Pretreatment of Rho kinase inhibitor inhibits systemic inflammation and prevents endotoxin-induced acute lung injury in mice.

BACKGROUND: Systemic inflammatory mediators play an important role in the development of sepsis. In this study, we analyzed the role of Rho kinase in the activation of immune response and acute lung injury in a mouse model of sepsis. METHODS: C57BL/6J mice were randomly divided into three groups: control, LPS, and LPS+fasudil. We used a mouse model of endotoxemia that consists of intraperitoneal injection of a high dose of LPS (30 mg/kg); a Rho kinase inhibitor, fasudil (10 mg/kg), dissolved in sterile saline (1 µL/g body weight) was applied by intraperitoneal injection at 18 and 1 h before injection of LPS (LPS+fasudil group). The control mice received vehicle sterile saline only. Blood was collected and lungs were harvested at 3 and/or 6 h for analysis. RESULTS: At 3 and 6 h, the increased TNF-α and IL-1ß levels in plasma and MPO activity in lung tissue by LPS could be significantly inhibited by fasudil. In addition, LPS-induced histologic changes in the lungs at 6 h could be effectively reversed by fasudil pretreatment. Furthermore, pretreatment of mice with fasudil inhibited LPS-induced increasing of TNF-α, IL-1ß mRNA expression (3 and 6 h) and AP-1/DNA binding activity (3 h) in blood cells. In survival studies, fasudil (10 mg/kg), which was administered 18 and 1 h before the application of LPS, conferred a protection against lethality induced by LPS (30 mg/kg). CONCLUSION: These results suggest that Rho kinase may play a role in the pathology of systemic inflammation during early phase of sepsis, and the potential mechanism of action may be partly through the adjustment of AP-1 pathway.

Retrospective Study of Critically Ill COVID-19 Patients With and Without Extracorporeal Membrane Oxygenation Support in Wuhan, China.

Background: Extracorporeal membrane oxygenation (ECMO) might benefit critically ill COVID-19 patients. But the considerations besides indications guiding ECMO initiation under extreme pressure during the COVID-19 epidemic was not clear. We aimed to analyze the clinical characteristics and in-hospital mortality of severe critically ill COVID-19 patients supported with ECMO and without ECMO, exploring potential parameters for guiding the initiation during the COVID-19 epidemic. Methods: Observational cohort study of all the critically ill patients indicated for ECMO support from January 1 to May 1, 2020, in all 62 authorized hospitals in Wuhan, China. Results: Among the 168 patients enrolled, 74 patients actually received ECMO support and 94 not were analyzed. The in-hospital mortality of the ECMO supported patients was significantly lower than non-ECMO ones (71.6 vs. 85.1%, P = 0.033), but the role of ECMO was affected by patients' age (Logistic regression OR 0.62, P = 0.24). As for the ECMO patients, the median age was 58 (47-66) years old and 62.2% (46/74) were male. The 28-day, 60-day, and 90-day mortality of these ECMO supported patients were 32.4, 68.9, and 74.3% respectively. Patients survived to discharge were younger (49 vs. 62 years, P = 0.042), demonstrated higher lymphocyte count (886 vs. 638 cells/uL, P = 0.022), and better CO2 removal (PaCO2 immediately after ECMO initiation 39.7 vs. 46.9 mmHg, P = 0.041). Age was an independent risk factor for in-hospital mortality of the ECMO supported patients, and a cutoff age of 51 years enabled prediction of in-hospital mortality with a sensitivity of 84.3% and specificity of 55%. The surviving ECMO supported patients had longer ICU and hospital stays (26 vs. 18 days, P = 0.018; 49 vs. 29 days, P = 0.001 respectively), and ECMO procedure was widely carried out after the supplement of medical resources after February 15 (67.6%, 50/74). Conclusions: ECMO might be a benefit for severe critically ill COVID-19 patients at the early stage of epidemic, although the in-hospital mortality was still high. To initiate ECMO therapy under tremendous pressure, patients' age, lymphocyte count, and adequacy of medical resources should be fully considered.

Possible relationship between cholecystectomy and subsequent occurrence of primary common bile duct stones: a retrospective review of data.

BACKGROUND: Most reports on the prognosis of cholecystectomy have been short-term studied, and few long-term reports have suggested variable incidences of common bile duct stones after cholecystectomy. We retrospectively reviewed the data to find the possible association between cholecystectomy and the subsequent occurrence of primary common bile duct stones. METHODS: The data were reviewed retrospectively of 478 patients with primary common bile duct stones diagnosed and treated by endoscopic sphincterotomy at our hospitals between January 1994 and December 2003. RESULTS: Sixty-one (14.1%) of the 432 patients had a history of cholecystectomy, with an incidence rate markedly higher than that in the general population. The mean interval between cholecystectomy and the occurrence of primary common bile duct stones was 8.23 years, with the longest being 28 years and the shortest 2 years. Compared with the patients who had not undergone a prior cholecystectomy, those who had had a prior cholecystectomy more often accompanied with acute cholangiolitis (chi(2)=8.259, P<0.01), and multiple stones or sand-like stones were frequently found (chi(2)=9.030, P<0.01). CONCLUSIONS: These results suggest a possible relationship between cholecystectomy and the subsequent occurrence of primary common bile duct stones. Perhaps patients with primary common bile duct stones who have had a prior cholecystectomy have a higher probability of infection of the biliary system. The infection may be one of the causes of occurrence of primary common bile duct stones after cholecystectomy.

Analysis of p53 and vascular endothelial growth factor expression in human gallbladder carcinoma for the determination of tumor vascularity.

AIM: To examine the expression of p53 and vascular endothelial growth factor (VEGF) as well as microvessel count (MVC) and to investigate the role of VEGF as an angiogenic marker and the possible role of p53 in the regulation of angiogenesis in human gallbladder carcinoma. METHODS: Surgically resected specimens of 49 gallbladder carcinomas were studied by immunohistochemical staining for p53 protein, VEGF, and factor VIII-related antigen. VEGF expression and mutant p53 expression were then correlated with Nevin stage, differentiation grade, MVC, and lymph node metastasis. RESULTS: Positive p53 protein and VEGF expressions were found in 61.2% and 63.3% of tumors, respectively. p53 and VEGF staining status was identical in 55.1% of tumors. The Nevin staging of p53- or VEGF-positive tumors was significantly later than that of negative tumors. The MVC in p53- or VEGF-positive tumors was significantly higher than that in negative tumors, and MVC in both p53- and VEGF-negative tumors was significantly lower than that in the other subgroups. CONCLUSION: Our findings suggest that p53-VEGF pathway can regulate tumor angiogenesis in human gallbladder carcinoma. Combined analysis of p53 and VEGF expression might be useful for predicting the tumor vascularity of gallbladder cancer.