Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are the clinical manifestations of severe lung damage and respiratory failure. Characterized by severe inflammation and compromised lung function, ALI/ARDS result in very high mortality of affected individuals. Currently, there are no effective treatments for ALI/ARDS, and ironically, therapies intended to aid patients (specifically mechanical ventilation, MV) may aggravate the symptoms. Key events contributing to the development of ALI/ARDS are: increased oxidative and proteotoxic stresses, unresolved inflammation, and compromised alveolar-capillary barrier function. Since the airways and lung tissues are constantly exposed to gaseous oxygen and airborne toxicants, the bronchial and alveolar epithelial cells are under higher oxidative stress than other tissues. Cellular protection against oxidative stress and xenobiotics is mainly conferred by Nrf2, a transcription factor that promotes the expression of genes that regulate oxidative stress, xenobiotic metabolism and excretion, inflammation, apoptosis, autophagy, and cellular bioenergetics. Numerous studies have demonstrated the importance of Nrf2 activation in the protection against ALI/ARDS, as pharmacological activation of Nrf2 prevents the occurrence or mitigates the severity of ALI/ARDS. Another promising new therapeutic strategy in the prevention and treatment of ALI/ARDS is the activation of autophagy, a bulk protein and organelle degradation pathway. In this review, we will discuss the strategy of concerted activation of Nrf2 and autophagy as a preventive and therapeutic intervention to ameliorate ALI/ARDS.
The major objective of this study was: discriminatory assessment of dry powder aerosol performance using standardized entrainment tubes (SETs) and lactose-based formulations with two model drugs. Drug/lactose interactive physical mixtures (2%w/w) were prepared. Their properties were measured: solid-state characterization of phase behavior and molecular interactions by differential scanning calorimetry and X-ray powder diffraction; particle morphology and size by scanning electron microscopy and laser diffraction; aerosol generation by SETs and characterization by twin-stage liquid impinger and Andersen cascade impactor operated at 60 L/min. The fine particle fraction (FPF) was correlated with SET shear stress (τs), using a novel powder aerosol deaggregation equation (PADE). Drug particles were s0.624 N/m2) gave a higher emitted dose (ED∼84-93%) and lower FPF (FPF6.4∼7-25%). In contrast, the highest shear SET (τs=13.143N/m2) gave a lower ED (ED∼75-89%) and higher FPF (FPF6.4∼15-46%). The performance of disodium cromoglycate was superior to albuterol sulfate at given ts, as was milled with respect to sieved lactose monohydrate. Excellent correlation was observed (R2∼0.9804-0.9998) when pulmonary drug particle release from the surface of lactose carriers was interpreted by PADE linear regression for dry powder formulation evaluation and performance prediction. © 2010 Wiley-Liss, Inc. and the American Pharmacists Association.
Autophagy is activated when the neonatal brain exposed to hypoxia ischemia (HI), but the mechanisms underlying its activation and its role in the neuronal cell death associated with HI is unclear. We have previously shown that reactive oxygen species (ROS) derived from nicotinamide adenine dinucleotide phosphate (NADPH) oxidase play an important role in HI-mediated neuronal cell death. Thus, the aim of this study was to determine if ROS is involved in the activation of autophagy in HI-mediated neonatal brain injury and to determine if this is a protective or deleterious pathway. Initial electron microscopy data demonstrated that autophagosome formation is elevated in P7 hippocampal slice cultures exposed to oxygen-glucose deprivation (OGD). This corresponded with increased levels of LC3II mRNA and protein. The autophagy inhibitor, 3-methyladenine (3-MA) effectively reduced LC3II levels and autophagosome formation in hippocampal slice cultures exposed to OGD. Neuronal cell death was significantly attenuated. Finally, we found that the pharmacologic inhibition of NADPH oxidase using apocynin or gp91ds-tat decreased autophagy in hippocampal slice cultures and the rat brain respectively. Thus, our results suggest that an activation of autophagy contributes to neonatal HI brain injury this is oxidative stress dependent.
To achieve maximum pharmacological effects with minimum side effects of drugs, drugs should be delivered to target sites without significant distribution to non-target areas. Using pharmaceutical nanocarrier systems for drug delivery is a useful delivery platform for improving target specificity, therapeutic activity, and reducing toxicity of drugs. Various sophisticated nanocarrier systems have been developed for drug delivery, and this review focuses on liposomes, polymeric nanoparticles, polymeric micelles, lipid nanoparticles, microemulsions, nanogels, and submicron lipid emulsions. This review outlines and explores nanocarrier systems for drug delivery by various administration routes including parenteral, oral, transdermal, pulmonary, ocular, and mucosal and discusses the product development and related issues in nanopharmaceutical drug delivery. © 2011 Inderscience Enterprises Ltd.