PAI-1 inhibits development of chronic otitis media and tympanosclerosis in a mouse model of otitis media.

CONCLUSION: Bullae of type 1 plasminogen activator inhibitor (PAI-1) knockout (KO) mice showed low levels of inflammation against nontypable Haemophilus influenzae (NTHi) at the early stage of otitis media (OM). However, PAI-1 KO mice fail to terminate inflammation, which may significantly contribute to the development of tympanosclerosis in PAI-1 KO mice. OBJECTIVE: To investigate the role of PAI-1 in the pathogenesis of OM and subsequent tympanosclerosis. METHODS: OM was induced with NTHi in PAI-1 KO and background control C57BL/6 mice. mRNA expression of PAI-1, tissue-type plasminogen activator (tPA), and urokinase-type plasminogen activator (uPA) was measured in the bullae of C57BL/6 mice. mRNA expression of interleukin (IL)-1ß, tumor necrosis factor (TNF) α, macrophage inflammatory protein (MIP-2), tPA, and uPA in PAI-1 KO and C57BL/6 mice was compared. Histological changes produced by OM were compared at 1, 3, and 7 days after NTHi inoculation. RESULTS: NTHi up-regulated the expression of PAI-1 and tPA in the bullae of C57BL/6 mice, but not uPA. mRNA expression of IL-1ß, TNFα, and MIP-2 was low in PAI-1 KO mice at early time points, but significantly higher at the later stage of OM. Similarly to the gene expression results, histological changes associated with OM were less at days 1 and 3 in PAI-1 KO mice. However, unlike the gradual resolution of OM pathologies in C57BL/6 mice, PAI-1 KO mice showed significant pathological changes of tympanosclerosis.

tPA promotes ADAMTS-4-induced CSPG degradation, thereby enhancing neuroplasticity following spinal cord injury.

Although tissue plasminogen activator (tPA) is known to promote neuronal remodeling in the CNS, no mechanism of how this plastic function takes place has been reported so far. We provide here in vitro and in vivo demonstrations that this serine protease neutralizes inhibitory chondroitin sulfate proteoglycans (CSPGs) by promoting their degradation via the direct activation of endogenous type 4 disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS-4). Accordingly, in a model of compression-induced spinal cord injury (SCI) in rats, we found that administration of either tPA or its downstream effector ADAMTS-4 restores the tPA-dependent activity lost after the SCI and thereby, reduces content of CSPGs in the spinal cord, a cascade of events leading to an improved axonal regeneration/sprouting and eventually long term functional recovery. This is the first study to reveal a tPA-ADAMTS-4 axis and its function in the CNS. It also raises the prospect of exploiting such cooperation as a therapeutic tool for enhancing recovery after acute CNS injuries.

Urokinase plasminogen activator and its inhibitor type-1 as prognostic factors in differentiated thyroid carcinoma patients.

OBJECTIVE: To investigate the prognostic value of urokinase-type plasminogen activator (uPA) and its inhibitor, type-1 plasminogen activator inhibitor (PAI-1), in differentiated thyroid cancer. STUDY DESIGN: Prospective cohort study. SETTING: University hospital. SUBJECTS AND METHODS: Cytosolic concentrations of uPA and PAI-1 were determined in 105 patients with differentiated thyroid carcinoma and normal matched tissues using an enzyme-linked immunoassay (ELISA). RESULTS: Both uPA and PAI-1 concentrations were significantly higher in differentiated thyroid tumors (uPA = 0.509 ± 0.767 and PAI-1 = 6.337 ± 6.415 ng/mg) compared to normal tissues (uPA = 0.237 ± 0.051, P < .001; PAI-1 = 2.368 ± 0.418 ng/mg, P < .001). uPA and PAI-1 were significantly higher if extrathyroidal invasion (uPA, P = .015; PAI-1, P < .001) or distant metastasis (PAI-1 P < .001) was present, as well as in tumors whose size exceeded 1 cm in diameter (uPA, P = .002; PAI-1, P = .001). Survival analysis revealed the significant impact of both uPA and PAI-1 on progression-free survival (PFS) (82.22 vs 49.478 months for patients with low and high uPA, respectively, P < .001; 87.068 vs 44.964 months for patients with low and high PAI-1, respectively, P < .001). Univariate analysis showed that gender, tumor size, tumor grade, extrathyroid invasion, local lymph node involvement, distant metastasis, uPA, and PAI-1 were significant predictors of PFS. However, multivariate analysis identified only distant metastasis and tumor tissue uPA and PAI-1 as independent prognostic factors. CONCLUSION: These findings indicate that high uPA and PAI-1 levels represent independent unfavorable prognostic factors in patients with differentiated thyroid carcinoma.

To study On the functional change of thrombosis and haemostasis system in patients with cerebral infarction / 国际检验医学杂志

Objective To investigate the change trend for D-dimer,antithrombin activity (AT:A),tissue plasminogen activator(t-PA),plasminogen activator inhibitor-1 (PAI-1)and yon Willebrand factor (vWF) before and after treatment in patients with cerebral infarction,so as to evaluate the clinical value of the above parameters in therapeutic effect monitoring of cerebral infarction.Methotis SYSMEX CA7000 blood coagulation analyzer was applied to determining plasma D-dimer,t-PA,PAI-1 and AT:A,and ELISA was adopted to measure vWF.Results Compared with those of healthy control group,D-dimer,PAI-1 and vWF were significantly increased (P<0.01),t-PA was significantly decreased (P<0.01),and AT:A had no change (P>0.05) in cerebral infarction group before treatment.In cerebral infarction group,compared with those of pre-treatment,D-dimer,PAI-1 and vWF were significantly decreased (P<0.01),t-PA was significantly increased(P<0.01),and AT:A had no change(P>0.05) after treatment.So was the situation between GCS>8 and GCS≤8group.Conclusion There are obvious changes of fibrinolytic system parameters and vWF level befor and after treatment in patients with cerebral infarction,and the changes are associated with the course of disease.

The influence of methyl-prednisone on extracellular matrix in rats with immune commplexes nephritis / 中国免疫学杂志

Objective:To observe the theraputic effect and changes of glomerular extracellular matrix components(ECM) and PAI-1 and their relationships after cure with methyl-prednisone on immune complexes nephritis rats.Methods:Immune complexes nephritis rats model were induced with C-BSA.Levels of FN,LN in different treatment groups were analyzed by ELISA, level of PAI-1 in rats renal tissue was determined by color developing substrate,was theraputic effect of methyl-prednisone with 24 hours volumes of urine protein.Results:The levels of PAI-1,FN and LN of model groups were significantly higher than those of normal and control groups,and PAI-1 was significantly correlated with LN and FN,Glomerular mesangial matrix proliferated slightly and moderately;The levels of FN,LN and PAI-1 decreased signifcantly and glomerular mesangial matrix proliferation lessen differently after cure of methyl-prednisone for 1 and 2 weeks,but not reaching the level of normal groups;24 hours volumes of urine protein decrease significantly in treatment groups.Conclusion:The ECM accumulation correlate with PAI-1 increase in immune complexes rats,methyl-prednisone may affect ECM accumulation by interfering with PA/PAI-1 system to reach a treatment purpose.

The Significance of Plasma Urokinase-type Plasminogen Activator and Type 1 Plasminogen Activator Inhibitor in Lung Cancer / 결핵

BACKGROUND: Cancer invasion and metastasis require the dissolution of the extracellular matrix in which several proteolytic enzymes are Involved. One of these enzymes is the urokinase - type plasminogen activator(u-PA), and plasminogen activator inhibitors(PAI-1, PAI-2) a]so have a possible role in cancer invasion and metastasis by protection of cancer itself from proteolysis by u-PA. It has been reported that the love]s of u-PA and plasminogen activator inhibitors in various cancer tissues are significantly higher than those in normal tissues and have significant correlations with tumor size and lymph node involvement Here, we measured the concentration of plasma u-PA and PAI- 1 antigens in the patients with lung cancer and compared the concentration of them with histologic types and staging parameters. METHODS: We measured the concentration of plasma u-PA and PAI-1 antigens using commercial ELISA kit in 37 lung cancer patients, 21 benign lung disease patients and 24 age-matched healthy controls, and we compared the concentration of them with histologic types and staging parameters in lung cancer patients. RESULTS: The concentration of u-PA was 1.0α0.3ng/mL in controls, 1.0α0.3ng/mL in benign lung disease patients and 0.9α0.3ng/mL in lung cancer patients. The concentration of PAI-1 was 14.2α6.7ng/mL in controls, 14.9α6.3ng/mL in benign lung disease patients, and 22.1 α9.8ng/mL in lung cancer patients. The concentration of PAI- 1 in lung cancer patients was higher than those of benign lung disease patients and controls. The concentration of u-PA was 0.7α0.4ng/mL in squamous cell carcinoma, 0.8α 0.3ng/mL in adenocarcinoma, 0.9ng/mL in large cell carcinoma, and 1.1α0.7ng/mL in small cell carcinoma. The concert traction of PAI-1 was 22.3α7.2ng/mL in squamous cell carcinoma, 22.6α9.9ng/mL in adenocarcinoma, 42ng/mL in large cell carcinoma, and 16.0α14.2ng/mL in small cell carcinoma. The concentration of u-PA was 0.74ng/mL in stage I, 1.2α0.6ng/mL in stage II, 0.7 α 0.4ng/mL in stage IIIA, 0.7α0.4ng/mL in stage IIIB, and 0.7α0.3ng/mL in stage IV. The concentration of PAI-1 was 21.8ng/mL in stage I, 22.7α8.7ng/mL in stage II, 18.4 α4.9ng/mL in stage IIIA, 25.3α9.0ng/mL in stage IIIB, and 21.5α10.8ng /mL in stage IV. When we divided T stage unto T1-3 and 74, the concentration of u-PA was 0.8α 0.4ng/mL in T1-3 and 0.7α0.4ng/mL in T4, and the concentration of PAI-1 was 17.9α 5.6ng/mL in T1-3 and 26.1α9.1ng/mL in T4. The concentration of PAI-1 in T4 was significantly higher than that in T1-3. The concentration of u-PA was 0.8α 0.4ng/mL in M0 and 0.7α0.3ng/mL in Ml, and the concentration of PAI-1 was 23.6α8.3ng/mL in M0 and 21.5α10.8ng/mL in M1 CONCLUSIONS: The plasma levels of PAI-1 in lung cancer were higher than benign lung disease and control, and the plasma levels of PAI-1 in 74 were significantly higher than T1-3. These findings suggest involvement of PAI-1 with local invasion of lung cancer, but it should be confirmed by the data on comparison with pathological staging and tissue level in lung cancer.