Connective tissue growth factor induces renal fibrosis via epidermal growth factor receptor activation

Connective tissue growth factor (CCN2/CTGF) is a matricellular protein that is overexpressed in progressive human renal diseases, mainly in fibrotic areas. In vitro studies have demonstrated that CCN2 regulates the production of extracellular matrix (ECM) proteins and epithelial–mesenchymal transition (EMT), and could therefore contribute to renal fibrosis. CCN2 blockade ameliorates experimental renal damage, including diminution of ECM accumulation. We have reported that CCN2 and its C‐terminal degradation product CCN2(IV) bind to epidermal growth factor receptor (EGFR) to modulate renal inflammation. However, the receptor involved in CCN2 profibrotic actions has not been described so far. Using a murine model of systemic administration of CCN2(IV), we have unveiled a fibrotic response in the kidney that was diminished by EGFR blockade. Additionally, in conditional CCN2 knockout mice, renal fibrosis elicited by folic acid‐induced renal damage was prevented, and this was linked to inhibition of EGFR pathway activation. Our in vitro studies demonstrated a direct effect of CCN2 via the EGFR pathway on ECM production by fibroblasts and the induction of EMT in tubular epithelial cells. Our studies clearly show that the EGFR regulates CCN2 fibrotic signalling in the kidney, and suggest that EGFR pathway blockade could be a potential therapeutic option to block CCN2‐mediated profibrotic effects in renal diseases. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.     

鼻咽癌EMT相关基因的筛选及生物信息学分析

目的 利用生物信息学方法 挖掘鼻咽癌上皮间充质转化(epithelial-mesenchymal transition,EMT)发生的潜在分子机制.方法 从公共基因芯片数据库GEO(gene expression omnibus)中寻找并下载鼻咽癌的相关基因芯片数据,并使用Genclip软件对下载的数据进行分析,寻找鼻咽癌公共基因芯片数据中与EMT相关的基因,并用生物信息学方法 对筛选出来的基因作进一步分析.结果 在公共的鼻咽癌芯片数据中找到35个与EMT相关的差异表达基因,这些基因功能大致与细胞组分、细胞粘附、通信、信号转导、分化、运动、迁移以及细胞表面受体相关的信号转导等有关,这些功能往往都被认为与肿瘤的侵袭和转移有关.结论 利用生物信息学的方法 能有效分析基因芯片数据并获取生物内在信息.鼻咽癌EMT是由于多种基因表达改变所致,这为确定鼻咽癌早期转移诊断标志与预后的预示开辟了新的思路.     

Roles of Neutrophil Gelatinase-Associated Lipocalin in Continuous Ambulatory Peritoneal Dialysis-Related Peritonitis

Introduction  We measured the neutrophil gelatinase-associated lipocalin (NGAL) concentration in peritoneal dialysate effluent (PDE) collected following an acute episode of continuous ambulatory peritoneal dialysis (CAPD)-related peritonitis. Results  NGAL concentration in PDE increased in the first 3 days after developing peritonitis and correlated well with the neutrophil count. In patients with culture-negative peritonitis, the NGAL in PDE was lower than that in patients with gram-positive or gram-negative peritonitis. Apart from providing additional diagnostic support to bacterial-induced peritonitis, measurement of NGAL in PDE may be useful to differentiate the neutrophil-dependent culture-negative peritonitis from that associated with non-bacterial or non-cellular etiologies. Conclusion  Human peritoneal mesothelial cell (HPMC) is another source of NGAL during peritonitis. NGAL was specifically induced in HPMC by IL-1β. Incubation of HPMC with recombinant NGAL reversed the transforming growth factor-β-induced up-regulation of Snail and vimentin but rescued the down-regulation of E-cadherin. Our data suggest that NGAL may exert a protective effect in modulating the epithelial-to-mesenchymal transition activated following peritonitis.     

Reversal of experimental renal fibrosis by BMP7 provides insights into novel therapeutic strategies for chronic kidney disease

Bone morphogenic protein-7 (BMP7) is a morphogen that is important for kidney development and which is also an integral part of the kidney's physiological response to repair of acute kidney injury. Several studies demonstrate that preexisting renal BMP7 pathways can be utilized by administering recombinant BMP7 to protect the kidney in experimental models of chronic kidney disease (CKD). Effectiveness of recombinant BMP7 in animal studies raises the possibility that the BMP7 pathway could be equally utilized to treat patients with CKD and interstitial fibrosis. However, regulation of BMP7 activity in the kidney is complex. BMP7 activity in the kidney is not only determined by availability of BMP7 itself, but also by a balance of agonists, such as Kielin/chordin-like protein (KCP) or BMP receptors, and antagonists including gremlin, noggin, or uterine sensitization-associated gene-1 (USAG-1). Presence of BMP7 agonists and antagonists has to be considered when recombinant BMP7 is supplemented to treat injured kidneys. Here we summarize recent insights into the role of BMP7 in acute and chronic kidney injury and discuss the implications for future directions of antifibrotic therapies.     

EMT与器官纤维化发生关系的研究进展

EMT是指上皮细胞在一些细胞因子的作用下转化为间质细胞,引起组织的病理改变。越来越多的学者认为,EMT在器官病理状况下纤维化的发生中起着重要的作用。研究EMT与器官纤维化的关系,对纤维化的治疗有着重要的意义。     

Technical considerations for analyzing EMT–MET data from surgical samples

With an increase of neoadjuvant therapy, biopsy samples have become imperative for cancer research; however, what kind of difference between surgical and endoscopic biopsy samples in gene expression profiles was still unclear. Recently, we reported artificially induced epithelial-mesenchymal transition (aiEMT) in the surgical samples by comparison between gene expression profiles of both samples of the esophagus. This was also found in mouse epithelium under an ischemic condition for 4 h. This study will evoke underestimation of the prognostic evaluation power of EMT related markers in past cancer research and prevalence of biopsy samples for in vivo expression profiling with low biases.     

Can First Responders Be Sent to Selected 9‐1‐1 Emergency Medical Services Calls without an Ambulance?

OBJECTIVES: To evaluate the feasibility and safety of initially dispatching only first responders (FRs) to selected low-risk 9-1-1 requests for emergency medical services. First responders are rapidly-responding fire crews on apparatus without transport capabilities, with firefighters trained to at least a FR level and in most cases to the basic emergency medical technician (EMT) level. Low-risk 9-1-1 requests include automatic medical alerts (ALERTs), motor vehicle incidents (MVIs) for which the caller was unable to answer any medical dispatch questions designed to prioritize the call, and 9-1-1 call disconnects (D/Cs). METHODS: A before-and-after study of patient dispositions was conducted using historical controls for comparison. During the historical control phase of six months, one year prior to the study phase, basic life support ambulances (staffed with two basic EMTs) were dispatched to selected low-risk 9-1-1 incidents. During the six-month study phase, a fire FR crew equipped with automated external defibrillators (AEDs) was sent initially without an ambulance to these incidents. RESULTS: For ALERTs (n = 290 in historical group vs. 330 in study group), there was no statistical difference in the transport rate (7% vs 10%), but there was a statistically significant increase in the follow-up use of advanced life support (ALS) (1% vs 4%, p = 0.009). No patient in the ALERTs historical group required airway management, while one patient in the study group received endotracheal intubation. No patient required defibrillation in either group. Analysis of the MVIs showed a significant decrease (p < 0.0001) in the patient transport rate from 39% of controls to 33% of study patients, but no change in the follow-up use of ALS interventions (2% for each group). For both the ALERTs and MVIs, the FR's mean response time was faster than ambulances (p < 0.0001). Among the 9-1-1 D/Cs with FRs only (n = 1,028), 15% were transported and 43 (4%) received subsequent ALS care. Four of these patients (0.4%) received intubation and two (0.2%) required defibrillation. However, no patient was judged to have had adverse outcomes as a result of the dispatch protocol change. CONCLUSIONS: Fire apparatus crews trained in the use of AEDs can safely be used to initially respond alone (without ambulances) to selected, low-risk 9-1-1 calls. This tactic improves response intervals while reducing ambulance responses to these incidents.