The American journal of pathology
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Autophagy is a highly conserved bulk protein degradation pathway involved in cellular homeostasis. Although emerging evidence indicates involvement of autophagy in various conditions, efforts to clarify the role of autophagy in renal tubules are beginning to be elucidated. In the present study, we examined the hypothesis that autophagy guards against acute kidney injury (AKI) by modulating several deteriorative pathways that lead to tubular cell death using a cisplatin-induced model of AKI. ⋯ Cisplatin treatment significantly increased reactive oxygen species-producing damaged mitochondria in immortalized autophagy-deficient proximal tubular cells when compared with autophagy-retrieved control cells. In conclusion, autophagy guards kidney proximal tubules against AKI, possibly by alleviating DNA damage and reactive oxygen species production and by eliminating toxic protein aggregates. Enhancing autophagy may provide a novel therapeutic option to minimize AKI.
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Acute kidney injury is a frequent and serious complication of sepsis. To better understand the development of sepsis-induced acute kidney injury, we performed the first time-dependent studies to document changes in renal hemodynamics and oxidant generation in the peritubular microenvironment using the murine cecal ligation and puncture (CLP) model of sepsis. CLP caused an increase in renal capillary permeability at 2 hours, followed by decreases in mean arterial pressure, renal blood flow (RBF), and renal capillary perfusion at 4 hours, which were sustained through 18 hours. ⋯ At 10 mg/kg administered 6 hours after CLP, MnTMPyP did not alter blood pressure, but blocked superoxide and peroxynitrite generation, reversed the decline in RBF, capillary perfusion, and glomerular filtration rate, preserved tubular architecture, and increased 48-hour survival. However, MnTMPyP administered at CLP did not prevent capillary permeability or the decrease in RBF and capillary perfusion, which suggests that these early events are not mediated by oxidants. These data demonstrate that renal hemodynamic changes occur early after sepsis and that targeting the later oxidant generation can break the cycle of injury and enable the microcirculation and renal function to recover.
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Nontypeable Haemophilus influenzae (NTHi) is an important bacterial pathogen associated with lower respiratory tract colonization and with acute exacerbations and disease progression in chronic obstructive pulmonary disease (COPD). Why the immune system fails to eliminate NTHi and the exact contribution of the organism to COPD progression are not well understood, in part because we lack an animal model that mimics all aspects of COPD. For this study, we used an established murine model that exhibits typical features of COPD. ⋯ Our results suggest that elastase/LPS-exposed mice show impaired bacterial clearance and sustained lung inflammation. Lack of SR-A expression may, in part, be responsible for impaired phagocytosis of bacteria by alveolar macrophages of elastase/LPS-exposed mice. These data validate the suitability of elastase/LPS model for investigating NTHi pathogenesis and progression of disease in COPD.
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We previously reported that ethanol consumption affects morbidity and mortality after traumatic brain injury (TBI) by accelerating brain edema via oxidative stress after TBI. Aquaporin-4 (AQP4), a water channel, is involved in brain edema formation. In this study, we found that acute ethanol administration increased AQP4 expression after TBI, leading to severe brain edema in rats. ⋯ Acetazolamide treatment improved the survival rate to 100% and decreased brain edema and AQP4 in ethanol-pretreated rats. These findings suggest that ethanol induces up-regulation of AQP4, leading to brain edema. The accumulation of AQP4 may play an important role in the augmentation of brain edema after TBI under ethanol consumption.