Loss of myeloid Tsc2 predisposes to angiotensin II-induced aortic aneurysm formation in mice.

RATIONALE: Genetic studies have proved the involvement of Tuberous sclerosis complex subunit 2 (Tsc2) in aortic aneurysm. However, the exact role of macrophage Tsc2 in the vascular system remains unclear. Here, we examined the potential function of macrophage Tsc2 in the development of aortic remodeling and aortic aneurysms. METHODS AND RESULTS: Conditional gene knockout strategy combined with histology and whole-transcriptomic analysis showed that Tsc2 deficiency in macrophages aggravated the progression of aortic aneurysms along with an upregulation of proinflammatory cytokines and matrix metallopeptidase-9 in the angiotensin II-induced mouse model. G protein-coupled receptor 68 (Gpr68), a proton-sensing receptor for detecting the extracellular acidic pH, was identified as the most up-regulated gene in Tsc2 deficient macrophages compared with control macrophages. Additionally, Tsc2 deficient macrophages displayed higher glycolysis and glycolytic inhibitor 2-deoxy-D-glucose treatment partially attenuated the level of Gpr68. We further demonstrated an Tsc2-Gpr68-CREB network in macrophages that regulates the inflammatory response, proteolytic degradation and vascular homeostasis. Gpr68 inhibition largely abrogated the progression of aortic aneurysms caused by Tsc2 deficiency in macrophages. CONCLUSIONS: The findings reveal that Tsc2 deficiency in macrophages contributes to aortic aneurysm formation, at least in part, by upregulating Gpr68 expression, which subsequently drives proinflammatory processes and matrix metallopeptidase activation. The data also provide a novel therapeutic strategy to limit the progression of the aneurysm resulting from Tsc2 mutations.

Infection during transgastric and transvaginal natural orifice transluminal endoscopic surgery in a live porcine model.

BACKGROUND: The infection risk of natural orifice transluminal endoscopic surgery (NOTES) is of concern. The aim of this study was to assess the safety of NOTES by investigating the intraperitoneal bacterial load during transgastric and transvaginal procedures with antiseptic or controlling perioperative preparation. METHODS: Forty-five female pigs were randomly assigned to five equal groups: the transgastric (TG) control group (group A), the TG middle volume gastric lavage group (group B), the TG high volume lavage group (group C), the transvaginal (TV) control group (group D) and the TV study group (group E). The study groups received gastric or vaginal lavage and abdominal antimicrobial irrigation, while the control groups received neither. All animals were administered intravenous antibiotics, underwent NOTES peritoneoscopy and transumbilical laparoscopic cholecystectomy under NOTES view with sterile instruments. The viscerotomy was closed by laparoscopic suture. The animals were observed until necropsy was performed 14 days postoperatively. Quantitative bacteriologic cultures were taken from the gastric or vaginal aspirate before and after lavage; peritoneal fluid was collected before and after peritoneal irrigation and at necropsy. RESULTS: The surgical procedures were completed for all the pigs and all of them survived. The mean operative time of the TG group and the TV group was (81 ± 27) minutes and (66 ± 12) minutes, respectively. All animals survived for 14 days. At necropsy, significantly more peritoneal infections were noted in group A than in group D (5:9 vs. 0:9; P < 0.05). No gross evidence of intra-peritoneal infection was found in groups B, C, D and E. Bacteriological evidence was seen in all pigs in group A, 7 pigs in group B, 6 pigs in group D, and none in groups C and E. CONCLUSIONS: Without gastric or vaginal lavage and antibiotic peritoneal irrigation, the TG procedure has a higher infection rate than the TV access. After antiseptic preparation, the bacterial load significantly decreased in the TG group, which seems as safe as the sterile TV approach.