IL-6: A Janus-like factor in abdominal aortic aneurysm disease

AbstractBackground and aimsAn abdominal aortic aneurysm (AAA) is part of the atherosclerotic spectrum of diseases. The disease is hallmarked by a comprehensive localized inflammatory response with striking IL-6 hyperexpression. IL-6 is a multifaceted cytokine that, depending on the context, acts as a pro- or anti-inflammatory factor. In this study, we explore a putative role for IL-6 in AAA disease.MethodsELISA’s, Western blot analysis, real time PCR and array analysis were used to investigate IL-6 expression and signaling in aneurysm wall samples from patients undergoing elective AAA repair. A role for IL-6 in AAA disease was tested through IL-6 neutralization experiments (neutralizing antibody) in the elastase model of AAA disease.ResultsWe confirmed an extreme disparity in aortic wall IL-6 content between AAA and atherosclerotic disease (median [5th–95th percentile] aortic wall IL-6 content: 281.6 [0.0–1820.8] (AAA) vs. 1.9 [0.0–37.8] μg/g protein (atherosclerotic aorta), (p < 0.001). Array analysis followed by pathway analysis showed that IL-6 hyper-expression is followed by increased IL-6 signaling (p < 0.000039), an observation confirmed by higher aneurysm wall pSTAT3 levels, and SOCS1 and SOCS3 mRNA expression, (p < 0.018).Remarkably, preventive IL-6 neutralization i.e. treatment started one day prior to the elastase-induction resulted in >40% 7-day mortality due to aortic rupture. In contrast, delayed IL-6 neutralization (i.e. neutralization started at day 4 after elastase induction) did not result in ruptures, and quenched AAA growth (p < 0.021).ConclusionsAAA disease is characterized by increased IL-6 signaling. In the context of the elastase model of AAA disease, IL-6 appears a multi-faceted factor, protective upon acute injury, but negatively involved in the perpetuation of the disease process

Identifying Women at High Risk of 90 Day Death after Elective Open Abdominal Aortic Aneurysm Repair:A Multicentre Case Control Study

Objective: The aim of this study was to identify risk factors for 90 day death after elective open surgical repair (OSR) of abdominal aortic aneurysms (AAAs) in women.Methods: This was a multicentre case control study. The nationwide Dutch Surgical Aneurysm Audit registry (2013–2019) was solely used to identify women who underwent elective OSR as eligible patients. Data for this study were subsequently collected from the patients’ medical files. Women with AAA were included and those who died (cases) were compared with those who survived (controls) 90 days after surgery. Inflammatory, mycotic, or symptomatic or ruptured AAA were excluded. The association between pre- and peri-operative risk factors and death was assessed by logistic regression analysis in the whole sample and after matching cases to controls of the same age at the time of repair. Mesenteric artery patency was also assessed on pre-operative computed tomography and used in the analysis.Results: In total, 266 patients (30 cases and 236 controls) from 21 hospitals were included. Cases were older (median [interquartile range; IQR] 75 years [71, 78.3] vs. 71 years [66, 77]; p =.002) and more often had symptomatic peripheral arterial disease (PAD) (14/29 [48%] vs. 49/227 [22%]; p =.002). Intra-operative blood loss (median [IQR] 1.6 L [1.1, 3.0] vs. 1.2 L [0.7, 1.8]), acute myocardial infarction (AMI) (10/30 [33%] vs. 8/236 [3%]), renal failure (17/30 [57%] vs. 33/236 [14%]), and bowel ischaemia (BI) (17/29 [59%] vs. 12/236 [5%]) were more prevalent among cases. Older age (odds ratio [OR] 1.11, 95% confidence interval [CI] 1.03–1.19) and PAD (OR 3.91, 95% CI 1.57–9.74) were associated with death. Multivariable analysis demonstrated that, after adjustment for age, AMI (OR 9.34, 95% CI 1.66–52.4) and BI (OR 35.6, 95% CI 3.41–370) were associated with death. Superior mesenteric artery stenosis of &gt;70% had a clinically relevant association with BI (OR 5.23, 95% CI 1.43–19.13; p =.012).Conclusion: Age, symptomatic PAD, AMI, and BI were risk factors for death after elective OSR in women. The association between a &gt;70% SMA stenosis and BI may call for action in selected cases.</p

Cathepsin K Is the Principal Protease in Giant Cell Tumor of Bone

Giant cell tumor (GCT) of bone is a neoplasm of bone characterized by a localized osteolytic lesion. The nature of GCT is an enigma and the cell type(s) and protease(s) responsible for the extensive localized clinicoradiological osteolysis remain unresolved. We evaluated protease expression and cellular distribution of the proteolytic machinery responsible for the osteolysis. mRNA profiles showed that cathepsin K, cathepsin L, and matrix metalloproteinase (MMP)-9 were the preferentially expressed collagenases. Moderate expression was found for MMP-13, MMP-14, and cathepsin S. Specific protease activity assays revealed high cathepsin K activity but showed that MMP-9 was primarily present (98%) as inactive proenzyme. Activities of MMP-13 and MMP-14 were low. Immunohistochemistry revealed a clear spatial distribution: cathepsin K, its associated proton pump V-H(+)-ATPase, and MMP-9 were exclusively expressed in osteoclast-like giant cells, whereas cathepsin L expression was confined to mononuclear cells. To explore a possible role of cathepsin L in osteolysis, GCT-derived, cathepsin L-expressing, mononuclear cells were cultured on dentine disks. No evidence of osteolysis by these cells was found. These results implicate cathepsin K as the principal protease in GCT and suggest that osteoclast-like giant cells are responsible for the osteolysis. Inhibition of cathepsin K or its associated proton-pump may provide new therapeutic opportunities for GCT

Improving outcomes for donation after circulatory death kidney transplantation: Science of the times

Contains fulltext : 221518.pdf (publisher's version ) (Open Access

CXCL8 hyper-signaling in the aortic abdominal aneurysm

There are indications for elevated CXCL8 levels in abdominal aortic aneurysm disease (AAA). CXCL8 is concurrently involved in neutrophil-mediated inflammation and angiogenesis, two prominent and distinctive characteristics of AAA. As such we considered an evaluation of a role for CXCL8 in AAA progression relevant. ELISA's, real time PCR and array analysis were used to explore CXCL8 signaling in AAA wall samples. A role for CXCL8 in AAA disease was tested through the oral CXCR1/2 antagonist DF2156A in the elastase model of AAA disease. There is an extreme disparity in aortic wall CXCL8 content between AAA and aortic atherosclerotic disease (median [IQR] aortic wall CXCL8 content: 425 [141–1261] (AAA) vs. 23 [2.8–89] (atherosclerotic aorta) µg/g protein (P < 1 · 10−14)), and abundant expression of the CXCR1 and 2 receptors in AAA. Array analysis followed by pathway analysis showed that CXCL8 hyper-expression in AAA is followed increased by IL-8 signaling (Z-score for AAA vs. atherosclerotic control: 2.97, p < 0.0001). Interference with CXCL8 signaling through DF2156A fully abrogated AAA formation and prevented matrix degradation in the murine elastase model of AAA disease (p < 0.001). CXCL8-signaling is a prominent and distinctive feature of AAA, interference with the pathway constitutes a promising target for medical stabilization of AAA

Circumventing the Crabtree effect in cell culture: A systematic review

Metabolic reprogramming and mitochondrial dysfunction are central elements in a broad variety of physiological and pathological processes. While cell culture established itself as a versatile technique for the elaboration of physiology and disease, studying metabolism using standard cell culture protocols is profoundly interfered by the Crabtree effect. This phenomenon refers to the adaptation of cultured cells to a glycolytic phenotype, away from oxidative phosphorylation in glucose-containing medium, and questions the applicability of cell culture in certain fields of research. In this systematic review we aim to provide a comprehensive overview and critical appraisal of strategies reported to circumvent the Crabtree effect

Histological evaluation of the aortic wall response following endovascular aneurysm repair and endovascular aneurysm sealing

Objective: The Nellix endovascular aneurysm sealing (EVAS) system was developed as an alternative to conventional endovascular aneurysm repair (EVAR) to minimize endoleaks. A significantly higher failure rate of EVAS may be related to an interaction between the filled endobags and the AAA wall. In general, biological information on aortic remodeling after traditional EVAR is scarce. In this light, we provide here the first histologic evaluation of aneurysm wall morphology after EVAR and EVAS. Methods: Fourteen histological human wall samples of EVAS and EVAR explantation were systematically analysed. Primary open aorta repair samples were included as reference. Results: Compared with primary open aortic repair samples, endovascular repair aortic samples were characterized by more pronounced fibrosis, a greater number of ganglionic structures, decreased cellular inflammation, less calcification, and a lower atherosclerotic load. EVAS was specifically associated with the presence of unstructured elastin deposits. Conclusions: The biological response of the aortic wall after endovascular repair resembles the maturation process of a scar rather than a bona fide healing response. Moreover, the inflammatory response in the aortic wall after placement of endovascular protheses is less prominent than after primary open repair. A specific post-EVAS aortic wall characteristic was unstructured elastin fragments

Red blood cells as oxygen carrier during normothermic machine perfusion of kidney grafts:Friend or foe?

Renal ex vivo normothermic machine perfusion (NMP) is under development as an assessment tool for high-risk kidney grafts and as a means of achieving more physiologically accurate organ preservation. On-going hemolysis has been reported during NMP, as this technique relies on red blood cells for oxygen delivery. In this study, we confirm the occurrence of progressive hemolysis during 6-hour kidney NMP. NMP-associated erythrostasis in the glomeruli and in peri-glomerular vascular networks points to an interaction between the red blood cells and the graft. Continuous hemolysis resulted in prooxidative changes in the perfusate, which could be quenched by addition of fresh frozen plasma. In a cell-based system, this hemolysis induced redox stress and exhibited toxic effects at high concentrations. These findings highlight the need for a more refined oxygen carrier in the context of renal NMP.</p