Cannabinoid Receptor 2 Deficiency in Haematopoietic cells Aggravates Early Atherosclerosis in LDL Receptor Deficient Mice

The cannabinoid receptor 2 (CB2) has been implicated to play a role in various inflammatory processes. Since atherosclerosis is currently considered a chronic inflammatory disease, we studied the effect of haematopoietic CB2 deficiency on atherosclerosis development. To investigate the effect of CB2 deficiency in immune cells on atherogenesis in vivo, a bone marrow transplantation was performed in irradiated LDL receptor deficient mice (LDLr(-/-)), using CB2 deficient (CB2(-/-)) or wildtype (WT) donor mice. After 12 weeks on a high fat-high cholesterol diet, en face analysis showed that atherosclerosis in the aortic arch was significantly increased in CB2(-/-) transplanted animals (6.40 ± 3.21%) as compared to WT transplanted mice (3.85 ± 1.61%). Although the total lesion area in the aortic root was not significantly different between WT and CB2(-/-) transplanted mice (0.45 ± 0.13 mm(2) and 0.51 ± 0.17 mm(2), respectively), CB2(-/-) transplanted mice showed a significantly larger plaque area (0.13 ± 0.07 mm(2)) than WT transplanted mice (0.08 ± 0.05 mm(2)) in the aortic valve in which atherogenesis is in an earlier stage than in the other aortic valves. Lack of endocannabinoid signaling via the CB2 receptor aggravates early atherosclerosis development in LDLr(-/-) mice, suggesting that CB2 specific activation may prevent the development of atherosclerosi

Исследование кинетики накопления коллоидного гептасульфида рения

SummaryInflammatory cytokines are well-recognized mediators of atherosclerosis. Depending on the pathological context, type I interferons (IFNs; IFNα and IFNβ) exert either pro- or anti-inflammatory immune functions, but their exact role in atherogenesis has not been clarified. Here, we demonstrate that IFNβ enhances macrophage-endothelial cell adhesion and promotes leukocyte attraction to atherosclerosis-prone sites in mice in a chemokine-dependent manner. Moreover, IFNβ treatment accelerates lesion formation in two different mouse models of atherosclerosis and increases macrophage accumulation in the plaques. Concomitantly, absence of endogenous type I IFN signaling in myeloid cells inhibits lesion development, protects against lesional accumulation of macrophages, and prevents necrotic core formation. Finally, we show that type I IFN signaling is upregulated in ruptured human atherosclerotic plaques. Hereby, we identify type I IFNs as proatherosclerotic cytokines that may serve as additional targets for prevention or treatment

A new poly(1,3-trimethylene carbonate) film provides effective adhesion reduction after major abdominal surgery in a rat model

Background Postoperative adhesions remain a major clinical problem after abdominal surgery. We evaluated the efficacy of a new poly(trimethylene carbonate) (PTMC) film as an antiadhesive material. In many abdominal operations, there is an increased risk of fecal contamination; the risk of (increased) infection in presence of PTMC film was studied in 2 additional animal models. Methods A validated rat adhesion model with peritoneal ischemic buttons was used to compare the new PTMC film with a hyaluronate carboxymethylcellulose (HA-CMC) sheet, icodextrin solution, and a control group. Primary endpoint was occurrence of adhesions at the ischemic buttons after 14 days in 44 rats (n = 11 per group). To evaluate potential risks associated with the film, both an anastomotic leakage model and a cecal ligation and puncture model were used. Kruskal–Wallis tests with subsequent Mann–Whitney tests were used to detect differences between groups. Results PTMC film showed a significant reduction in the amount of adhesions (median, 0.5 buttons) compared with control group (median, 4 buttons; P < .001) and icodextrin group (median, 4.5; P < .001). The amount of adhesions was similar to the HA-CMC group (median, 2; P = .04). The presence of the film did not increase the risk of anastomotic leakage or bacterial growth in a contaminated environment. Conclusion The presence of a PTMC film leads to a significant reduction in the amount of adhesions after 14 days in an ischemic button rat model. Furthermore, this film was found to be safe in an animal model, even in complex abdominal operations with an increased risk of fecal contaminatio

Macrophage Secretory Phospholipase A2 Group X Enhances Anti-inflammatory Responses, Promotes Lipid Accumulation, and Contributes to Aberrant Lung Pathology

Secreted phospholipase A2 group X (sPLA(2)-X) is one of the most potent enzymes of the phospholipase A(2) lipolytic enzyme superfamily. Its high catalytic activity toward phosphatidylcholine (PC), the major phospholipid of cell membranes and low-density lipoproteins (LDL), has implicated sPLA(2)-X in chronic inflammatory conditions such as atherogenesis. We studied the role of sPLA(2)-X enzyme activity in vitro and in vivo, by generating sPLA(2)-X-overexpressing macrophages and transgenic macrophage-specific sPLA(2)-X mice. Our results show that sPLA(2)-X expression inhibits macrophage activation and inflammatory responses upon stimulation, characterized by reduced cell adhesion and nitric oxide production, a decrease in tumor necrosis factor (TNF), and an increase in interleukin (IL)-10. These effects were mediated by an increase in IL-6, and enhanced production of prostaglandin E-2 (PGE(2)) and 15-deoxy-Delta 12,14-prostaglandin J(2) (PGJ(2)). Moreover, we found that overexpression of active sPLA(2)-X in macrophages strongly increases foam cell formation upon incubation with native LDL but also oxidized LDL (oxLDL), which is mediated by enhanced expression of scavenger receptor CD36. Transgenic sPLA(2)-X mice died neonatally because of severe lung pathology characterized by interstitial pneumonia with massive granulocyte and surfactant-laden macrophage infiltration. We conclude that overexpression of the active sPLA(2)-X enzyme results in enhanced foam cell formation but reduced activation and inflammatory responses in macrophages in vitro. Interestingly, enhanced sPLA(2)-X activity in macrophages in vivo leads to fatal pulmonary defects, suggesting a crucial role for sPLA(2)-X in inflammatory lung disease