Protective roles of thrombomodulin in cisplatin-induced nephrotoxicity through the inhibition of oxidative and endoplasmic reticulum stress.

Cisplatin is an effective chemotherapeutic agent widely used for the treatment of various solid tumors. However, cisplatin has an important limitation in its use; currently, there is no method to ameliorate cisplatin-induced acute kidney injury (AKI). Thrombomodulin (TM) is well known not only for its role as a cofactor in the clinically important natural anticoagulation pathway but also for its anti-inflammatory properties. Here, we investigated the effects of TM in cisplatin-induced AKI. In mice intraperitoneally injected with 15 mg/kg cisplatin, TM (10 mg/kg) or PBS was administered intravenously at 24 h after cisplatin injection. TM significantly attenuated cisplatin-induced nephrotoxicity with the suppressed elevation of blood urea nitrogen and serum creatinine, and reduced histological damages. Actually, TM treatment significantly alleviated oxidative stress-induced apoptosis by reducing reactive oxygen species (ROS) levels in cisplatin-treated renal proximal tubular epithelial cells (RPTECs) in vitro. Furthermore, TM clarified cisplatin-induced apoptosis by reducing caspase-3 levels. In addition, TM attenuated the endoplasmic reticulum (ER) stress signaling pathway in both renal tissues and RPTECs to protect the kidneys from cisplatin-induced AKI. These findings suggest that TM is a potential protectant against cisplatin-induced nephrotoxicity through suppressing ROS generation and ER stress in response to cisplatin.

An autopsy case of fatal Japanese spotted fever in Wakayama.

Japanese spotted fever (JSF) is potentially fatal infection transmitted by tick bites which vectors Rickettsia (R.) japonica. Since JSF was first described in 1984, the incidence has gradually been increased. We experienced a case of JSF of fatal outcome. A female in 70's was found dead on her bed, whose house was so called 'hoarding house' filled with many waists and unused items. The following day, the autopsy was performed. As representative symptom of external findings, skin rashes were seen on the trunk and extremities, and there were tick-bite eschars on the left upper arm. Internal findings showed no specific findings in each organ. Histopathological examination demonstrated massive inflammatory cell infiltrates mainly consisted of neutrophils in the dermis beneath the external eschar. Furthermore, destruction of glomeruli in kidney with microhemorrhage from mesangial regions was observed. The numerous inflammatory infiltrates were also observed in pulmonary interstitium, which were accompanied with histopathologic features of vasculitis. Biochemical examination showed severe systemic inflammation as monitored by elevated CRP of 16 mg/dL and renal dysfunction by BUN of 171.2 mg/dL and creatinine of 6.07 mg/dL. Subsequently polymerase chain reaction revealed specifically amplified signals for R. japonica from the samples of tick-bites eschar and blood. Thus, we diagnosed her cause of death as JSF which had been occurred multiorgan failure such as acute renal failure and possibly acute respiratory failure. (224 terms).