RESUMO
Decline in oxygen availability experienced under hypobaric hypoxia (HH) mediates imbalance in lung fluid clearance and is a causative agent of acute lung injury. Here, we investigate the pathological events behind acute HH mediated lung injury and assess the therapeutic efficacy of nanocurcumin in its amelioration. We assess the protective efficacy of nanotized curcumin (nanocurcumin) in ameliorating HH induced lung injury and compare to curcumin. Rats exposed to acute HH (6, 12, 24, 48 and 72 h) were subjected to histopathology, blood-gas analysis and clinical biochemistry, cytokine response and redox damage. HH induced lung injury was analysed using markers of lung injury due to pulmonary vasoconstriction (ET-1/2/3 and endothelin receptors A and B) and trans-vascular fluid balance mediator (Na+/K+ ATPase). The protective efficacy of nanocurcumin was analysed by examination of Akt/Erk signalling cascade by western blot. HH induced lung injury was associated with discrete changes in blood analytes, differential circulatory cytokine response and severe pulmonary redox damages. Up-regulation of ET-1/2/3 and its receptors along with down-regulation of Na+/K+ ATPase confirmed defective pulmonary fluid clearance which promoted edema formation. Nanocurcumin treatment prevented lung edema formation and restored expression levels of ET-1/2/3 and its receptors while restoring the blood analytes, circulatory cytokines and pulmonary redox status better than curcumin. Modulation in Akt/Erk signalling pathway in rat lungs under HH confirmed the protective efficacy of nanocurcumin.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Curcumina/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipóxia/tratamento farmacológico , Nanoestruturas/uso terapêutico , Substâncias Protetoras/farmacologia , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/genética , Lesão Pulmonar Aguda/patologia , Animais , Biomarcadores/metabolismo , Modelos Animais de Doenças , Endotelina-1/genética , Endotelina-1/metabolismo , Endotelina-2/genética , Endotelina-2/metabolismo , Endotelina-3/genética , Endotelina-3/metabolismo , Hipóxia/complicações , Hipóxia/genética , Hipóxia/patologia , Masculino , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Nanoestruturas/química , Oxirredução/efeitos dos fármacos , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley , Receptor de Endotelina A/genética , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/genética , Receptor de Endotelina B/metabolismo , Transdução de Sinais , ATPase Trocadora de Sódio-Potássio/genética , ATPase Trocadora de Sódio-Potássio/metabolismoRESUMO
Polycystic ovary syndrome (PCOS) is a major health problem in reproductive-aged women worldwide, but the precise pathogenesis of PCOS remains unclear. Our previous study revealed that hypoxia-inducible factor (HIF)-1a mediated endothelin (ET)-2 signaling plays an important role in ovulation in rats. Therefore, the present study used a PCOS rat model to test the hypotheses that HIF-1a signaling is expressed and inhibited in ovaries during PCOS formation and that the HIF-1a/ET-2 signaling pathway is a target of dimethyldiguanide (DMBG) in the clinical treatment of PCOS. First, the development of a PCOS model and the effect of DMBG treatment were examined through ovarian histology and serum hormone levels, which were consistent with previous reports. Second, HIF-1a and ET-2 expression were detected by immunohistochemistry and western blot. The results showed decreased HIF-1a/ET-2 expression in the ovaries of PCOS rats, whereas DMBG treatment reversed the protein decreases and improved the PCOS symptoms. Third, to understand the molecular mechanism, HIF-1a/ET-2 mRNA expression was also examined. Interestingly, HIF-1a mRNA increased in the ovaries of PCOS rats, while ET-2 mRNA decreased, indicating that HIF-1a protein degradation may be involved in POCS development and treatment. Finally, HIF prolyl hydroxylase (PHD) activity was examined to further clarify the contribution of HIF-1a signaling to the development and treatment of PCOS. The results suggested that the inhibition of HIF-1a/ET-2 signaling may be caused by increased PHD activity in PCOS. DMBG-treated PCOS may further activate HIF-1a signaling at least partly through inhibiting PHD activity. Taken together, these results indicate that HIF-1a signaling is inhibited in a PCOS rat model through increasing PHD activity. DMBG treatment improved PCOS by rescuing this pathway, suggesting that HIF-1a signaling plays an important role in the development and treatment of PCOS. This HIF-1a-mediated ET-2 signaling pathway may be an important mechanism regulating PCOS formation and treatment in mammalian ovaries in vivo and should be a new clinical target for PCOS prevention and treatment in the future.