RESUMEN
We have shown that p-arylthio cinnamides can inhibit the interaction of LFA-1 and ICAM-1, which is involved in cell adhesion and the inflammatory process. We now show that 2,3-disubstitution on the aryl portion of the cinnamide results in enhanced activity over mono substitution on the ring. The best 2,3-substituents were chlorine and trifluoromethyl groups. Compounds 39 and 40 which contain two CF3 groups have IC(50) values of 0.5 and 0.1 nM, respectively, in inhibiting JY8 cells expressing LFA-1 on their surface, from adhering to ICAM-1. The structure-activity relationship (SAR) was examined using an NMR based model of the LFA-1 I domain/compound 31 complex. One of our compounds (38) was able to reduce cell migration in two different in vivo experiments.
Asunto(s)
Cinamatos/síntesis química , Indoles/síntesis química , Molécula 1 de Adhesión Intercelular/metabolismo , Antígeno-1 Asociado a Función de Linfocito/metabolismo , Sulfuros/síntesis química , Amidas/síntesis química , Amidas/química , Amidas/farmacología , Animales , Línea Celular , Quimiotaxis de Leucocito/efectos de los fármacos , Cinamatos/química , Cinamatos/farmacología , Enterotoxinas/farmacología , Eosinófilos/patología , Indoles/química , Indoles/farmacología , Espectroscopía de Resonancia Magnética , Ratones , Modelos Moleculares , Neutrófilos/efectos de los fármacos , Neutrófilos/fisiología , Ovalbúmina/inmunología , Neumonía/inmunología , Neumonía/patología , Ratas , Staphylococcus aureus , Relación Estructura-Actividad , Sulfuros/química , Sulfuros/farmacologíaRESUMEN
We examine the respiratory, bronchomotor, cardiac, and vascular responses to histamine and ragweed allergen delivered to the bronchi or alveoli compartments and the potential role of sensory nerves and reflexes mediating the histamine-induced responses. The masses of aerosols deposited in the bronchi and alveoli were quantitated using radioaerosol techniques. Activation of sensory nerves and/or histamine-induced mediator release were characterized by depositing nedocromil sodium aerosol prior to histamine challenge. The histamine-induced responses due to vagosympathetic transmission were determined by performing bilateral vagotomy. Both histamine and ragweed increased respiratory rate, ventilation, and bronchomotor tone whether deposited in the bronchial or alveolar regions. However, these responses were not elicited when histamine was administered intravenously. Precipitous allergen-induced decreases in heart rate and systolic and diastolic pressure were maximal 72 sec following ragweed deposition in alveolar regions of the lungs. Increases in respiratory rate were mediated via the vagus whether delivered to the bronchi, alveoli, or vasculature. Histamine-induced increases in respiratory rate and bronchomotor tone were attenuated by nedocromil. When histamine was delivered to the alveolar regions, increases in lung resistance appeared to be mediated primarily via the vagus and when delivered to the bronchial airways primarily by its action on smooth muscle or local reflexes. Histamine-induced hypotension and bradycardia appear to be mediated by the direct action of histamine on the cardiovascular system rather than through a vagally mediated reflex.
Asunto(s)
Alérgenos/farmacología , Anafilaxia/fisiopatología , Histamina/farmacología , Alérgenos/efectos adversos , Anafilaxia/inducido químicamente , Animales , Bronquios/efectos de los fármacos , Modelos Animales de Enfermedad , Perros , Femenino , Hemodinámica/efectos de los fármacos , Histamina/efectos adversos , Masculino , Polen/efectos adversos , Alveolos Pulmonares/efectos de los fármacos , Respiración/efectos de los fármacosAsunto(s)
Asma/tratamiento farmacológico , Broncoconstrictores/farmacología , Modelos Animales de Enfermedad , Enfermedades de los Monos/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Infecciones por Virus Sincitial Respiratorio/tratamiento farmacológico , Enfermedad Aguda , Alérgenos/farmacología , Animales , Asma/inducido químicamente , Líquido del Lavado Bronquioalveolar/química , Líquido del Lavado Bronquioalveolar/citología , Enfermedad Crónica , Femenino , Macaca fascicularis , Masculino , Ratones , Ratones Endogámicos BALB C , Neumonía , Eosinofilia Pulmonar/tratamiento farmacológico , Virus Sincitiales RespiratoriosRESUMEN
In allergic airways disease, we hypothesized that an acute allergen inhalation activates cells in the bronchial and alveolar regions of the lungs to initiate cardiopulmonary anaphylactic responses that include the stimulation of bronchial mucociliary clearance. Seven beagles were neonatally sensitized to ragweed allergen, and four were sham-sensitized. Adult dogs were anesthetized with propofol and etomidate. Bronchial retention of radiotagged particles deposited in the lungs was monitored with a gamma camera. Then 0.4-1.8 micrograms of ragweed allergen was deposited either proximally or peripherally in the lungs while achieving a similar total mass deposited. Both proximal and peripheral allergen deposition elicited cardiopulmonary responses characteristic of anaphylaxis. Following proximal allergen deposition, the mean bronchial mucuciliary clearance at 60 min increased from 27.5% +/- 4.9% to 59.9% +/- 3.3% (p < .01), and following peripheral deposition it increased from 5.9% +/- 3.1% to 52.9% +/- 7.2% (p < .01). No allergen-induced suppression of bronchial mucociliary clearance was detected within the 140-min postexposure period. No changes in cardiopulmonary responses or bronchial mucociliary clearance in the unsensitized dogs could be ascribed to the inhalation of allergen. Both the bronchi and alveoli are target sites for the initiation of allergen-induced respiratory and cardiovascular anaphylactic responses and the stimulation of bronchial mucociliary clearance.
Asunto(s)
Alérgenos/efectos adversos , Anafilaxia/inmunología , Enfermedades Bronquiales/inmunología , Trastornos de la Motilidad Ciliar/inmunología , Depuración Mucociliar , Análisis de Varianza , Animales , Trastornos de la Motilidad Ciliar/etiología , Modelos Animales de Enfermedad , Perros , Inmunoglobulina E/análisis , Plantas , Polen , Pruebas de Función Respiratoria , Sensibilidad y EspecificidadRESUMEN
Bronchial mucociliary clearance (CB) and tracheal mucus velocity (TMV) were measured during the course of repeated inhalations of histamine in six subjects with asthma who had no symptoms in a double-blind, crossover study with a radioaerosol technique. Subjects inhaled a technetium 99m-labeled ferric oxide aerosol with an aerodynamic diameter of approximately 8 microns. CB was recorded for 2.5 hours with a gamma camera, and TMV measured with a multidetector probe situated over the extrathoracic trachea. Histamine was administered repeatedly in concentrations previously shown to produce a 20% fall in forced expired volume in 1 second and at intervals allowing 90% recovery of pulmonary function. Histamine produced a 28% increase in CB (p less than 0.001, analysis of variance) and an 87% increase in TMV (p less than 0.001, analysis of variance) above control values, which was not significantly different from that previously observed in normal subjects receiving significantly higher concentrations of histamine. We conclude that histamine stimulates the mucus transport mechanism in subjects with asthma and that there is a relative hypersensitivity to histamine when these subjects are compared with normal subjects.
Asunto(s)
Asma/fisiopatología , Histamina/farmacología , Pulmón/metabolismo , Depuración Mucociliar/efectos de los fármacos , Administración por Inhalación , Adulto , Femenino , Histamina/administración & dosificación , Humanos , Masculino , TaquifilaxisRESUMEN
The effect of inhaled histamine on human tracheal mucus velocity (TMV) and bronchial mucociliary clearance (CB) was investigated in six healthy subjects using radioaerosol techniques in a randomized double-blind crossover study. Subjects inhaled repeated doses of either phosphate-buffered saline (PBS) or histamine, immediately after the inhalation of a radioaerosol and during the subsequent 2.5-h clearance measurements. Histamine was administered in concentrations previously demonstrated to induce a 20% fall in FEV1 at intervals permitting 90% recovery (mean recovery time = 25 min). Both TMV and CB were significantly increased by inhaled histamine (p less than 0.001). Average TMV throughout the 2.5-h studies increased from 4.9 +/- 1.3 to 8.4 +/- 1.6 mm/min. The increase in TMV above control values became apparent from 5 to 20 min after the first histamine administration. The percentage of aerosol clearance in 60 min increased 33%. The enhancement of CB became statistically significant at 21 min and persisted throughout the 2.5-h measurements (p less than 0.05). The increase in CB could not be attributed to differences in aerosol deposition because measurements of aerosol penetration were not significantly different between PBS and histamine studies. These data indicate that the bronchoconstriction caused by histamine is accompanied by an increase in tracheal and bronchial mucus transport. Release of histamine, as part of an inflammatory response, may alter mucociliary clearance in humans.