BACKGROUND:Urokinase-type plasminogen activator(uPA) and urokinase-type plasminogen activator receptor(uPAR) are known as important factors,which mediate a variety of functions in terms of vascular homeostasis,inflamm...BACKGROUND:Urokinase-type plasminogen activator(uPA) and urokinase-type plasminogen activator receptor(uPAR) are known as important factors,which mediate a variety of functions in terms of vascular homeostasis,inflammation and tissue repair.However,their role in systemic inflammatory response syndrome(SIRS) has been less well studied.This study aimed to test the hypothesis that the abnormalities of fibrinolysis and degradation of extracellular matrix mediated by uPA and uPAR are directly related to the patients with SIRS.We therefore analyzed their role and clinicopathological significance in patients with SIRS.METHODS:A case-control study was conducted with 85 patients who were divided into two groups according to the diagnostic criteria of SIRS:SIRS group(n=50) and non-SIRS group(/7=35).The SIRS group was divided into MODS group(n=26) and non-MODS group(n=24) by their severity,and survival group(n=35) and non-survival group(n=15) by their prognosis.Another 30 healthy adults served as normal controls.uPA and uPAR in plasma were detected by commercial enzyme-linked immunosorbent assay(ELISA) kits.RESULTS:The plasma level of uPA was lower in the SIRS group than in the non-SIRS group and controls(P<0.001 and P<0.001).It was lower in sepsis patients and the MODS group than in the non-sepsis patients and the non-MODS patients(all P<0.05).However,there was no difference in uPA level between survivors and non-survivors(P>0.05).The plasma level of uPAR increased in the SIRS group compared with the non-SIRS group and controls(P<0.001 and P<0.001).There was a significant elevation of uPAR in sepsis patients,MODS patients and non-survivors as compared with non-sepsis patients,non-MODS patients and survivors respectively(all P<0.05).Plasma uPAR levels were positively correlated with APACHE Ⅱ score(r=0.575,P<0.001) and SOFA score(r=0.349,P=0.013).AUCs for the prediction of SIRS mortality were 0.67 and 0.51,respectively,for uPA and uPAR.CONCLUSION:uPAR could be a predictor of poor outcome in patients with SIRS.展开更多
The repair of injured tissue is a highly complex process that involves cell prolife ration,differentiation,and migration.Cell migration requires the dismantling of intercellular contacts in the injured zone and their ...The repair of injured tissue is a highly complex process that involves cell prolife ration,differentiation,and migration.Cell migration requires the dismantling of intercellular contacts in the injured zone and their subsequent reconstitution in the wounded area.Urokinase-type plasminogen activator(u PA)is a serine proteinase found in multiple cell types including endothelial cells,smooth muscle cells,monocytes,and macrophages.A substantial body of experimental evidence with different cell types outside the central nervous system indicates that the binding of uPA to its receptor(uPAR)on the cell surface prompts cell migration by inducing plasmin-mediated degradation of the extracellular matrix.In contrast,although uPA and uPAR are abundantly found in astrocytes and u PA binding to uPAR triggers astrocytic activation,it is unknown if uPA also plays a role in astrocytic migration.Neuronal cadherin is a member of cell adhesion proteins pivotal for the formation of cell-cell conta cts between astrocytes.More specifically,while the extracellular domain of neuronal cadherin interacts with the extracellular domain of neuronal cadherin in neighboring cells,its intracellular domain binds toβ-catenin,which in turn links the complex to the actin cytos keleton.Glycogen synthase kinase 3βis a serine-threonine kinase that prevents the cytoplasmic accumulation ofβ-catenin by inducing its phosphorylation at Ser33,Ser37,and Ser41,thus activating a sequence of events that lead to its proteasomal degradation.The data discussed in this perspective indicate that astrocytes release u PA following a mechanical injury,and that binding of this u PA to uPAR on the cell membrane induces the detachment ofβ-catenin from the intracellular domain of neuronal cadherin by triggering its extracellular signal-regulated kinase 1/2-mediated phosphorylation at Tyr650.Remarkably,this is followed by the cytoplasmic accumulation ofβ-catenin because uPA-induced extracellular signalregulated kinase 1/2 activation also phosphorylates lipoprotein receptor-related protein 6 at Ser1490,which in turn,by recruiting glycogen synthase kinase 3βto its intracellular domain abrogates its effect onβ-catenin.The cytoplasmic accumulation ofβ-catenin is followed by its nuclear translocation,where it induces the expression of uPAR,which is required for the migration of astrocytes from the injured edge into the wounded area.展开更多
The high prevalence and mortality of lung cancer, together with a poor 5-year survival of only approximately 15%, emphasize the need for prognostic and predictive factors to improve patient treatment. C4.4A, a member ...The high prevalence and mortality of lung cancer, together with a poor 5-year survival of only approximately 15%, emphasize the need for prognostic and predictive factors to improve patient treatment. C4.4A, a member of the Ly6/uP AR family of membrane proteins, qualifies as such a potential informative biomarker in non-small cell lung cancer. Under normal physiological conditions, it is primarily expressed in suprabasal layers of stratified squamous epithelia. Consequently, it is absent from healthy bronchial and alveolar tissue, but nevertheless appears at early stages in the progression to invasivecarcinomas of the lung, i.e., in bronchial hyperplasia/metaplasia and atypical adenomatous hyperplasia. In the stages leading to pulmonary squamous cell carcinoma, expression is sustained in dysplasia, carcinoma in situ and invasive carcinomas, and this pertains to the normal presence of C4.4A in squamous epithelium. In pulmonary adenocarcinomas, a fraction of cases is positive for C4.4A, which is surprising, given the origin of these carcinomas from mucin-producing and not squamous epithelium. Interestingly, this correlates with a highly compromised patient survival and a predominant solid tumor growth pattern. Circumstantial evidence suggests an inverse relationship between C4.4A and the tumor suppressor LKB1. This might provide a link to the prognostic impact of C4.4A in patients with adenocarcinomas of the lung and could potentially be exploited for predicting the efficacy of treatment targeting components of the LKB1 pathway.展开更多
文摘BACKGROUND:Urokinase-type plasminogen activator(uPA) and urokinase-type plasminogen activator receptor(uPAR) are known as important factors,which mediate a variety of functions in terms of vascular homeostasis,inflammation and tissue repair.However,their role in systemic inflammatory response syndrome(SIRS) has been less well studied.This study aimed to test the hypothesis that the abnormalities of fibrinolysis and degradation of extracellular matrix mediated by uPA and uPAR are directly related to the patients with SIRS.We therefore analyzed their role and clinicopathological significance in patients with SIRS.METHODS:A case-control study was conducted with 85 patients who were divided into two groups according to the diagnostic criteria of SIRS:SIRS group(n=50) and non-SIRS group(/7=35).The SIRS group was divided into MODS group(n=26) and non-MODS group(n=24) by their severity,and survival group(n=35) and non-survival group(n=15) by their prognosis.Another 30 healthy adults served as normal controls.uPA and uPAR in plasma were detected by commercial enzyme-linked immunosorbent assay(ELISA) kits.RESULTS:The plasma level of uPA was lower in the SIRS group than in the non-SIRS group and controls(P<0.001 and P<0.001).It was lower in sepsis patients and the MODS group than in the non-sepsis patients and the non-MODS patients(all P<0.05).However,there was no difference in uPA level between survivors and non-survivors(P>0.05).The plasma level of uPAR increased in the SIRS group compared with the non-SIRS group and controls(P<0.001 and P<0.001).There was a significant elevation of uPAR in sepsis patients,MODS patients and non-survivors as compared with non-sepsis patients,non-MODS patients and survivors respectively(all P<0.05).Plasma uPAR levels were positively correlated with APACHE Ⅱ score(r=0.575,P<0.001) and SOFA score(r=0.349,P=0.013).AUCs for the prediction of SIRS mortality were 0.67 and 0.51,respectively,for uPA and uPAR.CONCLUSION:uPAR could be a predictor of poor outcome in patients with SIRS.
基金National Institutes of Health Grant NS-091201(to MY)VA MERIT Award I01BX003441(to MY)。
文摘The repair of injured tissue is a highly complex process that involves cell prolife ration,differentiation,and migration.Cell migration requires the dismantling of intercellular contacts in the injured zone and their subsequent reconstitution in the wounded area.Urokinase-type plasminogen activator(u PA)is a serine proteinase found in multiple cell types including endothelial cells,smooth muscle cells,monocytes,and macrophages.A substantial body of experimental evidence with different cell types outside the central nervous system indicates that the binding of uPA to its receptor(uPAR)on the cell surface prompts cell migration by inducing plasmin-mediated degradation of the extracellular matrix.In contrast,although uPA and uPAR are abundantly found in astrocytes and u PA binding to uPAR triggers astrocytic activation,it is unknown if uPA also plays a role in astrocytic migration.Neuronal cadherin is a member of cell adhesion proteins pivotal for the formation of cell-cell conta cts between astrocytes.More specifically,while the extracellular domain of neuronal cadherin interacts with the extracellular domain of neuronal cadherin in neighboring cells,its intracellular domain binds toβ-catenin,which in turn links the complex to the actin cytos keleton.Glycogen synthase kinase 3βis a serine-threonine kinase that prevents the cytoplasmic accumulation ofβ-catenin by inducing its phosphorylation at Ser33,Ser37,and Ser41,thus activating a sequence of events that lead to its proteasomal degradation.The data discussed in this perspective indicate that astrocytes release u PA following a mechanical injury,and that binding of this u PA to uPAR on the cell membrane induces the detachment ofβ-catenin from the intracellular domain of neuronal cadherin by triggering its extracellular signal-regulated kinase 1/2-mediated phosphorylation at Tyr650.Remarkably,this is followed by the cytoplasmic accumulation ofβ-catenin because uPA-induced extracellular signalregulated kinase 1/2 activation also phosphorylates lipoprotein receptor-related protein 6 at Ser1490,which in turn,by recruiting glycogen synthase kinase 3βto its intracellular domain abrogates its effect onβ-catenin.The cytoplasmic accumulation ofβ-catenin is followed by its nuclear translocation,where it induces the expression of uPAR,which is required for the migration of astrocytes from the injured edge into the wounded area.
基金Supported by Copenhagen University Hospital(Rigshospitalets Forskningspuljer)The Danish National Research Foundation(Danish-Chinese Centre for Proteases and Cancer)Harboefonden,Torben og Alice Frimodts Fond,Fabrikant Einar Willumsens Mindelegat,Holger Rabitz and hustrus Legat,The Lundbeck Foundation.
文摘The high prevalence and mortality of lung cancer, together with a poor 5-year survival of only approximately 15%, emphasize the need for prognostic and predictive factors to improve patient treatment. C4.4A, a member of the Ly6/uP AR family of membrane proteins, qualifies as such a potential informative biomarker in non-small cell lung cancer. Under normal physiological conditions, it is primarily expressed in suprabasal layers of stratified squamous epithelia. Consequently, it is absent from healthy bronchial and alveolar tissue, but nevertheless appears at early stages in the progression to invasivecarcinomas of the lung, i.e., in bronchial hyperplasia/metaplasia and atypical adenomatous hyperplasia. In the stages leading to pulmonary squamous cell carcinoma, expression is sustained in dysplasia, carcinoma in situ and invasive carcinomas, and this pertains to the normal presence of C4.4A in squamous epithelium. In pulmonary adenocarcinomas, a fraction of cases is positive for C4.4A, which is surprising, given the origin of these carcinomas from mucin-producing and not squamous epithelium. Interestingly, this correlates with a highly compromised patient survival and a predominant solid tumor growth pattern. Circumstantial evidence suggests an inverse relationship between C4.4A and the tumor suppressor LKB1. This might provide a link to the prognostic impact of C4.4A in patients with adenocarcinomas of the lung and could potentially be exploited for predicting the efficacy of treatment targeting components of the LKB1 pathway.
