): 1086-95, 2000 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-10623860

RESUMEN

In vitro and in vivo studies, in both animal models and human asthmatics, have implicated IL-4 as an important inflammatory mediator in asthma. In a murine asthma model, we examined the anti-inflammatory activities of soluble IL-4R (sIL-4R). In this model, mice sensitized to OVA by i.p. and intranasal (i.n.) routes are challenged with the allergen by i.n. administration. The OVA challenge elicits an eosinophil infiltration into the lungs, with widespread mucus occlusion of the airways, and results in bronchial hyperreactivity. sIL-4R (0.1-100 microgram) was administered by either i.n. or i.p. routes before OVA challenge in OVA-sensitized mice. Both blood and bronchoalveolar lavage fluid levels of sIL-4R were significantly elevated compared with controls by i.n. delivery of 100 microgram sIL-4R; i.p. delivery of 100 microgram sIL-4R only raised blood levels of sIL-4R. The i.n. administration of 100 microgram sIL-4R before allergen challenge significantly reduced late phase pulmonary inflammation, blocking airway eosinophil infiltration, VCAM-1 expression, and mucus hypersecretion. In contrast, i.p. delivery of 100 microgram sIL-4R inhibited only the influx of eosinophils into the lungs, but not airway mucus release. Furthermore, sIL-4R treatment by either i.n. or i.p. routes did not reduce airway hyperreactivity in response to methacholine challenge. Thus, elevating airway levels of sIL-4R through the administration of exogenous sIL-4R is effective in blocking the late phase pulmonary inflammation that occurs in this murine allergen-challenge asthma model. These results suggest that sIL-4R may have beneficial anti-inflammatory effects in asthmatic patients.


Asunto(s)
Alérgenos/administración & dosificación , Asma/patología , Asma/prevención & control , Pulmón/inmunología , Pulmón/patología , Receptores de Interleucina-4/metabolismo , Administración Intranasal , Animales , Asma/sangre , Asma/inmunología , Hiperreactividad Bronquial/inducido químicamente , Hiperreactividad Bronquial/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Movimiento Celular/inmunología , Modelos Animales de Enfermedad , Eosinófilos/patología , Femenino , Humanos , Inmunoglobulina E/sangre , Inyecciones Intraperitoneales , Leucocitos Mononucleares/patología , Pulmón/metabolismo , Cloruro de Metacolina , Ratones , Ratones Endogámicos BALB C , Moco/inmunología , Ovalbúmina/administración & dosificación , Ovalbúmina/inmunología , Receptores de Interleucina-4/administración & dosificación , Receptores de Interleucina-4/sangre , Solubilidad
10.
J Appl Physiol (1985) ; 84(4): 1185-9, 1998 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-9516183

RESUMEN

The extreme thinness of the pulmonary blood-gas barrier results in high mechanical stresses in the capillary wall when the capillary pressure rises during exercise. We have previously shown that, in elite cyclists, 6-8 min of maximal exercise increase blood-gas barrier permeability and result in higher concentrations of red blood cells, total protein, and leukotriene B4 in bronchoalveolar lavage (BAL) fluid compared with results in sedentary controls. To test the hypothesis that stress failure of the barrier only occurs at the highest level of exercise, we performed BAL in six healthy athletes after 1 h of exercise at 77% of maximal O2 consumption. Controls were eight normal nonathletes who did not exercise before BAL. In contrast with our previous study, we did not find higher concentrations of red blood cells, total protein, and leukotriene B4 in the exercising athletes compared with control subjects. However, higher concentrations of surfactant apoprotein A and a higher surfactant apoprotein A-to-phospholipid ratio were observed in the athletes performing prolonged exercise, compared with both the controls and the athletes from our previous study. These results suggest that, in elite athletes, the integrity of the blood-gas barrier is altered only at extreme levels of exercise.


Asunto(s)
Barrera Alveolocapilar/fisiología , Ejercicio Físico/fisiología , Pulmón/fisiología , Aptitud Física/fisiología , Adulto , Líquido del Lavado Bronquioalveolar , Broncoscopía , Eicosanoides/sangre , Recuento de Eritrocitos , Femenino , Humanos , Masculino , Consumo de Oxígeno/fisiología , Proteínas/metabolismo
11.
J Infect Dis ; 177(5): 1437-43, 1998 May.
Artículo en Inglés | MEDLINE | ID: mdl-9593043

RESUMEN

Mast cells participate in the host defense against parasites. Mast cells release leukotrienes (LTs), potent 5-lipoxygenase (LO) products of arachidonic acid well-known to be involved in the inflammatory process. After incubation with Toxoplasma gondii, mast cells were found to degranulate and release LTB4; this interaction damages the tachyzoites. This mast cell activity against the tachyzoites was inhibited by the 5-LO inhibitor A-63162 and the 5-LO-activating protein inhibitor MK-886 but not by the cyclooxygenase inhibitor indomethacin. Reactive oxygen species were not implicated in the mast cell-mediated toxoplasmacidal activity. The generation of LTs is important for mast cell secretion, and LTB4 released by mast cells and other inflammatory cells may be a key factor in the host defense against T. gondii.


Asunto(s)
Araquidonato 5-Lipooxigenasa/metabolismo , Leucotrieno B4/biosíntesis , Leucotrienos/fisiología , Mastocitos/fisiología , Mastocitos/parasitología , Toxoplasma/fisiología , Acetamidas/farmacología , Animales , Adhesión Celular , Células Cultivadas , Activación Enzimática , Indoles/farmacología , Leucotrienos/biosíntesis , Inhibidores de la Lipooxigenasa/farmacología , Masculino , Mastocitos/ultraestructura , Microscopía Electrónica , Éteres Fenílicos , Ratas , Ratas Sprague-Dawley , Toxoplasma/efectos de los fármacos , Toxoplasma/ultraestructura
12.
Am J Respir Crit Care Med ; 155(3): 1090-4, 1997 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-9116992

RESUMEN

The blood-gas barrier must be very thin to allow gas exchange and it is therefore subjected to high mechanical stresses when the capillary pressure rises. In some animals, such as the thoroughbred race-horse during intense exercise, the stresses are so large that the capillaries fail and bleeding occurs. We tested the hypothesis that, in elite human athletes, the high capillary pressure that occurs during severe exercise alters the structure and function of the blood-gas barrier. We performed bronchoalveolar lavage (BAL) in six healthy athletes, who had a history suggestive of lung bleeding, 1 h after a 7-min cycling race simulation and four normal sedentary control subjects who did not exercise before BAL. The athletes had higher (p < 0.05) concentrations of red blood cells (0.51 x 10(5) versus 0.01 x 10(5).ml-1), total protein (128.0 versus 94.1 micrograms/ml), albumin (65.6 versus 53.0 micrograms/ml), and leukotriene B4 (LTB4) (243 versus 0 pg/ml) in BAL fluid than control subjects. The proportion of neutrophils was similar in athletes and control subjects but the proportion of lymphocytes in BAL fluid was reduced (p < 0.05). There were no differences in levels of surfactant apoprotein A, tumor necrosis factor bioactivity, lipopolysaccharide, or interleukin-8 (IL-8) between groups. These results show that brief intense exercise in athletes with a history suggestive of lung bleeding alters blood-gas barrier function resulting in higher concentrations of red cells and protein in BAL fluid. The lack of activation of proinflammatory pathways (except LTB4) in the airspaces supports the hypothesis that the mechanism for altered blood-gas barrier function is mechanical stress.


Asunto(s)
Ejercicio Físico/fisiología , Pulmón/irrigación sanguínea , Intercambio Gaseoso Pulmonar/fisiología , Adulto , Apolipoproteínas A/análisis , Líquido del Lavado Bronquioalveolar/química , Broncoscopía , Capilares , Permeabilidad Capilar , Femenino , Hemorragia/fisiopatología , Humanos , Leucotrieno B4/análisis , Enfermedades Pulmonares/fisiopatología , Masculino , Estudios Prospectivos , Factor de Necrosis Tumoral alfa/análisis
13.
Am J Respir Crit Care Med ; 155(2): 661-9, 1997 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-9032210

RESUMEN

We used various ovalbumin sensitization and challenge protocols to determine the importance of the route of allergen administration and the genetic background in modulating the physiologic, inflammatory, and immunologic features characteristic of allergen-induced asthma. In BALB/c mice, induction of maximal airway hyperresponsiveness and airspace eosinophilia required administration of ovalbumin by both the intraperitoneal and the intranasal routes (combination protocol), whereas intraperitoneal immunization alone resulted in maximal ovalbumin-specific IgE plasma levels. Thus, a systemic immune response to allergen, in addition to, or independent of IgE production, as well as local allergen challenge were necessary for maximal induction of pulmonary disease. BALB/c mice treated with ovalbumin by the combination protocol had increased Th2-type cytokine mRNA levels in bronchial lymph node tissue compared with control mice. In contrast, C57BL/6 mice treated with ovalbumin by the combination protocol had significantly decreased responses compared with BALB/c mice for all parameters of allergic pulmonary disease examined, with the exception of airspace eosinophilia. Genetic background has a striking and selective effect on the phenotype of murine allergic pulmonary disease. Further analysis of this murine model should be useful in helping define the critical pathogenetic events in allergen-induced asthma.


Asunto(s)
Alérgenos/genética , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/genética , Enfermedades Pulmonares/inmunología , Ovalbúmina/administración & dosificación , Inhibidores de Serina Proteinasa/administración & dosificación , Administración Intranasal , Animales , Formación de Anticuerpos , Bronquios/patología , Líquido del Lavado Bronquioalveolar/química , Femenino , Inmunoglobulina E/sangre , Inyecciones Intraperitoneales , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Fenotipo , Especificidad de la Especie
14.
J Clin Invest ; 100(12): 3083-92, 1997 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-9399955

RESUMEN

Immunized mice after inhalation of specific antigen have the following characteristic features of human asthma: airway eosinophilia, mucus and Th2 cytokine release, and hyperresponsiveness to methacholine. A model of late-phase allergic pulmonary inflammation in ovalbumin-sensitized mice was used to address the role of the alpha4 integrin (CD49d) in mediating the airway inflammation and hyperresponsiveness. Local, intrapulmonary blockade of CD49d by intranasal administration of CD49d mAb inhibited all signs of lung inflammation, IL-4 and IL-5 release, and hyperresponsiveness to methacholine. In contrast, CD49d blockade on circulating leukocytes by intraperitoneal CD49d mAb treatment only prevented the airway eosinophilia. In this asthma model, a CD49d-positive intrapulmonary leukocyte distinct from the eosinophil is the key effector cell of allergen-induced pulmonary inflammation and hyperresponsiveness.


Asunto(s)
Antígenos CD/fisiología , Asma/inmunología , Leucocitos/inmunología , Pulmón/inmunología , Alérgenos , Animales , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales/metabolismo , Antígenos CD/inmunología , Asma/inducido químicamente , Asma/patología , Broncoconstrictores/farmacología , Movimiento Celular , Modelos Animales de Enfermedad , Eosinófilos/inmunología , Femenino , Humanos , Integrina alfa4 , Cloruro de Metacolina/farmacología , Ratones , Ratones Endogámicos BALB C , Ovalbúmina , Hipersensibilidad Respiratoria/inmunología , Células Th2/efectos de los fármacos , Células Th2/inmunología
15.
J Exp Med ; 184(4): 1483-94, 1996 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-8879219

RESUMEN

Inhalation of antigen in immunized mice induces an infiltration of eosinophils into the airways and increased bronchial hyperreactivity as are observed in human asthma. We employed a model of late-phase allergic pulmonary inflammation in mice to address the role of leukotrienes (LT) in mediating airway eosinophilia and hyperreactivity to methacholine. Allergen intranasal challenge in OVA-sensitized mice induced LTB4 and LTC4 release into the airspace, widespread mucus occlusion of the airways, leukocytic infiltration of the airway tissue and broncho-alveolar lavage fluid that was predominantly eosinophils, and bronchial hyperreactivity to methacholine. Specific inhibitors of 5-lipoxygenase and 5-lipoxygenase-activating protein (FLAP) blocked airway mucus release and infiltration by eosinophils indicating a key role for leukotrienes in these features of allergic pulmonary inflammation. The role of leukotrienes or eosinophils in mediating airway hyperresponsiveness to aeroallergen could not be established, however, in this murine model.


Asunto(s)
Asma/fisiopatología , Leucotrieno B4/metabolismo , Leucotrieno C4/metabolismo , Eosinofilia Pulmonar/etiología , Proteínas Activadoras de la 5-Lipooxigenasa , Alérgenos/inmunología , Animales , Asma/inmunología , Pruebas de Provocación Bronquial , Broncoconstrictores/farmacología , Proteínas Portadoras/antagonistas & inhibidores , Modelos Animales de Enfermedad , Femenino , Inmunoglobulina E/biosíntesis , Inflamación/etiología , Leucotrieno B4/antagonistas & inhibidores , Leucotrieno C4/antagonistas & inhibidores , Inhibidores de la Lipooxigenasa , Proteínas de la Membrana/antagonistas & inhibidores , Cloruro de Metacolina/farmacología , Ratones , Ratones Endogámicos BALB C , Moco/metabolismo , Ovalbúmina/inmunología , Pruebas de Función Respiratoria , Sistema Respiratorio
16.
J Invest Dermatol ; 107(1): 51-6, 1996 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-8752839

RESUMEN

Increased cyclic AMP-phosphodiesterase activity in peripheral blood leukocytes is associated with the immune and inflammatory hyperreactivity that characterizes atopic dermatitis. Atopic phosphodiesterase has high sensitivity to a variety of enzyme inhibitors, suggesting an increased therapeutic advantage. The objective of this study was to use in vitro assays to identify a potent phosphodiesterase inhibitor and then to investigate its effectiveness in treating atopic dermatitis. Leukocyte enzyme activity was measured by radioenzyme assay, whereas prostaglandin E2 and interleukins 10 (IL-10) and 4 (IL-4) were measured in 24-h culture supernatants of mononuclear leukocytes by immunoassays. The effect of a topical phosphodiesterase inhibitor on atopic dermatitis lesional skin was assessed by double-blind, paired comparisons of active drug and placebo ointments applied to symmetrically involved sites over a 28-d period. Using in vitro, assays, we demonstrated the ability of selective high-potency phosphodiesterase inhibitors to reduce prostaglandin E2, IL-10, and IL-4 production in atopic mononuclear leukocyte cultures. We selected the Type 4 phosphodiesterase inhibitor, CP80,633, based on its inhibitory potency, for clinical testing by topical, bilateral paired comparisons in 20 patients with atopic dermatitis and demonstrated significant reductions of all inflammatory parameters. Phosphodiesterase inhibitors modulate several pathways contributing to the exaggerated immune and inflammatory responses, which characterize atopic dermatitis. This in vivo demonstration of anti-inflammatory efficacy may provide a useful alternative to the over-reliance on corticosteroid therapy in atopic disease.


Asunto(s)
Antiinflamatorios/uso terapéutico , Dermatitis Atópica/tratamiento farmacológico , Inhibidores de Fosfodiesterasa/uso terapéutico , Administración Tópica , Adulto , Dermatitis Atópica/sangre , Dinoprostona/antagonistas & inhibidores , Femenino , Humanos , Interleucina-10/antagonistas & inhibidores , Interleucina-4/antagonistas & inhibidores , Masculino , Persona de Mediana Edad , Monocitos/metabolismo , Inhibidores de Fosfodiesterasa/clasificación
17.
Chest ; 109(6): 1536-40, 1996 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-8769507

RESUMEN

BACKGROUND: Underestimation of allergic bronchopulmonary aspergillosis (ABPA) prevalence in the cystic fibrosis (CF) population is suspected due to nonuniform diagnostic criteria, nonspecific signs and symptoms, assessment during asymptomatic intervals, and physician nonaggressiveness in making the diagnosis. OBJECTIVE: To define the prevalence of ABPA in adult patients with CF, as the increased duration of bronchiectasis may increase the probability of Aspergillus fumigatus (Af) colonization. We also sought to determine whether atopy increases the prevalence of ABPA in adults with CF. METHODS: We examined a cross-sectional population of adult patients with CF at the University of Washington for 1 year. RESULTS: Information was collected on 53 of 65 (82%) patients. Fifteen of 51 (29%) had an immediate skin test reaction to Af, and 30 of 51 (59%) had at least one positive skin test. Increased total serum IgE (>450 IU/mL) was present in 0 of 53; increased IgE-Af and IgG-Af were found in 12 of 53 (23%) and 9 of 53 (17%), respectively; 24 of 53 (45%) had Af-precipitins. Peripheral blood eosinophilia was present in one patient. Eight of 49 (16%) patients' sputum cultures grew Af. ABPA-CB (ABPA-central bronchiectasis) was present in one patient and ABPA-S (ABPA-seropositive) in no patients. Atopy was present in 20 of 51 (39%). CONCLUSION: There was a low prevalence of ABPA in the adult CF population despite frequent immunologic responses to Af. The prevalence of ABPA was too small to determine an association with atopy.


Asunto(s)
Aspergilosis Broncopulmonar Alérgica/complicaciones , Fibrosis Quística/complicaciones , Hipersensibilidad Inmediata/complicaciones , Adulto , Aspergilosis Broncopulmonar Alérgica/diagnóstico , Aspergillus fumigatus/inmunología , Estudios Transversales , Femenino , Humanos , Hipersensibilidad Inmediata/diagnóstico , Inmunoglobulina E/análisis , Pruebas Intradérmicas , Masculino , Pruebas Cutáneas
18.
J Allergy Clin Immunol ; 97(1 Pt 1): 85-94, 1996 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8568141

RESUMEN

Past studies of peripheral blood mononuclear cells (PBMC) from patients with atopic dermatitis (AD) have demonstrated reduced proliferation. We have studied phytohemagglutinin-induced lymphocyte proliferation in the context of interleukin-4 (IL-4), interferon-gamma (IFN-gamma), and prostaglandin E2 (PGE2) production in cultures of PBMC from patients without and with AD. The proliferation index was found to correlate proportionally to IFN-gamma production and inversely to T-cell IL-4 and monocyte PGE2 production. Assays in parallel cultures showed significantly increased PGE2 production by purified AD monocytes. The proliferation index in PBMC from persons with AD was significantly reduced compared with normal PBMC. This difference was normalized in the presence of extrinsic IFN-gamma but exaggerated when IL-4 was added. Increased AD monocyte production of inflammatory factors (e.g., PGE2) and cytokines appears to increase IL-4 production by Th2 while suppressing IFN-gamma production by Th1. Restoration of the normal proliferation of PBMC by the addition of IFN-gamma may represent one mechanism for the clinical efficacy of IFN-gamma treatment of AD.


Asunto(s)
Dermatitis Atópica/inmunología , Dinoprostona/biosíntesis , Interferón gamma/biosíntesis , Interleucina-4/biosíntesis , Linfocitos T/inmunología , Adulto , División Celular/efectos de los fármacos , Células Cultivadas , Dermatitis Atópica/patología , Dinoprostona/farmacología , Humanos , Interferón gamma/farmacología , Interleucina-4/farmacología , Linfocitos T/patología
19.
Ann Allergy Asthma Immunol ; 76(1): 20-6, 1996 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-8564624

RESUMEN

BACKGROUND: Asthma prevalence and mortality rates have been increasing for the past two decades for reasons that are not definitively known. Few studies of asthma mortality rates have concentrated on subnational regions, such as individual states. OBJECTIVE: To determine geographic and demographic patterns of asthma mortality in Washington State during 1980 through 1989 and to compare aggregated data with patterns of chronic bronchitis mortality. METHODS: Age-adjusted mortality rates for asthma and chronic bronchitis were calculated from 1980 through 1989 for all age groups. Rates were then disaggregated by county, gender, age, and race. Rates were calculated from death certificates listed by the Washington State Center for Health Statistics as either asthma (ICD9-493) or chronic bronchitis (ICD9-490 and 491) and census data. RESULTS: During the period 1980-1989, age-adjusted mortality rates for asthma increased by 15% while those for bronchitis decreased by 43%. There was no consistent geographic pattern in the increase, though one county with a very small population had the highest rate of increase. Female asthma mortality rates increased during the decade, while male asthma mortality rates and both male and female bronchitis rates decreased. Two populations demonstrated pronounced increases in asthma mortality rates: females between ages 40 and 69 years and non-whites. CONCLUSIONS: While increased asthma mortality rates have been noted elsewhere for non-whites, this is the first study to demonstrate elevated mortality rates for middle aged women. The explanation for this remains a mystery.


Asunto(s)
Asma/mortalidad , Adolescente , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Bronquitis/mortalidad , Niño , Preescolar , Enfermedad Crónica , Certificado de Defunción , Demografía , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Distribución por Sexo , Washingtón/epidemiología
20.
Am J Pathol ; 147(4): 1016-28, 1995 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-7573347

RESUMEN

A family of beta-galactoside-binding animal lectins has recently been designated as galectins. One member of this family, galectin-3, has been known as epsilon BP for its IgE-binding activity and as Mac-2, a macrophage surface antigen, CBP35, CBP30, L-29, and L-34. Although much information has accumulated on the expression of this lectin in murine macrophages and human monocytic cell lines, little is known about the expression and function of this protein in normal human monocytes/macrophages. We now report that galectin-3 is expressed in normal human peripheral blood monocytes and its level increases dramatically as human monocytes differentiate into macrophages upon culturing in vitro. Immunoblot analysis showed that there was a 5-fold increase in the level of galectin-3 after 1 day of culture and greater than a 12-fold increase after 5 days. Immunocytochemical analysis confirmed this progressive increase of galectin-3 expression in cultured monocytes. Immunogold cytochemistry/electron microscopy analysis revealed that galectin-3 was expressed on the surface of human monocytes and that the level of cell surface galectin-3 increased progressively as these cells differentiated into macrophages. The level of galectin-3 in human monocytes/macrophages was modulated by stimuli such as lipopolysaccharide and interferon-gamma, and galectin-3 was secreted when monocytes were stimulated by calcium ionophore A23187 Soluble galectin-3 caused superoxide release from human monocytes; this activity was dependent on the lectin property of galectin-3, as it was inhibitable by lactose. Thus, galectin-3 may modulate the function of this cell type in an autocrine or paracrine fashion through binding to cell surface glycoconjugates.


Asunto(s)
Antígenos de Diferenciación/fisiología , Galactósidos/metabolismo , Macrófagos/metabolismo , Monocitos/metabolismo , Animales , Calcimicina/farmacología , Diferenciación Celular , Células Cultivadas , Galectina 3 , Humanos , Inmunohistoquímica , Interferón gamma/farmacología , Lectinas/metabolismo , Lipopolisacáridos/farmacología , Macrófagos/citología , Microscopía Electrónica , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/microbiología , Superóxidos/metabolismo , Toxoplasma/fisiología
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