AMP-activated protein kinase regulates autophagic protection against cisplatin-induced tissue injury in the kidney.

Although the nephrotoxicity of cisplatin has been well documented as a major side effect of chemotherapy, the exact mechanism by which prosurvival and apoptotic pathways interplay to determine renal pathology remains elusive. Recent studies suggested that autophagy might serve as an adaptive mechanism to promote cell survival during acute kidney injury (AKI). We have used AKI as a disease model to investigate the mechanism regulating the cytoprotective role of autophagy in cisplatin-induced tissue damage. Pharmacological inhibitors such as chloroquine were used to manipulate autophagy during AKI, and DNA damage was evaluated by using the cellular marker γH2AX. Cisplatin induced extensive DNA damage during AKI. Autophagy activation served as a survival strategy to suppress cisplatin-induced DNA damage in the pathology of AKI both in vitro and in vivo. Interestingly, in the kidney, cisplatin treatment can activate AMP-activated protein kinase (AMPK), a signaling molecule that is also critical for p53-mediated inactivation of mammalian target of rapamycin (mTOR) pathways. As a result, inhibition or knockdown of AMPK can lead to repressed autophagy in cisplatin-induced AKI, resulting in more DNA damage. Activation of AMPK regulates autophagy during cisplatin-induced AKI. Given the fact that p53 can regulate autophagy by inactivating mTOR via AMPK, our results suggest that the p53 pathway may also play a critical role in the pathogenesis of cisplatin-induced renal damage. This study may further our understanding of the physiological roles of autophagy in the pathogenesis of renal injuries, and thus may have pathological implications in the clinical setting.

Effectiveness of bacterial infection-related cytokine profile (BIRCP) determination for monitoring pathogen infections in children with hemopathy in the bone marrow inhibition phase.

Serum cytokine profiles were analyzed before and after infection in children with hemopathy in the bone marrow inhibition phase to explore the utility of cytokine variations for detecting infections. Serum Th1/Th2 cytokine levels, including tumor necrosis factor, interleukin (IL)-2, IL-4, IL-6, IL-10, and interferon, were quantitatively determined by cytometric bead array technology in 480 cases (230 children) of children with hemopathy in the bone marrow inhibition phase with signs of infection, such as fever, and without, to establish baseline and affected levels for comparison with healthy control children. We used the cytokine profile of infected, blood culture-positive children to establish a bacterial infection-related cytokine profile (BIRCP) for predicting infections by pathogens in blood culture-negative children. Overall, 82.9% of children with Gram-negative bacterial infections were accompanied by marked increases of IL-6 and IL-10 levels [>10 times (means ± SD)], whereas only a mild increase of IL-6 levels occurred in Gram-positive bacteria-infected children [>2 times (means ± SD)] and only a mild increase of IFN-γ levels occurred in fungal culture-positive children [>2 times (means ± SD)]. Gram-positive bacterial and fungal infections did not cause a marked increase in IL-6 or IL- 10 levels. The effective rate (86.05%, N = 43) of infectious cases predicted by BIRCP was significantly higher than that obtained using traditional methods for selecting antibiotics based on clinical indications (65.45%, N = 55, P < 0.05). In summary, BIRCP can be used to predict the infections by pathogens in children with hemopathy and to select appropriate antibiotics.