RESUMEN
Pulmonary arterial hypertension (PAH) is a female predominant disease in which progressive vascular remodeling and vasoconstriction result in right ventricular (RV) failure and death. Most PAH patients utilize multiple therapies. In contrast, the majority of preclinical therapeutic studies are performed in male rats with a single novel drug often markedly reversing disease in the model. We sought to differentiate single drug therapy from combination therapy in female rats with severe disease. One week after left pneumonectomy, we induced PH in young female Sprague-Dawley rats with an injection of monocrotaline (45 mg/kg). Female rats were then randomized to receive combination therapy (ambrisentan plus tadalafil), ambrisentan monotherapy, tadalafil monotherapy, or vehicle. We measured RV size and function on two serial echocardiograms during the development of disease. We measured RV systolic pressure (RVSP) invasively at day 28 after monocrotaline before analyzing the vascular volume with microcomputed tomography (microCT) of the right middle lobe. RVSP was significantly lower in female rats treated with combination therapy, and combination therapy resulted in increased small vessel volume density measured by microCT compared with untreated rats. Combination-treated rats had the smallest RV end-diastolic diameter on echocardiogram as compared with the other groups. In summary, we report a female model of pulmonary hypertension that can distinguish between one and two drug therapies; this model may facilitate better preclinical drug testing for novel compounds.
Asunto(s)
Antihipertensivos/farmacología , Hipertensión Pulmonar/tratamiento farmacológico , Hipertrofia Ventricular Derecha/tratamiento farmacológico , Fenilpropionatos/farmacología , Piridazinas/farmacología , Tadalafilo/farmacología , Disfunción Ventricular Derecha/tratamiento farmacológico , Animales , Modelos Animales de Enfermedad , Quimioterapia Combinada/métodos , Ecocardiografía , Femenino , Hipertensión Pulmonar/inducido químicamente , Hipertensión Pulmonar/diagnóstico por imagen , Hipertensión Pulmonar/fisiopatología , Hipertrofia Ventricular Derecha/inducido químicamente , Hipertrofia Ventricular Derecha/diagnóstico por imagen , Hipertrofia Ventricular Derecha/fisiopatología , Pulmón/diagnóstico por imagen , Pulmón/efectos de los fármacos , Pulmón/fisiopatología , Monocrotalina/administración & dosificación , Neumonectomía , Arteria Pulmonar/efectos de los fármacos , Arteria Pulmonar/fisiopatología , Ratas , Ratas Sprague-Dawley , Remodelación Vascular/efectos de los fármacos , Vasoconstricción/efectos de los fármacos , Disfunción Ventricular Derecha/inducido químicamente , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/fisiopatología , Microtomografía por Rayos XAsunto(s)
Lesión Pulmonar/inducido químicamente , Lesión Pulmonar/complicaciones , Proteinosis Alveolar Pulmonar/inducido químicamente , Proteinosis Alveolar Pulmonar/diagnóstico , Proteinosis Alveolar Pulmonar/tratamiento farmacológico , Esteroides/uso terapéutico , Vapeo/efectos adversos , Adulto , Sistemas Electrónicos de Liberación de Nicotina , Femenino , Humanos , Resultado del Tratamiento , Adulto JovenAsunto(s)
Oxigenación por Membrana Extracorpórea/métodos , Insuficiencia Cardíaca/terapia , Trasplante de Corazón/efectos adversos , Corazón Auxiliar , Edema Pulmonar/etiología , Edema Pulmonar/terapia , Terapia Combinada , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/fisiopatología , Trasplante de Corazón/métodos , Humanos , Masculino , Persona de Mediana Edad , Monitoreo Fisiológico/métodos , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/terapia , Pronóstico , Edema Pulmonar/patología , Respiración Artificial/métodos , Medición de Riesgo , Tetralogía de Fallot/diagnóstico , Tetralogía de Fallot/cirugía , Traqueostomía/métodosAsunto(s)
Infecciones Comunitarias Adquiridas/diagnóstico por imagen , Hipertensión Pulmonar/complicaciones , Interleucina-2/efectos adversos , Pulmón/diagnóstico por imagen , Pulmón/patología , Técnicas Analíticas Microfluídicas , Modelos Biológicos , Neumonía/diagnóstico por imagen , Edema Pulmonar/inducido químicamente , Disfunción Ventricular Derecha/fisiopatología , Animales , Femenino , Humanos , Masculino , UltrasonografíaRESUMEN
Several gene array studies have suggested that osteopontin (Opn) expression strongly correlates with albuminuria and glomerular disease. Urinary Opn concentration and kidney Opn immunoreactivity were found to be increased in patients with steroid-sensitive nephrotic syndrome. In addition, renal Opn mRNA was increased in the Ins2(Akita) mouse model of type 1 diabetic nephropathy, in the LPS-induced albuminuria model, and in glomeruli of puromycin aminonucleotide-induced nephrotic rats. Opn knockout mice did not develop albuminuria in response to LPS injection, and Opn knockout mice were protected from diabetes-induced albuminuria and mesangial expansion. In the glomerulus, Opn immunostaining was increased specifically in podocytes. Treatment of podocytes with recombinant Opn activated the NF-kappaB pathway, increased expression of urokinase plasminogen activator and matrix metalloproteinases 2 and 9, and increased podocyte motility. Taken together, these results indicate that Opn plays an important role in the development of albuminuria, possibly by modulating podocyte signaling and motility.