系膜增生性肾病与TGF-β、MMPs、NF-KB和PDGF关系的研究进展

系膜细胞的增生是多种原发性和继发性肾小球疾病的主要病理特点,系膜细胞增殖和细胞外基质沉积是导致肾小球硬化的重要因素。系膜增生性肾炎(MsPGN)是我国原发性肾小球疾病中常见的病理类型,约占我国肾穿刺病人的20%～25%。因此,抑制系膜细胞增生及细胞外基质的沉积成为治疗此类疾病的关键。本篇就系膜增生性肾病与TGF-β的表达、基质金属蛋白酶类(ma-trix metalloproteinases,MMPs)的活化、NF-KB的活化和PDGF的旁分泌或自分泌之间的关系加以论述。     

Effects of sarpogrelate hydrochloride in a patient with chronic graft-versus-host disease: a case report

Chronic graft-versus-host disease (cGVHD) is a frequent complication of allogenic bone marrow transplantation. Even with aggressive treatment, cGVHD is associated with a significant degree of morbidity and mortality. cGVHD resembles autoimmune disorder, particularly systemic sclerosis (SSc). Sarpogrelate hydrochloride (SH) is an antagonist of the 5-hydroxytryptamine2A (5HT2A) receptor and has been reported to be effective in the treatment of systemic sclerosis (SSc) patients with Raynaud phenomenon. We used SH to treat a cGVHD patient, and we measured plasma PDGF and total TGF-beta levels. After SH treatment, his plasma PDGF and total TGF-beta levels decreased, and he noticed improvement in his skin pigmentation. In the present case, SH may have improved the skin lesion by inhibiting the synthesis of PDGF and TGF-beta.     

乙肝后肝硬化患者血清CTGF、PDGF、TGF-β_1测定的意义

目的：探讨乙型肝炎后肝硬化患者血清CTGF、PDGF、TGF-β1水平的变化及临床意义。方法：将50例乙肝后肝硬化患者按不同的病情分为轻度、中度及重度三组;设体检健康人45名作为对照组。血清TGF-β1水平采用放射免疫分析;CTGF及PDGF则采用ELISA测定。并将测定结果进行统计分析。结果：结果显示,血清CTGF水平轻度组与对照组比较略有升高,但无统计学意义（P〉0.05）;中度组患者该指标水平则显著高于对照组（P〈0.05）;重度组水平更为显著（P〈0.01）。且发现其递增规律与肝硬化病情的严重程度呈明显的平行关系。PDGF测定值显示,轻度组水平显著高于对照组（P〈0.05）,中度和重度两组水平则较对照组升高更为显著（P均〈0.01）。其水平的递增关系也与病情的严重程度相一致。TGF-β1水平的变化趋势同PDGF。结论：本文患者三项血清指标水平的变化与乙肝后肝硬化的发病及病情进展有关;其测定有助于了解本病的发生机制和预后评估。     

Shp2 is involved in neuronal differentiation of hippocampal precursor cells

HiB5 is a multipotent hippocampal stem cell line whose differentiation into cells of a neuronal phenotype is promoted by neurotrophic factors such as PDGF and brain-derived neurotrophic factor (BDNF). We examined the potential role of Src homology 2 (SH2)-containing protein tyrosine phosphatase (Shp2) in this differentiation process. We found that Shp2 became tyrosine phosphorylated following PDGF treatment. Wild-type Shp2 enhanced the expression of neurofilament, synapsin I and PSD95 by PDGF and BDNF, whereas their expression was attenuated by the catalytically inactive mutants Shp2C/S and Shp2DeltaP. Formation of dendritic spine-like structures increased with wild-type Shp2, but diminished with Shp2C/S and Shp2DeltaP. PSD95, localized in the post-synaptic density region of dendritic spines, PDGFRbeta and TrkB were co-immunoprecipitated with Shp2 antibodies. These results suggest that Shp2 plays a positive role in mediating PDGF- and BDNF-activated signaling which promotes the formation of dendritic spines.     

Natural killer cells ameliorate liver fibrosis by killing activated stellate cells in NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent manners

BACKGROUND & AIMS: Viral hepatitis infection, which is a major cause of liver fibrosis, is associated with activation of innate immunity. However, the role of innate immunity in liver fibrosis remains obscure. METHODS: Liver fibrosis was induced either by feeding mice with the 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) diet or by injecting them with carbon tetrachloride. The Toll-like receptor 3 ligand, polyinosinic-polycytidylic acid, was used to activate innate immunity cells and mediators, including natural killer cells and interferon gamma. RESULTS: In the mouse model of DDC-induced liver fibrosis, natural killer cell activation by polyinosinic-polycytidylic acid induced cell death to activated hepatic stellate cells and attenuated the severity of liver fibrosis. Polyinosinic-polycytidylic acid treatment also ameliorated liver fibrosis induced by carbon tetrachloride. The observed protective effect of polyinosinic-polycytidylic acid on liver fibrosis was diminished through either depletion of natural killer cells or by disruption of the interferon gamma gene. Expression of retinoic acid early inducible 1, the NKG2D ligand, was undetectable on quiescent hepatic stellate cells, whereas high levels were found on activated hepatic stellate cells, which correlated with the resistance and susceptibility of quiescent hepatic stellate cells and activated hepatic stellate cells to natural killer cell lysis, respectively. Moreover, treatment with polyinosinic-polycytidylic acid or interferon gamma enhanced the cytotoxicity of natural killer cells against activated hepatic stellate cells and increased the expression of NKG2D and tumor necrosis factor-related apoptosis-inducing ligand on liver natural killer cells. Blocking NKG2D or tumor necrosis factor-related apoptosis-inducing ligand with neutralizing antibodies markedly diminished the cytotoxicity of polyinosinic-polycytidylic acid-activated natural killer cells against activated hepatic stellate cells. CONCLUSIONS: Our findings suggest that natural killer cells kill activated hepatic stellate cells via retinoic acid early inducible 1/NKG2D-dependent and tumor necrosis factor-related apoptosis-inducing ligand-dependent mechanisms, thereby ameliorating liver fibrosis.     

PDGF-BB enhances monocyte chemoattractant protein-1 mRNA stability in smooth muscle cells by downregulating ribonuclease activity

Platelet-derived growth factor (PDGF) has protean manifestations, including the regulation of growth and migration, in many cell types. We have previously reported that PDGF-BB induces the accumulation of monocyte chemoattractant protein (MCP)-1 mRNA in smooth muscle cells (SMC), in large part due to an increase in mRNA stability. To elucidate the mechanism by which PDGF-BB stabilizes MCP-1 mRNA, we have employed in vitro RNA gel mobility shift and decay assays. Cytoplasmic extracts from PDGF-BB-treated SMC increased the half-life of in vitro transcribed MCP-1 mRNA from approximately 45 min to >2 h. PDGF-BB-inhibitable degradation was not dependent on specific regions of the MCP-1 mRNA and was equally effective on a variety of in vitro transcribed mRNAs. Angiotensin II had a similar effect on MCP-1 mRNA stability, whereas tumor necrosis factor-alpha and basic fibroblast growth factor did not. The PDGF-BB-inhibitable RNAse activity was active at pH 6.6 and heat stable, but was sensitive to proteinase K. Extracts from PDGF-BB- or angiotensin II-treated cells inhibited the RNAse activity of control extracts, suggesting that the effect of PDGF-BB and angiotensin II are due to activation of a soluble inhibitor of the RNAse. The effect of PDGF-BB was blocked by inhibitors of tyrosine phosphorylation, but not by inhibitors of phosphatidylinositol 3-kinase or mitogen-activated protein kinases. These studies provide new insights into the mechanisms by which PDGF-BB enhances mRNA accumulation.     

Patent focus on cancer chemotherapeutics. IV Angiogenesis agents: April 2001 - August 2001

Angiogenesis refers to the formation of capillary blood vessels from existing blood vessels: a process that is believed to be a key driver in cancer growth and metastasis. Angiogenesis inhibition represents an active area of cancer drug discovery, with several agents and approaches now entering late clinical development. This review summarises the key aspects of recent patent applications referring to cancer chemotherapy and cancer drug discovery that involve inhibition or modulation of angiogenesis. The scope includes applications that have been published between April and August 2001. The review covers the main mechanism-based approaches such as MMPIs, inhibitors of the growth factor signalling pathways, integrin antagonists and urokinase inhibitors.     

Agents in development for the treatment of diabetic nephropathy

Diabetic nephropathy is a leading cause of end-stage renal disease, and accounts for significant morbidity and mortality in patients with diabetes. Diabetic nephropathy seems to occur as a result of an interaction between metabolic and haemodynamic factors, which activate common pathways that lead to renal damage. In the past, the treatment of diabetic nephro-pathy has focused on the control of hyperglycaemia. Newer targets, some of which are linked to glucose-dependent pathways, appear to be a major focus of new treatments directed against the development and progression of renal damage as a result of diabetes. It is anticipated that additional thera-peutic approaches that inhibit both metabolic and haemodynamic pathways will include strategies that target growth factors, cytokines and intracellular second messengers. Such an approach is expected to lead to improved therapies for the treatment of diabetic nephropathy.     

Targeting platelet-derived growth factor with imatinib in idiopathic pulmonary arterial hypertension

Background: In pulmonary arterial hypertension (PAH) vascular remodelling is a complex process which involves platelet-derived growth factor (PDGF), therefore its therapeutic targeting could be useful. Objective: To evaluate PDGF as a therapeutic target in idiopathic PAH (IPAH). Methods/results: Analysis of an study evaluating the pathogenic role of PDGF in IPAH and the effects of its blockade with imatinib. In IPAH the PDGF pathway was found to be overexpressed and imatinib showed antiproliferative effects on pulmonary artery smooth muscle cells. Conclusions: These results encourage clinical evaluation of imatinib as a potential antiremodelling therapy in IPAH.