RESUMEN
Ischemia-reperfusion (I/R) injury (IRI), which involves inflammation, vascular permeability, and edema, remains a major challenge after lung transplantation. Pannexin-1 (Panx1) channels modulate cellular ATP release during inflammation. This study tests the hypothesis that endothelial Panx1 is a key mediator of vascular inflammation and edema after I/R and that IRI can be blocked by Panx1 antagonism. A murine hilar ligation model of IRI was used whereby left lungs underwent 1 h of ischemia and 2 h of reperfusion. Treatment of wild-type mice with Panx1 inhibitors (carbenoxolone or probenecid) significantly attenuated I/R-induced pulmonary dysfunction, edema, cytokine production, and neutrophil infiltration versus vehicle-treated mice. In addition, VE-Cad-CreERT2+/Panx1fl/fl mice (tamoxifen-inducible deletion of Panx1 in vascular endothelium) treated with tamoxifen were significantly protected from IRI (reduced dysfunction, endothelial permeability, edema, proinflammatory cytokines, and neutrophil infiltration) versus vehicle-treated mice. Furthermore, extracellular ATP levels in bronchoalveolar lavage fluid is Panx1-mediated after I/R as it was markedly attenuated by Panx1 antagonism in wild-type mice and by endothelial-specific Panx1 deficiency. Panx1 gene expression in lungs after I/R was also significantly elevated compared with sham. In vitro experiments demonstrated that TNF-α and/or hypoxia-reoxygenation induced ATP release from lung microvascular endothelial cells, which was attenuated by Panx1 inhibitors. This study is the first, to our knowledge, to demonstrate that endothelial Panx1 plays a key role in mediating vascular permeability, inflammation, edema, leukocyte infiltration, and lung dysfunction after I/R. Pharmacological antagonism of Panx1 activity may be a novel therapeutic strategy to prevent IRI and primary graft dysfunction after lung transplantation.
Asunto(s)
Conexinas/metabolismo , Células Endoteliales/metabolismo , Pulmón/metabolismo , Proteínas del Tejido Nervioso/metabolismo , Edema Pulmonar/metabolismo , Daño por Reperfusión/metabolismo , Vasculitis/metabolismo , Animales , Permeabilidad Capilar/efectos de los fármacos , Permeabilidad Capilar/genética , Carbenoxolona/farmacología , Conexinas/genética , Modelos Animales de Enfermedad , Células Endoteliales/patología , Inflamación/tratamiento farmacológico , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Pulmón/irrigación sanguínea , Pulmón/patología , Ratones , Ratones Noqueados , Proteínas del Tejido Nervioso/genética , Probenecid/farmacología , Edema Pulmonar/dietoterapia , Edema Pulmonar/genética , Edema Pulmonar/patología , Daño por Reperfusión/tratamiento farmacológico , Daño por Reperfusión/genética , Daño por Reperfusión/patología , Vasculitis/tratamiento farmacológico , Vasculitis/genética , Vasculitis/patologíaAsunto(s)
Cardiotónicos/administración & dosificación , Dobutamina/administración & dosificación , Hemodinámica/efectos de los fármacos , Edema Pulmonar/dietoterapia , Edema Pulmonar/etiología , Picaduras de Escorpión/complicaciones , Picaduras de Escorpión/dietoterapia , Escorpiones , Choque/etiología , Choque/terapia , Termodilución/métodos , Animales , Pruebas de Función Cardíaca , Humanos , Estudios Prospectivos , Edema Pulmonar/fisiopatología , Picaduras de Escorpión/fisiopatología , Choque/fisiopatología , Adulto JovenRESUMEN
Phosgene, widely used in industrial processes, can cause life-threatening pulmonary edema and acute lung injury. One mechanism of protection against phosgene-induced lung injury may involve the use of antioxidants. The present study focused on dietary supplementation in mice using n-propyl gallate (nPG)--a gallate acid ester compound used in food preservation--and vitamin E. Five groups of male mice were studied: group 1, control-fed with Purina rodent chow 5002; group 2, fed 0.75% nPG (w/w) in 5002; group 3, fed 1.5% nPG (w/w) in 5002; group 4 fed 1% (w/w) vitamin E in 5002; and group 5, fed 2% (w/w) vitamin E also in 5002. Mice were fed for 23 days. On day 23 mice were exposed to 32 mg m-3 (8 ppm) phosgene for 20 min (640 mg. min m-3) in a whole-body exposure chamber. Survival rates were determined at 12 and 24 h. In mice that died within 12 h, the lungs were removed and lung wet weights, dry weights, wet/dry weight ratios, lipid peroxidation (thiobarbituric acid reactive substances, TBARS) and glutathione (GSH) were assessed. Vitamin E had no positive effect on any outcome measured. There was no significant difference between 1.5% nPG and any parameter measured or survival rate compared with 5002 + phosgene. However, dietary treatment with 0.75% nPG significantly increased survival rate (P
Asunto(s)
Antioxidantes/administración & dosificación , Fosgeno/toxicidad , Galato de Propilo/administración & dosificación , Edema Pulmonar/dietoterapia , Vitamina E/administración & dosificación , Administración por Inhalación , Animales , Dieta , Glutatión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Masculino , Ratones , Tamaño de los Órganos/efectos de los fármacos , Fosgeno/administración & dosificación , Edema Pulmonar/inducido químicamente , Edema Pulmonar/mortalidad , Edema Pulmonar/prevención & control , Tasa de Supervivencia , Factores de TiempoRESUMEN
Adult rats exposed to hyperoxia develop anorexia, weight loss, and a lung injury characterized by pulmonary edema and decreased lung liquid clearance. We hypothesized that maintenance of nutrition during hyperoxia could attenuate hyperoxia-induced pulmonary edema. To test this hypothesis, we enterally fed adult male Sprague-Dawley rats via gastrostomy tubes and exposed them to oxygen (inspired O(2) fraction >0.95) for 64 h. In contrast to controls, enterally fed hyperoxic animals did not lose weight and had smaller pleural effusions and wet-to-dry weight ratios (a measure of lung edema) that were not different from room air controls. Enterally fed rats exposed to hyperoxia had increased levels of mRNA for the Na(+)-K(+)-ATPase alpha(1)- and beta(1)-subunits and glutathione peroxidase. These findings suggest that maintenance of nutrition during an oxidative lung injury reduces lung edema, perhaps by allowing for continued expression and function of protective proteins such as the Na(+)-K(+)-ATPase.