Hepatocyte growth factor ameliorates methylglyoxal-induced peritoneal inflammation and fibrosis in mouse model

Clinical and Experimental Nephrology - Peritoneal dialysis (PD) is essential for patients with end-stage renal disease. Peritoneal fibrosis (PF) is a complex inflammatory, fibrogenic process. No...     

Dialysis solution containing hyaluronan: effect on peritoneal permeability and inflammation in rats

BACKGROUND: Hyaluronan (HA), a high molecular weight mucopolysaccharide found in interstitial tissues and fluid, is lost from the peritoneal cavity during peritoneal dialysis. In order to determine the role of HA in peritoneal function, we investigated the effects of exogenous HA on peritoneal permeability, markers of intraperitoneal inflammation, and peritoneal morphology in rats exposed to peritoneal dialysis solution for four weeks. METHODS: Wistar rats were infused intraperitoneally, twice daily, with conventional, hypertonic dialysis solution (Dianeal 3.86%; control) or Dianeal solution containing 10 mg/dL of high molecular weight HA. Peritoneal permeabilities and clearances of solutes and protein were determined using a modified peritoneal permeability test (peritoneal equilibration test) at the beginning and the end of the treatment. Peritoneal volume and ultrafiltration were determined using a macromolecular marker and by gravimetric methods. Peritoneal inflammation was determined by cell counts and differential and by the measurement of cytokine concentrations in the dialysate effluent. Peritoneal thickness and HA content were determined in liver and mesentery biopsies taken at the end of the experiment. RESULTS: After four weeks of exposure to the dialysis solution, transperitoneal protein equilibration was significantly lower in HA-treated rats compared with rats treated with Dianeal alone (46% lower for albumin, P < 0.003; 33% lower for total protein, P < 0.001). The total drained volume after a four hour dwell was 29% higher in the HA group compared with the control (P < 0.001), yielding a positive net ultrafiltration in the HA group versus a negative net ultrafiltration in controls. Peritoneal clearances of urea and creatinine tended to be elevated in HA-treated rats, while clearances of total protein and albumin tended to be lower. Dialysate effluent from rats exposed to HA contained a lower percentage of neutrophils (8.8 +/- 22.8 +/- 9.5%, P < 0.01) and lower levels of the cytokines, tumor necrosis factor-alpha (11.2 +/- 14.7 vs. 42.3 +/- 35.3 pg/mL, P < 0.05) and monocyte chemoattractant protein-1 MCP-1 (72.0 +/- 86.5 vs. 402.4 +/- 258.3 pg/mL, P < 0.02), compared with rats treated with Dianeal alone. The thickness of the peritoneal interstitium showed a similar increase in both groups, but mesenteric tissue from the HA group contained more HA (48%, P < 0.01) than tissue from control animals. CONCLUSIONS: The addition of HA to peritoneal dialysis solution decreases protein permeability, increases ultrafiltration, and decreases cytokine levels and the proportion of peritoneal neutrophils in dialysate from rats exposed to hypertonic dialysis solution. These results suggest that exogenous HA may help to protect the peritoneal membrane during exposure to dialysis solutions. These benefits, if sustained in the clinical setting, could lead to improvements in the therapy of peritoneal dialysis.     

Protamine sulfate induces enhanced peritoneal permeability to proteins

We present a direct link between the neutralization of anionic sites by intraperitoneal protamine and a rise in protein passage to the peritoneal cavity during isosmotic peritoneal dialysis in rabbits. Each experiment included two 1-hour exchanges. No drugs were added in the first exchange. In group A (control) there were no drugs in the second hour either. In group B, protamine (50 micrograms/ml) was added to the second exchange volume. In group C, protamine and heparin (50 U/ml) were added. In groups A and C, appearance curves of metabolites during the first (baseline) and the second (experimental) hours were not statistically different. In group B, differences for urea, glucose and uric acid were not significant, but they were highly so for protein (increase of 100%, p less than 0.01). Transperitoneal passage of albumin is substantially enhanced by protamine. Neutralization of protamine with heparin prevents this, showing that availability of anionic sites is the crucial limiting factor. Protamine did not significantly affect the transfer of small neutral molecules.     

Docetaxel-induced Meibomian duct inflammation and blockage leading to chalazion formation

We report a 71-year male with castration-resistant metastatic prostate cancer who was treated with weekly docetaxel for 12 weeks and developed significant eye irritation and dryness during treatment. Subsequently, the patient presented with a lower eyelid mass, which on excision was demonstrated to be a chalazion. Docetaxel induced Meibomian duct inflammation and blockage is the likely cause of this presentation in a patient with no history of eyelid masses in the past.     

Peritonitis, peritoneal inflammation and membrane permeability: a longitudinal study of dialysate and serum MCP-1 in stable patients on peritoneal dialysis

BACKGROUND: Increase in peritoneal membrane permeability (D/P) correlates with systemic and peritoneal markers of inflammation and neoangiogenesis. Monocyte chemoattractant protein-1 (MCP-1, CCL2) is a potent chemoattractant and activator of monocytes/macrophages. We measured the serum (sMCP-1) and dialysate MCP-1 (dMCP-1) concentrations of stable peritoneal dialysis (PD) patients and studied various factors affecting MCP-1 production. We also looked at the correlation of dMCP-1 concentrations with change in D/P over 12 months. METHODS: Forty-five stable prevalent and 6 new PD patients (22 CAPD, 29 APD) were studied. Median PD duration was 21 months (range 1-114). D/P was measured by standardized peritoneal equilibration test (PET). Patients with recent peritonitis within 3 months of the start of study were excluded. MCP-1 concentrations were measured in serum, overnight dialysate and post-PET dialysate, both at baseline and at 12 months by ELISA. RESULTS: On univariate analysis, post-PET dMCP-1 concentrations positively correlated with sMCP-1 (p=0.0002), duration of PD (p=0.02), dialysate volume (p=0.001), peritoneal creatinine clearance (p=0.0002) and D/P (p=0.001). There was a negative correlation with residual renal function (p=0.001). dMCP-1 concentrations were higher in patients with past peritonitis (p=0.001). On multivariate analysis, factors independently associated with dMCP-1 were sMCP-1 (p=0.003) and past peritonitis (p=0.001). Thirty patients completed this study, and D/P rose by > 0.1 in 20% patients. dMCP-1 concentrations were higher in baseline and 12-month samples in patients with change in D/P >0.1. CONCLUSIONS: We conclude that dMCP-1 concentrations are related to past peritonitis and serum MCP-1. It is difficult to interpret the relationship of dMCP-1 with change in D/P over time due to the small number of patients.     

Notch通路在高浓度葡萄糖腹膜透析液所致大鼠腹膜纤维化模型中的活化

目的 观察Notch通路在高浓度葡萄糖透析液所致大鼠腹膜纤维化模型中的变化并探讨其可能机制。 方法 给予SD雄性大鼠每日腹腔注射高浓度葡萄糖腹膜透析液，于实验后2周和4周杀检。取壁层腹膜组织行光镜检查；免疫印迹检测转化生长因子β1 （TGF-β1）、 E钙黏蛋白(E-cadherin)、α平滑肌肌动蛋白(α-SMA) 和I型胶原蛋白（Col I）的表达；RT-PCR检测Notch通路的下游靶基因Hes-1的表达；免疫印迹和RT-PCR检测Notch配体Jagged-1和Notch通路的负性调节因子Numb的表达。 结果 HE染色显示模型组腹膜明显增厚，间皮细胞减少；Masson染色显示壁层腹膜中可见明显的胶原沉积。与健康对照组相比，模型组的TGF-β1、α-SMA 和 Col I的表达增加而E-cadherin的表达下降（均P < 0.01）。4周模型组与对照组相比Jagged-1表达明显增加（P < 0.05），同时Hes-1的表达亦明显增加（P < 0.01），而Notch通路的负性调节因子Numb的表达下降（P < 0.01）。 结论 在高浓度葡萄糖腹膜透析液所致的大鼠腹膜纤维化模型中有Notch通路的活化，而该通路的活化可能与Notch通路的负性调节因子Numb表达的下调有关。高表达Notch通路的负性调节因子，如Numb，可能是治疗腹膜透析患者腹膜纤维化的新途径。     

Mechanisms and interventions in peritoneal fibrosis

Peritoneal dialysis (PD) is an attractive treatment for patients with end-stage kidney disease (ESKD). However, long-term peritoneal dialysis is associated with development of functional and structural alterations of the peritoneal membrane. Several factors are implicated in the development of peritoneal fibrosis in PD patients. Inflammatory cytokines, which are induced in the peritoneal cavity during peritonitis, may also induce chronic inflammation and fibrosis. Transforming growth factor β1 (TGF-β1) is generally considered to play an important role in peritoneal fibrosis. The objective of this review is to summarize the mechanisms of peritoneal fibrosis using in vitro and in vivo studies, and the current status and future prospects of interventions in the peritoneal fibrosis.     

结缔组织生长因子:腹膜纤维化防治的新靶点

腹膜透析是终末期慢性肾功能衰竭的主要替代治疗方法之一。腹膜纤维化导致透析效能的减退是慢性腹透病人退出的主要原因。腹膜纤维化的发生主要与非生理性的腹膜透析液、反复发作的腹膜炎、增塑剂、糖基化代谢产物等有关。近年来转化生长因子-β1(transforminggrowthfactor-β1,TGF-β1)、结缔组织生长因子(connectivetissuegrowthfactor,CTGF)在腹膜纤维化的发生中备受关注。TGF-β1在腹膜纤维化过程中起中枢作用。但TGF-β1为一多功能细胞因子,其效应复杂,完全将其阻断后果难以预料。CTGF是介导TGF-β1促纤维化作用的一个重要的下游因子。可调节细胞外基质的生成。由于CTGF主要介导TGF-β1的负面效应,而其正面效应却不由CTGF途径介导,直接抑制CTGF的表达可以避免在上游阻断TGF-β1带来的副作用。因此,CTGF成为腹膜纤维化防治的新靶点。     

Targeted proximal tubule injury triggers interstitial fibrosis and glomerulosclerosis

Chronic kidney disease (CKD) remains one of the leading causes of death in the developed world, and acute kidney injury (AKI) is now recognized as a major risk factor in its development. Understanding the factors leading to CKD after acute injury are limited by current animal models of AKI, which concurrently target various kidney cell types including epithelial, endothelial, and inflammatory cells. Here, we developed a mouse model of kidney injury using the Six2-Cre-LoxP technology to selectively activate expression of the simian diphtheria toxin (DT) receptor in renal epithelia derived from the metanephric mesenchyme. By adjusting the timing and dose of DT, a highly selective model of tubular injury was created to define the acute and chronic consequences of isolated epithelial injury. The DT-induced sublethal tubular epithelial injury was confined to the S1 and S2 segments of the proximal tubule rather than being widespread in the metanephric mesenchyme-derived epithelial lineage. Acute injury was promptly followed by inflammatory cell infiltration and robust tubular cell proliferation, leading to complete recovery after a single toxin insult. In striking contrast, three insults to renal epithelial cells at 1-week intervals resulted in maladaptive repair with interstitial capillary loss, fibrosis, and glomerulosclerosis, which was highly correlated with the degree of interstitial fibrosis. Thus, selective epithelial injury can drive the formation of interstitial fibrosis, capillary rarefaction, and potentially glomerulosclerosis, substantiating a direct role for damaged tubule epithelium in the pathogenesis of CKD.     

Airway remodelling and its relationship to inflammation in cystic fibrosis

Pulmonary disease is the most important cause of morbidity and mortality in cystic fibrosis (CF). Most patients with CF die from respiratory failure with extensive airway destruction. Airway remodelling, defined as structural airway wall changes, begins early in life in CF but the sequence of remodelling events in the disease process is poorly understood. Airway remodelling in CF has traditionally been thought to be solely the consequence of repeated cycles of inflammation and infection. However, new evidence obtained from developmental, physiological and histopathological studies suggests that there might instead be multiple mechanisms leading to airway remodelling in CF including (1) changes related to infection and inflammation; (2) changes specific to CF as a result of CF transmembrane conductance regulator (CFTR) dysfunction in the airway wall, independent of infection and inflammation; and (3) protective responses to (1) and/or (2). Recent advances in bronchoscopic techniques have allowed airway mucosal (endobronchial) biopsies to be taken in children and even infants. Endobronchial biopsy studies may provide insight into the role and relative contribution of the different mechanisms of airway remodelling in CF, with the main limitation that they assess only changes in proximal large airways and not in peripheral small airways from where CF disease is thought to originate. Findings from biopsy studies could encourage the development of novel therapeutic strategies targeting structural changes in addition to infection and inflammation.     

Mechanistic connection between inflammation and fibrosis

Fibrosis of the kidney is caused by the prolonged injury and deregulation of normal wound healing and repair processes, and by an excess deposition of extracellular matrices. Despite intensive research, our current understanding of the precise mechanism of fibrosis is limited. There is a connection between fibrotic events involving inflammatory and non-inflammatory glomerulonephritis, inflammatory cell infiltration, and podocyte loss. The current review will discuss the inflammatory response after renal injury that leads to fibrosis in relation to non-inflammatory mechanisms.     

Malnutrition and inflammation in peritoneal dialysis patients

BACKGROUND: Malnutrition, cardiovascular disease, and heightened inflammation are highly prevalent in dialysis patients, and major contributors to morbidity and mortality. We have investigated the inter-relationship between malnutrition and inflammation, and their impact on morbidity and mortality in peritoneal dialysis (PD) patients. METHOD: We enrolled 63 PD patients beginning in November 2000, and measured C-reactive protein (CRP) and various nutritional markers, including prealbumin. RESULTS: CRP level was elevated in 29% of the PD patients. Diabetics had higher CRP than non-diabetics (24 vs. 9.3 mg/L, P = 0.016). Patients who were hospitalized during the study had higher enrollment CRP (16 vs. 12.5 mg/L, P = 0.05) and lower enrollment albumin (3.5 vs. 3.9 g/dL, P = 0.002), blood urea nitrogen (BUN) (40 vs. 49 mg/dL, P = 0.034), and protein catabolic rate (nPCR) (0.88 vs. 1.0 g/kg/day, P = 0.02) than those who were not hospitalized. Enrollment level of CRP was inversely correlated with nutritional markers prealbumin (r = -0.5, P < 0.0001) and creatinine (r =-0.35, P < 0.01). After adjusting for age, race, gender, diabetes, and CRP level, prealbumin continued to correlate with other nutritional markers. There was a trend toward association of elevated CRP with all-cause mortality in PD patients. CONCLUSION: It is useful to incorporate prealbumin and CRP in the regular assessment of PD patients, whose survival may be improved by better management of malnutrition and inflammation.     

Chronic plantar fascial inflammation and fibrosis

The authors present two cases involving heel spur syndrome and plantar fasciitis. Histologic changes in the plantar fascia are compared, and changes found in chronic inflammation are discussed.     

腹膜纤维化中EMT与BMP-7

随着腹膜透析的开展,腹膜失超滤的发生率逐年增高,而腹膜失超滤主要由腹膜纤维化造成,因此腹膜纤维化越来越受到重视,本文就腹膜纤维化的成因之一EMT的发病机理及针对其的处理BMP-7等相关方面作一综述.     

Mediators leading to fibrosis - how to measure and control them in tissue engineering

Fibrosis is the result of an excessive amount of fibrous connective tissue deposited into the extracellular matrix (ECM) space of damaged tissues from injury or disease. Collagens, particularly types I and III are the main constituents of the fibrotic scar tissue as well as a mixture of fibrotic cells. Severely fibrotic tissue will develop chronic healing problems resulting in tissue/organ dysfunction. More attention needs to be given to the fibrotic differentiation and related effects in bioengineered tissues. The current review provides an update on the mechanism behind fibrosis formation as well as technical measurements and preventions.     

腹膜透析相关腹膜纤维化的防治进展

腹膜纤维化(PF)是终末期肾病(ESRD)患者退出腹膜透析的主要原因。腹膜组织长期暴露于腹膜透析液中,致腹膜形态及功能发生改变,并最终走向腹膜纤维化,使得腹膜超滤量下降,患者无法再利用腹膜透析进行肾脏替代治疗。近年来,越来越多的研究将目光聚集在腹膜纤维化的防治上,利用涌现出的"新药"开展了一系列的细胞实验以及动物实验,在这些实验中尤以吡非尼酮对纤维化的防治效果引人注目。本文将针对近年来防治腹膜纤维化试验成果进行总结,同时对吡非尼酮的临床应用前景进行阐述。