Assuntos
Lesão Pulmonar/induzido quimicamente , Lesão Pulmonar/complicações , Proteinose Alveolar Pulmonar/induzido quimicamente , Proteinose Alveolar Pulmonar/diagnóstico , Proteinose Alveolar Pulmonar/tratamento farmacológico , Esteroides/uso terapêutico , Vaping/efeitos adversos , Adulto , Sistemas Eletrônicos de Liberação de Nicotina , Feminino , Humanos , Resultado do Tratamento , Adulto JovemRESUMO
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.
Assuntos
Anti-Hipertensivos/farmacologia , Hipertensão Pulmonar/tratamento farmacológico , Hipertrofia Ventricular Direita/tratamento farmacológico , Fenilpropionatos/farmacologia , Piridazinas/farmacologia , Tadalafila/farmacologia , Disfunção Ventricular Direita/tratamento farmacológico , Animais , Modelos Animais de Doenças , Quimioterapia Combinada/métodos , Ecocardiografia , Feminino , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/diagnóstico por imagem , Hipertensão Pulmonar/fisiopatologia , Hipertrofia Ventricular Direita/induzido quimicamente , Hipertrofia Ventricular Direita/diagnóstico por imagem , Hipertrofia Ventricular Direita/fisiopatologia , Pulmão/diagnóstico por imagem , Pulmão/efeitos dos fármacos , Pulmão/fisiopatologia , Monocrotalina/administração & dosagem , Pneumonectomia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/fisiopatologia , Ratos , Ratos Sprague-Dawley , Remodelação Vascular/efeitos dos fármacos , Vasoconstrição/efeitos dos fármacos , Disfunção Ventricular Direita/induzido quimicamente , Disfunção Ventricular Direita/diagnóstico por imagem , Disfunção Ventricular Direita/fisiopatologia , Microtomografia por Raio-XRESUMO
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.