Junya Kusaka

Age-dependent responses to renal ischemia-reperfusion injury.

BACKGROUND The incidence of acute kidney injury (AKI) in the elderly population has steadily increased in recent years. Functional recovery after AKI is also impaired in the elderly; however, the mechanism underlying these age-related differences is not well understood. In the present study, we assessed kidney morphology, function, and oxidative stress in young and aged rats after renal ischemia and reperfusion. MATERIALS AND METHODS Young (6- to 7-wk-old) and aged (60- to 65-wk-old) male Wistar rats were divided into four groups based on age and treatment: renal ischemia-reperfusion in young rats (young IR); renal ischemia-reperfusion in aged rats (aged IR); sham treatment in young rats (young control), and sham treatment in aged rats (aged control). Rats were sacrificed 24 h after treatment, serum blood urea nitrogen (BUN) and creatinine (Cre) concentrations were determined, and kidney tissue histology and 8-hydroxydeoxyguanosine (8-OHdG) levels were evaluated. RESULTS After ischemia-reperfusion, serum BUN, and Cre levels were higher in aged rats than in young rats. Reperfusion-induced kidney damage and kidney tissue 8-OHdG levels were also more severe in the aged IR group. Moreover, plasma antioxidant potential was lower in aged IR rats than in young IR rats. CONCLUSIONS Aged rats exhibited reduced antioxidant potential and increased oxidative stress after ischemia-reperfusion. Our findings demonstrate that aged rats experience more severe reperfusion-induced injuries compared with young rats.

Cepharanthine Exerts Anti-Inflammatory Effects Via NF-κB Inhibition in a LPS-Induced Rat Model of Systemic Inflammation

BACKGROUND Systemic inflammatory response syndromes involving sepsis continue to have extremely high mortality rates. Inflammation is difficult to control when it spreads throughout the body and often progresses into multiple organ dysfunction, eventually leading to death. Cepharanthine (CE) is a plant alkaloid that possesses bioactive properties, with various known actions. In the present study, we investigated protective effects of CE in a lipopolysaccharide (LPS)-induced systemic inflammatory response model and examined underlying mechanisms. MATERIALS AND METHODS We intravenously administered LPS (7.5 mg/kg) to male Wistar rats after intraperitoneal injections of either physiologic saline (LPS group) or CE (10 mg/kg; CE + LPS group), or 2 h before intraperitoneal injection of CE (post-CE + LPS group). We then compared changes in serum cytokine and nitrogen oxide levels over time, and performed histologic examinations of the lungs and liver in each group. Using mouse macrophage RAW264.7 cells, we determined the effect of CE on LPS-induced cytokine secretion into the cell culture medium, as well as NF-κB activity. RESULTS The increase in LPS-induced cytokine levels in rat serum was significantly inhibited by CE treatment; this effect was also seen in the post-CE + LPS group. In addition, we observed histologic improvements with CE co-treatment. In vitro, CE inhibited NF-κB activation by inhibiting the IKK pathway. CONCLUSIONS These results suggest that CE exerts protective effects, at least in part, via NF-κB inhibition. CE may thus be a potential agent for treating systemic inflammatory response syndromes such as sepsis.

Human Atrial Natriuretic Peptide Attenuates Renal Ischemia-Reperfusion Injury

BACKGROUND Acute kidney injury (AKI) is common in the intensive care unit, and one of its primary causes is renal ischemia-reperfusion (I/R) injury. Human atrial natriuretic peptide (hANP) exerts various pharmacologic effects, including renal protection. In the present study, we evaluated the renal protective effect of hANP in a rat model of renal I/R. MATERIALS AND METHODS Male Wistar rats were divided into three groups that received the following treatments: induction of renal I/R (I/R group); continuous intravenous injection of hANP followed 30 min later by induction of renal I/R (hANP+I/R group); and sham treatment (control group). Rats were sacrificed after 60 min of ischemia and 24 h of reperfusion or sham treatment. To evaluate the renal protective effects if hANP, serum blood urea nitrogen (BUN) and creatinine (Cre) concentrations were determined, kidneys were histologically assessed, and serum biomarkers of oxidative stress were evaluated. In addition, antimycin A (AMA)-stimulated RAW264.7 cells were treated with hANP to assess its antioxidant effects. RESULTS Serum BUN and Cre levels were elevated in the I/R group; however, these increases were significantly inhibited in the hANP + I/R group. Similarly, kidney tissue damage observed in the I/R group was attenuated in the hANP + I/R group. In vitro, AMA-stimulated cells treated with hANP showed reduced reactive oxygen species activity compared to cells treated with AMA alone. CONCLUSIONS Our findings indicate that hANP may be effective in the treatment of various types of I/R injuries.

Anti-inflammatory effects of perioperative intensive insulin therapy during cardiac surgery with cardiopulmonary bypass.

PurposeRecent studies have reported that controlling blood glucose with insulin can suppress systemic inflammation. In the present study, we evaluated how perioperative intensive insulin therapy (IIT) influences the inflammatory response in an artificial pancreas during cardiac surgery with cardiopulmonary bypass.MethodsWe randomly divided the patients undergoing cardiac surgery with cardiopulmonary bypass into two groups: an IIT group (n = 13) and a conventional treatment (CT) group (n = 12). For the IIT group, blood glucose control was initiated with an artificial pancreas at initiation of surgery. Blood glucose was maintained at 100 mg/dl until 24 h postoperatively. Blood samples were collected to determine changes in serum cytokine levels over time.ResultsPatients’ characteristics did not differ significantly between groups. Blood glucose levels were significantly higher in the CT group after surgery. Serum levels of tumor necrosis factor-α, interleukin-6, and high-mobility group box 1 were higher in the CT group than in the IIT group.ConclusionsUse of IIT in the artificial pancreas during the perioperative period signifiantly decreased the inflammatory response. Moreover, we did not find evidence of hypoglycemia in those treated with IIT. This suggests that use of IIT in an artificial pancreas can be safe and effective for critically ill patients.

Cepharanthine Improves Renal Ischemia-Reperfusion Injury in Rats

BACKGROUND Acute renal damage has numerous causes, including renal ischemia-reperfusion injury. Due to its diverse actions, cepharanthine is used to treat many acute and chronic diseases, including pit viper bites, alopecia areata, and leucopenia in radiation therapy. In this study, we examined whether cepharanthine provides a renal-protective effect in a renal ischemia-reperfusion model. MATERIALS AND METHODS Male Wistar rats were divided into four groups that received the following treatments: induction of renal ischemia-reperfusion (I/R group); subcutaneous injection of cepharanthine (10 mg/kg) followed 1 h later by induction of renal ischemia-reperfusion (Cepha + I/R group); subcutaneous injection of cepharanthine (10 mg/kg) (Cepha group); and subcutaneous injection of saline followed 1 h later by sham treatment (control group). Rats were sacrificed 24 h after renal ischemia-reperfusion or sham treatment. Serum blood urea nitrogen (BUN) and creatinine (Cre) concentrations were determined, histologic examination was performed, and oxidative stress was evaluated in kidney tissue. In addition, antimycin A (AMA)-stimulated RAW264.7 cells were treated with cepharanthine to determine its antioxidant effects. RESULTS Serum BUN and Cre levels were increased in the I/R group; however, these increases were significantly inhibited in the Cepha + I/R group. Similarly, kidney tissue damage observed in the I/R group was attenuated in the Cepha + I/R group. In vitro, cells treated with both cepharanthine and AMA showed reduced reactive oxygen species activity compared with cells treated with AMA alone. CONCLUSIONS Our findings suggest that cepharanthine may be effective in the treatment of various types of ischemia-reperfusion injuries.

Remifentanil and glucose suppress inflammation in a rat model of surgical stress

PurposePostoperative stress produces an inflammatory response. Recent studies have shown that narcotic analgesics suppress the immune system. Nutritional management during perioperative care has also been reported to affect inflammation. We therefore examined whether remifentanil or glucose administration could ameliorate postsurgical inflammatory responses using a rat model of surgical stress.MethodsWe divided male Wistar rats randomly into five groups: (1) control, (2) sevoflurane+lactated Ringer’s solution, (3) sevoflurane+lactated Ringer’s solution with 1% glucose, (4) sevoflurane+remifentanil+lactated Ringer’s solution, and (5) sevoflurane+remifentanil+ lactated Ringer’s solution with 1% glucose. In all groups, serum samples were obtained at various time points after surgery, and secreted cytokine concentrations were determined. In addition, we assessed the activation of protein kinase B (Akt) and forkhead/winged helix box class O (FOXO3), which play a role in gluconeogenesis/stress responses.ResultsSurgical stress increased the serum concentrations of tumor necrosis factor-α and interleukin-6. Groups receiving remifentanil with anesthesia showed an attenuated inflammatory response. The inflammatory response was also reduced by administering 1% glucose. Furthermore, 1% glucose induced Akt and FOXO3 phosphorylation in the quadriceps femoris muscle 12 h after surgery.ConclusionsAnesthesia based on remifentanil and perioperative administration of lactated Ringer’s solution containing 1% glucose may be able to control inflammatory responses caused by surgical stress.

Effects of the Antioxidant-Enriched Concentrated Liquid Diet ANOM on Oxidative Stress and Multiple Organ Injury in Patients with Septic Shock:A Pilot Study

Purpose: In patients with septic shock, excessive production of reactive oxygen species (ROS) by activated neutrophils injures the vascular endothelium. The body responds by recruiting systemic antioxidants, among which vitamin C most rapidly responds. Excessive and prolonged ROS production quickly depletes vitamin C, which is not synthesized by the human body. To improve the prognosis of patients with septic shock, we evaluated the ability of an antioxidant-enriched liquid diet to alleviate oxidative stress and multiple organ failure. Methods: We evaluated 15 patients with septic shock complicated by multiple organ failure who underwent treatment with ANOM® (antioxidant-enriched concentrated liquid diet, Otsuka Pharmaceutical Co, Tokushima, Japan). Vitamin C concentration was determined by measuring serum levels of vitamin C radicals (VCR) with electron spin resonance (ESR) spectroscopy. Results: Serum VCR concentration was significantly increased from the baseline level of 0.155±0.026 after 1 day of ANOM infusion, reaching the normal range at day 3, and 0.642±0.059 at day 7. Serum 8-hydroxydeoxyguanosine (8-OHdG) concentration, a measure of ROS-induced oxidative injury, was 0.495±0.061 ng/mL at day 7, which was significantly lower than the baseline level of 0.896±0.065 ng/mL. The Sepsis-related Organ Failure Assessment (SOFA) score, a measure of multiple organ failure, decreased significantly from 10.9±1.9 at baseline to 6.2±1.7 at day 7. Conclusions: These findings show that ANOM rapidly restores vitamin C levels, suggesting that it protects against excessive oxidative stress and alleviates multiple organ failure in patients with septic shock.

Catecholamine-resistant shock and hypoglycemic coma after cardiotomy in a patient with unexpected isolated ACTH deficiency

Isolated adrenocorticotropic hormone (ACTH) deficiency is an extremely rare disease in which ACTH-producing cells of the pituitary gland are selectively damaged. The resulting decline in ACTH production and secretion results in chronic secondary adrenocortical insufficiency. The patient in this case did not present with adrenal insufficiency symptoms prior to surgery. However, after cardiotomy under extracorporeal circulation, the patient lapsed into a catecholamine-resistant shock and hypoglycemic coma. Acute adrenal insufficiency was strongly suspected, and the patient was diagnosed with isolated ACTH deficiency after careful examination. Because the demand for cortisol increases after highly invasive surgeries, cortisol supplementation therapy is essential for patients with complications from isolated ACTH deficiency. There is a high risk of a lethal outcome when surgery is carried out without a diagnosis, as in this case. Therefore, cortisol must be supplemented without delay when acute adrenal insufficiency is suspected during the perioperative period.

Use of perioperative ureteral stent in abdominal aortic aneurysm with retroperitoneal fibrosis - A report of two cases -

Retroperitoneal fibrosis is associated with fibroblast proliferation due to inflammatory changes in adipose/fibrous tissue. Given that aortic dilation in abdominal aortic aneurysm can cause compression of the ureter, abdominal aortic aneurysm complicated by retroperitoneal fibrosis is likely to result in urinary tract obstruction. Accordingly, close attention to changes in perioperative urine volume is warranted when operating on patients with abdominal aortic aneurysm complicated by retroperitoneal fibrosis. We have recently performed laparotomies on two cases of abdominal aortic aneurysm complicated by retroperitoneal fibrosis. In the first case, surgery was performed without the placement of a ureteral stent. The patient developed postrenal acute renal failure caused by postoperative urinary retention. In the second case, ureteral stent placement in advance enabled perioperative management without complications. The clinical course of these cases suggests that, in laparotomy with concomitant retroperitoneal fibrosis, preoperative ureteral stent placement can prevent postoperative complications in the renal and urinary systems.