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Objective: To investigate the usefulness of the homeostasis model assessment as an index of insulin resistance (HOMA-IR) for evaluating the clinical course of patients with type 2 diabetes.Research Design and Methods: The usefulness of HOMA-IR and its relationship with insulin resistance assessed by the hyperinsulinemic-euglycemic clamp study (clamp IR) were evaluated in 55 Japanese patients with type 2 diabetes before and after treatment. The patients were subjected to diet (approximately 1,440-1,720 kcal/day) and exercise therapy (walking 10,000 steps daily) for 6 weeks during their hospitalization.Results: Univariate regression analysis disclosed a significant correlation between log-transformed HOMA-IR and log-transformed clamp IR before (r = -0.613, P < 0.0001) and after ( = -0.734, P < 0.0001) treatment. Neither the slopes (-0.71 +/- 0.12 vs. -0.79 +/- 0.09, F = 0.25, P = 0.61) nor the intercepts (y-intercept = 1.67 vs. 1.70, x-intercept = 2.36 vs. 2.15, F = 0.02, P = 0.88) of the regression lines between HOMA-IR and clamp IR were significantly different before and after treatment. There was a significant correlation between the decrease in log-transformed HOMA-IR and the increase in clamp IR during treatment (r = -0.617, P < 0.0001).Conclusions: HOMA-IR may constitute a useful method not only for diagnosing insulin resistance, but also for follow-up during the treatment of patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Unlabelled: Essentials Epithelial cell apoptosis is critical in the pathogenesis of idiopathic pulmonary fibrosis. Protein S, a circulating anticoagulant, inhibited apoptosis of lung epithelial cells. Overexpression of protein S in lung cells reduced bleomycin-induced pulmonary fibrosis. Intranasal therapy with exogenous protein S ameliorated bleomycin-induced pulmonary fibrosis., Summary: Background Pulmonary fibrosis is the terminal stage of interstitial lung diseases, some of them being incurable and of unknown etiology. Apoptosis plays a critical role in lung fibrogenesis. Protein S is a plasma anticoagulant with potent antiapoptotic activity. The role of protein S in pulmonary fibrosis is unknown. Objectives To evaluate the clinical relevance of protein S and its protective role in pulmonary fibrosis. Methods and Results The circulating level of protein S was measured in patients with pulmonary fibrosis and controls by the use of enzyme immunoassays. Pulmonary fibrosis was induced with bleomycin in transgenic mice overexpressing human protein S and wild-type mice, and exogenous protein S or vehicle was administered to wild-type mice; fibrosis was then compared in both models. Patients with pulmonary fibrosis had reduced circulating levels of protein S as compared with controls. Inflammatory changes, the levels of profibrotic cytokines, fibrosis score, hydroxyproline content in the lungs and oxygen desaturation were significantly reduced in protein S-transgenic mice as compared with wild-type mice. Wild-type mice treated with exogenous protein S showed significant decreases in the levels of inflammatory and profibrotic markers and fibrosis in the lungs as compared with untreated control mice. After bleomycin infusion, mice overexpressing human protein S showed significantly low caspase-3 activity, enhanced expression of antiapoptotic molecules and enhanced Akt and Axl kinase phosphorylation as compared with wild-type counterparts. Protein S also inhibited apoptosis of alveolar epithelial cells in vitro. Conclusions These observations suggest clinical relevance and a protective role of protein S in pulmonary fibrosis., (© 2016 International Society on Thrombosis and Haemostasis.)

Background: C4b-binding protein (C4BP), a multimeric protein structurally composed of alpha chains (C4BPalpha) and a beta chain (C4BPbeta), regulates the anticoagulant activity of protein S (PS). Patients with sepsis have increased levels of plasma C4BP, which appears to be induced by interleukin (IL)-6. However, it is not fully understood how lipopolysaccharide (LPS) and IL-6 affect the plasma C4BP antigen level and C4BPalpha and C4BPbeta expression in hepatocytes., Objectives: To assess the effect of LPS and IL-6 on plasma C4BP, PS-C4BP complex levels, PS activity, and C4BP expression by rat liver in vivo and on C4BP expression by isolated rat hepatocytes in vitro., Results: Plasma C4BP antigen level transiently decreased from 2 to 12 h after LPS (2 mg kg(-1)) injection, and then it abruptly increased up to 24 h after LPS injection. Plasma C4BP antigen level increased until 8 h after IL-6 (10 microg kg(-1)) injection, and then gradually decreased up to 24 h after IL-6 injection. LPS significantly decreased the protein and mRNA expression of both C4BPalpha and C4BPbeta in rat hepatocytes, and this effect was inhibited by NFkappaB and MEK/ERK inhibitors. IL-6 mediated increase in C4BPbeta expression in rat hepatocytes, which leads to increased plasma PS-C4BP complex level and to decreased plasma PS activity, was inhibited by inhibition of STAT-3., Conclusion: LPS decreases both C4BPalpha and C4BPbeta expression via the NFkappaB and MEK/ERK pathways, whereas IL-6 specifically increases C4BPbeta expression via the STAT-3 pathway, causing an increase in plasma PS-C4BP complex, and thus decreasing the anticoagulant activity of PS.

There are no prospective comparison of the etiology and clinical outcome between hospital-acquired pneumonia (HAP) and nursing home-acquired pneumonia (NHAP) in non-intubated elderly. This study prospectively evaluated the etiology of HAP and NHAP in non-intubated elderly. A prospective cohort study was carried out in a rural region of Japan where the population over 65 years of age represents 30% of the population. A total of 108 patients were enrolled. There were 33 patients with HAP and 75 with NHAP. Etiologic diagnosis was established in 78.8% of HAP and in 72% of NHAP patients. The most frequent pathogens were Chlamydophila pneumoniae followed by Streptococcus pneumoniae, Staphylococcus aureus and Influenza virus. The frequency of Streptococcus pneumoniae and Influenza virus was significantly higher, whereas the frequency of Staphylococcus aureus and Enterobacteriaceae was significantly lower in NHAP compared to HAP. Performance and nutritional status were significantly worse in patients with HAP than in those with NHAP. Hospital mortality was significantly lower in patients with NHAP compared to those with HAP. This study demonstrated that C. pneumoniae, Streptococcus pneumoniae, Staphylococcus aureus and Influenza virus are frequent causative agents of pneumonia in non-intubated elderly and that the responsible pathogens and clinical outcome differ between NHAP and HAP.

It is well recognized that activation of the coagulation system plays an important role in bleomycin (BLM)-induced lung injury and fibrosis. The protein C (PC) pathway is an important regulator of the coagulation system. In this study, we evaluated the bronchoalveolar lavage fluid (BALF) concentration of activated PC (APC) and the therapeutic effect of the intratracheal administration of APC on BLM-induced lung fibrosis in mice. APC levels in BALF were significantly lower in BLM-treated animals than in the saline-treated group. Fibrotic changes were progressive in mice treated with BLM and intratracheal instillation of vehicle (BLM/Veh) after 14 and 21 d of BLM infusion. Compared with the BLM/Veh group, histologic findings on Days 14 and 21 in mice treated with BLM and intratracheal instillation of APC (BLM/APC) showed less fibrotic lesions in the subpleural and central areas of the lung. The mean Aschcroft's fibrosis score in the BLM/Veh group was significantly (p < 0.05) higher than in the BLM/APC group. The lung hydroxyproline content on Day 21 was significantly higher (p < 0.05) in the BLM/Veh group (1.78 +/- 0.07 micromol/lung weight) than in the BLM/APC (1.30 +/- 0.06 micromol/lung weight) group. The ratio of plasminogen activator activity to thrombin level in BALF was significantly increased in the BLM/APC group compared with the BLM/ Veh group on Day 21. The expression of tumor necrosis factor-alpha and interleukin-1beta was significantly decreased in the lungs of the BLM/APC group compared with the BLM/Veh group on Day 14 after BLM infusion. These results showed that intratracheal APC administration inhibits the development of lung fibrosis in BLM-induced lung injury, giving further support to the important role that the PC pathway plays in the mechanism of lung fibrosis.

Inhalation of nitric oxide (NO) is useful for the treatment of patients with pulmonary hypertension. However, the potential toxicity of inhaled NO is still unclear. Coagulation activation plays an important role in lung injury. We assessed the effect of low- and high-dose inhaled NO on the coagulation system in the intraalveolar space of mice. The animals were assigned to five groups (n = 6): [RA] group, mice exposed to fresh air alone; [RA+2 ppm NO] group, fresh air and 2 ppm NO; [RA+40 ppm NO] group, fresh air and 40 ppm NO; [RA+2 ppm NO+O(2)] group, fresh air, 2 ppm NO and O(2); and [RA+40 ppm NO+O(2)] group, fresh air, 40 ppm NO and O(2). Each group was treated for 3 wk. Lung specimens of [RA+40 ppm NO] and [RA+40 ppm NO+O(2)] groups showed significant nitrotyrosine immunoreactivity. BALF concentrations of total protein, thrombin and soluble tissue factor were significantly increased in mice of [RA+40 ppm NO] and [RA+40 ppm NO+O(2)] groups compared with [RA] group. However, BALF concentrations of total protein, thrombin, and soluble tissue factor were not significantly increased in mice of [RA+2 ppm NO] and [RA+2 ppm NO+O(2)] groups compared with [RA] group. Lung tissue factor mRNA expression was higher in the high-dose NO group than in the low-dose NO group. NO donor increased significantly tissue factor activity on alveolar epithelial cells. This study has shown for the first time that long-term inhalation of high, but not low, concentration of NO may activate the clotting system by increasing the lung expression of tissue factor.

To investigate the relationship between peripheral blood levels of agouti-related protein (AGRP) and various parameters of obesity, we measured the plasma level of AGRP in 15 obese and 15 nonobese men and evaluated its relationship with body mass index (BMI), body fat weight, and visceral, sc, and total fat areas measured by computed tomography, fasting insulin levels, glucose infusion rate during an euglycemic hyperinsulinemic clamp study, serum leptin, and plasma alpha-MSH. Obese men had significantly higher plasma concentrations of AGRP than nonobese men (P < 0.01). Univariate analysis showed that the plasma levels of AGRP are proportionally correlated with BMI, body fat weight, and sc fat area in obese men (BMI: r = 0.732, P < 0.01; body fat weight: r = 0.603, P < 0.02; sc fat area: r = 0.668, P < 0.01) and in all men (BMI: r = 0.839, P < 0.0001; body fat weight: r = 0.818, P < 0.0001; sc fat area: r = 0.728, P < 0.0001). In all men, the plasma levels of AGRP were significantly correlated with the visceral fat area (r = 0.478, P < 0.01), total fat area (r = 0.655, P < 0.0001), fasting insulin level (r = 0.488, P < 0.01), glucose infusion rate (r = -0.564, P < 0.01), serum level of leptin (r = 0.661, P < 0.0001), and the plasma level of alpha-MSH (r = 0.556, P < 0.01). In all subjects, multiple regression analysis showed that the plasma levels of AGRP are significantly (F = 15.522, r = 0.801, P < 0.03) correlated with the plasma levels of alpha-MSH, independently from the total fat area. However, the correlation between plasma levels of AGRP and serum levels of leptin was found to be dependent on the total fat area. In brief, these findings showed that the circulating levels of AGRP are increased in obese men and that they are correlated with various parameters of obesity. Although correlation does not prove causation, the results of this study suggest that peripheral AGRP may play a role in the pathogenesis of obesity.

The patient was a 32-year-old obese woman with a history of type 2 diabetes and hypertension for 6 years. Although she was treated with antihypertensive agents and intensive insulin therapy, her hyperglycemia was difficult to control. She wanted to have a baby but pregnancy was not recommended because her diabetes was under poor control and the use of antihypertensive medication. To achieve good control of obesity, diabetes and hypertension, she was admitted to our clinical department for weight reduction using very low calorie diet (VLCD). During VLCD she had a 19.8 kg reduction in body weight and her blood glucose and blood pressure were in good control without the use of drugs. Five months later, she became pregnant after the fourth trial of intrauterine insemination (IUI) and gave birth to a female baby under insulin therapy. This is the first report that showed the usefulness of VLCD for prepregnant control of glucose metabolism and blood pressure in an obese hypertensive patient with type 2 diabetes mellitus.

Plasma levels of tissue factor pathway inhibitor (TFPI)-activated factor Xa (FXa) complex were measured in patients with disseminated intravascular coagulation (DIC), pre-DIC, and DIC. Plasma levels of plasmin-plasmin inhibitor complex (PPIC), D-dimer, and soluble fibrin monomer (SFM) were significantly higher in patients with DIC than in those with pre-DIC or non-DIC; the levels of these hemostatic markers were significantly higher in patients with pre-DIC than in those with non-DIC. Plasma levels of thrombin-antithrombin complex (TAT) were significantly higher in patients with DIC or pre-DIC than in those with non-DIC. Plasma levels of tissue factor (TF), total TFPI, free TFPI, and TFPI-Xa complex were significantly higher in patients with DIC than in those with non-DIC. Plasma levels of TFPI-Xa complex were significantly increased in patients with pre-DIC as compared to those with non-DIC; however, plasma free TFPI levels were significantly decreased in patients with pre-DIC as compared to those with non-DIC. These findings suggest that free TFPI might be consumed in the pre-DIC state, thereby confirming the activation of the extrinsic pathway. Plasma levels of TFPI-Xa complex were significantly correlated with TF, free TFPI, and total TFPI. Increased plasma TFPI-Xa complex levels might be useful for the diagnosis of DIC or pre-DIC, particularly that occurring by activation of the extrinsic pathway of blood coagulation.

Plasma levels of activated protein C (APC)-protein C inhibitor (PCI) were significantly increased in patients with disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), acute myocardial infarction (AMI), pulmonary embolism (PE), or deep vein thrombosis (DVT) and in patients undergoing hemodialysis (HD). Plasma levels of APC-alpha(1)-antitrypsin (AT) complex were significantly increased in patients with DIC and in those with TTP. Plasma levels of PCI were significantly decreased in patients with DIC, non-DIC, or TTP and in those undergoing HD. In the pre-DIC stage, the plasma levels of APC-PCI complex were significantly increased but not those of APC-alpha(1)-AT complex. These data suggest that measurements of APC-PCI complex and APC-alpha(1)-AT complex may be useful for the diagnosis of DIC. After treatment of DIC, the plasma levels of APC-PCI complex and APC-alpha(1)-AT complex were significantly decreased, but not those of PCI. Plasma levels of thrombin-antithrombin complex (TAT), plasmin-alpha(2)-plasmin complex (PPIC), D-dimer, and soluble fibrin monomer (SFM) were markedly increased in patients with DIC or pre-DIC and were moderately increased in patients with non-DIC, TTP, AMI, PE, or DVT and in those undergoing HD. The receiving operating characteristic (ROC) analysis showed that SFM and the APC-PCT complex are useful markers for diagnosis of DIC. The specificity of plasma TAT and PPIC levels was low. The positive rate of APC-PCI complex was higher than 90% with DIC, TTP, AMI, PE, and it was higher than 60% with DVT and HD. Since the APC-PCI complex was elevated not only in patients with venous thrombosis but also in those with arterial thrombosis, components of the protein C pathway might be useful markers for the diagnosis of arterial thrombosis., (Copyright 2000 Wiley-Liss, Inc.)

Several growth factors, including platelet-derived growth factor (PDGF), have been implicated in the mechanism of lung and airway remodeling. In the present study, we evaluated whether thrombin may promote lung and airway remodeling by increasing PDGF production from lung and airway epithelial cells. Conditioned medium (CM) was prepared by treating epithelial cells with increasing concentrations of thrombin; before use in the assays, CM was treated with hirudin until complete inhibition of thrombin activity. CM from epithelial cells stimulated the proliferation of lung fibroblasts and bronchial smooth muscle cells. Anti-PDGF antibody significantly inhibited this CM proliferative activity, implicating PDGF in this effect. Enzyme immunoassay and RT-PCR demonstrated that thrombin induced the secretion and expression of PDGF from bronchial and alveolar epithelial cells. RT-PCR showed that epithelial cells express the thrombin receptors protease-activated receptor (PAR)-1, PAR-3, and PAR-4. The PAR-1 agonist peptide was also found to induce PDGF secretion from epithelial cells, suggesting that the cellular effect of thrombin occurs via a PAR-1-mediated mechanism. Overall, this study showed for the first time that thrombin may play an important role in the process of lung and airway remodeling by stimulating the expression of PDGF via its cellular receptor, PAR-1.

This study evaluated hemostatic data in 28 patients with newly diagnosed acute promyelocytic leukemia (APL) and 15 patients with relapsed APL. Activated partial thromboplastin time and prothrombin time were prolonged at initial onset of APL. Plasma level of fibrinogen was significantly decreased in patients with initial disease of APL, but it was not decreased significantly during the relapse of APL. Plasma fibrin and fibrinogen degradation products levels were significantly increased and platelet counts significantly decreased in both groups. Plasma levels of antiplasmin significantly decreased at initial onset but not during relapse. Plasma levels of antithrombin were within normal range in patients with initial disease but significantly decreased in those with relapse. Plasma levels of D-dimer, soluble fibrin monomer (sFM), plasmin-plasmin inhibitor complex (PPIC), and thrombin antithrombin complex (TAT) levels were significantly high in both groups. Plasma levels of PPIC, sFM, and D-dimer were significantly higher at initial onset of APL than during relapse. However, there was no significant difference in DIC score between patients with initial onset and those with relapse; plasma levels of tissue factor (TF) significantly increased in both groups, but they were significantly higher at initial onset of APL than during relapse. TF and tissue type plasminogen activator (t-PA) antigen levels in leukemic cell lysate were significantly increased in both groups, and they were significantly lower during relapse than at initial onset. Hemostatic abnormalities occurring in patients with relapsed APL might be the result of the decrease of TF and t-PA in leukemic cells. These findings suggest that DIC in APL patients with relapse might not be caused only by TF and t-PA and thus should be treated with different therapy from patients with initial onset of APL., (Copyright 2000 Wiley-Liss, Inc.)

Changes of hemostatic parameters during percutaneous transluminal coronary angioplasty (PTCA) in 75 patients with chronic coronary artery disease were evaluated. Plasma levels of D-dimer, soluble fibrin monomer, plasmin-alpha2 antiplasmin inhibitor complex, and tissue factor (TF) were significantly increased in all patients with chronic coronary artery disease. The activity of antithrombin and protein C and the levels of protein C antigen were significantly decreased 1 hr after PTCA, but they returned to normal range 1 day after PTCA. There was no significant difference in the level of plasma APC-PCI complex before and 1 hr after PTCA. The plasma levels of D-dimer, soluble fibrin monomer, thrombomodulin, TF and PPIC were significantly decreased 1 hr, and the plasma levels of plasmin-alpha2 antiplasmin inhibitor complex 1 day after PTCA. These findings suggest that the decrease of protein C and antithrombin resulted in activation of the coagulation system. One hour after PTCA, the plasma levels of (total-free) TF pathway inhibitor (TFPI) were significantly decreased, but the plasma levels of total and free-TFPI were significantly increased, suggesting that consumption of (total-free) TFPI occurs during PTCA. Overall, these findings suggest that the hypercoagulable state improves during PTCA and that transient decrease of antithrombin, protein C, (total-free) TFPI or plasmin-alpha2 antiplasmin inhibitor complex may cause restenosis of coronary artery., (Copyright 1999 Wiley-Liss, Inc.)

Brain natriuretic peptide (BNP), a member of the natriuretic peptide family, is produced and released from cardiac ventricles. BNP regulates the body fluid volume, blood pressure, and vascular tones through the A-type guanylate cyclase-coupled receptor. The presence of renal dysfunction in patients with diabetes affects the plasma levels of atrial natriuretic peptide (ANP). In the present study, we investigated the plasma levels of BNP and ANP and their relationship in normotensive diabetic patients with normoalbuminuria and microalbuminuria. Forty-seven normotensive lean noninsulin-dependent diabetic patients (31 with normoalbuminuria, 16 with microalbuminuria), with normal cardiac function, and 30 age-matched control subjects were enrolled in this study. The plasma levels of BNP in diabetic patients with microalbuminuria were significantly higher than those in diabetic patients with normoalbuminuria (16.7+/-2.4 vs. 9.6+/-1.3 pg/mL, P<0.01) or normal subjects (16.7+/-2.4 vs. 7.0+/-0.6 pg/mL, P<0.01). There was a significant positive correlation between plasma BNP levels and urinary albumin excretion rate in all diabetic patients (r = 0.58, P<0.0001). There was also a significantly positive correlation between plasma BNP and ANP levels in diabetic patients (r = 0.62, P<0.0001). The increased plasma level of BNP in patients with microalbuminuria and its significant correlation with urinary albumin excretion rate suggest that the elevated circulating levels of BNP are caused by the presence of diabetic nephropathy. Down-regulation of A-type guanylate cyclase-coupled receptor of renal tubules may explain the increased plasma levels of both BNP and ANP in normotensive diabetic patients with microalbuminuria.

We retrospectively measured various hemostatic markers in 240 patients with disseminated intravascular coagulation (DIC) before the onset of DIC and in 110 non-DIC patients, and examined their usefulness for the diagnosis of pre-DIC. Changes in prothrombin time ratio and fibrinogen levels were not significant before the onset of DIC. The plasma levels of fibrinogen and fibrin degradation products before the onset of DIC were increased and the platelet count was gradually reduced in nonleukemic patients; these changes were already significant in the non-DIC state. The plasma levels of thrombin-antithrombin complex (TAT), plasmin-plasmin inhibitor complex (PPIC), D-dimer, and soluble fibrin monomer (sFM) were increased before the onset of DIC. In leukemic patients, the plasma levels of sFM on day 5, those of TAT on day 3, and D-dimer on day 1, were significantly increased before the onset of DIC. The levels of most hemostatic markers 7 days before the onset of DIC were not different from those observed in the non-DIC state. In nonleukemic patients, only D-dimer, sFM, and TAT levels were significantly increased 7 days before the onset of DIC compared with values in the non-DIC state. The positive rate of hemostatic markers for the diagnosis of DIC, TAT, and PPIC were high during the pre-DIC and non-DIC groups. The plasma levels of sFM and D-dimer were low in non-DIC and increased gradually during the pre-DIC state. These findings suggest that hemostatic molecular markers such as sFM, D-dimer, and TAT are useful for the diagnosis of pre-DIC, although their cutoff values were different among various diseases.

To evaluate that the relationship between the truncated form of tissue factor pathway inhibitor (TFPI) and the stage of disseminated intravascular coagulation (DIC), we measured the plasma levels of tissue factor (TF) antigen and the intact and truncated forms of TFPI antigens in 41 patients with DIC, 12 with pre-DIC, and 20 with non-DIC. The plasma TF and total TFPI antigen levels were significantly higher in patients with DIC than in non-DIC patients. Plasma levels of intact TFPI antigen in the pre-DIC groups were significantly lower than in the non-DIC and DIC groups. The truncated form of TFPI antigen levels in DIC patients were significantly increased compared with those in non-DIC and pre-DIC patients. The fact that the intact form of TFPI was decreased in pre-DIC patients compared with that in non-DIC patients, suggests that it is consumed in the pre-DIC state and that hypercoagulability occurs in pre-DIC patients. The increased level of the truncated form of TFPI in DIC patients may be attributed to proteolysis of the intact form of TFPI in these patients. The increased level of the truncated form of TFPI may be a useful index for the diagnosis of DIC.

Excessive procoagulant activity in the alveolar space may play a relevant role in the pathogenesis of pulmonary fibrosis. Hypercoagulability results from the disruption of the balance between the procoagulant and anticoagulant factors. The aim of this study was to assess the levels of molecular markers of the anticoagulant protein C (PC) pathway in the bronchoalveolar lavage fluid (BALF) and plasma of 11 patients with idiopathic pulmonary fibrosis (IPF), 14 with sarcoidosis and 16 with collagen vascular disease (CVD)-associated interstitial lung disease (CVD-ILD). Six healthy nonsmoking volunteers served as control subjects. BALF concentrations of the marker of clotting activation, thrombin- antithrombin III complex (TAT), in patients with sarcoidosis and CVD-ILD were significantly greater than those in control subjects. PC levels in BALF were markedly higher in patients with IPF (610 +/- 150 ng/ml), sarcoidosis (680 +/- 170 ng/ml), and CVD-ILD (1,580 +/- 600 ng/ml) than in control subjects (230 +/- 140 ng/ml). BALF concentrations of activated PC-PC inhibitor (APC-PCI) complex were significantly decreased in IPF (0.46 +/- 0.16 ng/ml), sarcoidosis (0. 43 +/- 0.11 ng/ml), and CVD-ILD (0.50 +/- 0.15 ng/ml) patients as compared with control subjects (1.08 +/- 0.23 ng/ml). APC-PCI/PC ratios were significantly lower in patients with IPF (2.70 +/- 1.74 ng/microg), sarcoidosis (1.94 +/- 0.82 ng/microg), and CVD-ILD (1.89 +/- 0.68 ng/microg) than in control subjects (15.91 +/- 8.45 ng/microg). Plasma levels of APC- PCI and the APC-PCI/PC ratio were also significantly decreased in patients with CVD-ILD as compared with control subjects. Overall, these findings suggest that decreased PC activation with increased procoagulant activity occurs in patients with ILD.

Dilazep, an antiplatelet agent, is generally used as an antithrombotic drug in clinical practice. Dilazep is also known to exert cytoprotective and antioxidant effects on endothelial cells. However, its effect on the endothelial or monocyte procoagulant activity is unknown. In the current study, the effect of dilazep on the expression of tissue factor (TF) in human umbilical vein endothelial cells (HUVECs) after the stimulation with tumor necrosis factor-alpha (TNF), thrombin, or phorbol 12-myristate 13-acetate (PMA) was evaluated. We also evaluated the effect of dilazep on TNF (1,000 U/mL)-induced TF expression on monocytes. Dilazep inhibited TF activity induced on HUVECs by each stimulant, TNF (1000 U/mL), thrombin (25 nmol/L), or PMA (5 nmol/L) in a dose-dependent fashion (1 to 100 microg/mL). TF activity decreased to approximately 10% after treating with 100 microg/mL of dilazep. Dilazep also blocked the expression of TF antigen induced by each stimulant on the surface of HUVECs as determined by flow cytometric analysis. In addition, in HUVECs, it significantly decreased the expression of TF mRNA and the total TF antigen induced by thrombin or PMA, but not those induced by TNF, suggesting that dilazep blocks the TF expression induced by PMA or thrombin at a transcriptional level and that induced by TNF at a posttranscriptional level. Western blot analysis showed that dilazep reduces the accumulation of native TF but increases that in lower molecular weight TF derivatives. The adenosine receptor antagonist, 8-(p-sulfophenyl) theophylline, partially counteracted the anticoagulant activity of dilazep on HUVECs, thereby suggesting that the inhibitory effect of dilazep on TF expression in HUVECs depends, at least in part, on its adenosine potentiating activity. Dilazep also inhibited TNF-induced TF expression on monocytes in a dose-dependent fashion (0.1 to 100 microg/mL). In brief, the current study showed for the first time that dilazep, a commonly used antiplatelet drug, strongly inhibits the TF expression in HUVECs and monocytes. Dilazep may have a potent therapeutic value in patients with hypercoagulable state for its inhibitory property on the procoagulant activity of endothelial cells and monocytes.

This study was undertaken to assess the arterial plasma levels of endothelin-1 (ET-1) and their relationship with pulmonary haemodynamic and gas exchange variables during exercise in patients with emphysema and interstitial lung disease (ILD). Incremental cycle ergometry was performed in all patients up to maximal capacity. At rest, arterial ET-1 levels were higher in emphysema (1.86 +/- 0.35 pg.mL-1; p < 0.02) and ILD (1.75 +/- 0.25 pg.mL-1; p < 0.03) patients than in controls (1.35 +/- 0.18 pg.mL-1). Emphysema (2.08 +/- 0.26 versus 1.70 +/- 0.40 pg.mL-1) and ILD (1.98 +/- 0.21 versus 1.67 +/- 0.02 pg.mL-1) patients with pulmonary hypertension (PH) presented significantly (p < 0.05) higher arterial ET-1 levels than those without. At rest, arterial ET-1 levels were significantly correlated with mean pulmonary arterial pressure (Ppa) in both ILD (r = 0.8, p = 0.01) and emphysema (r = 0.5, p = 0.03) patients. During exercise, the arterial ET-1 levels were significantly correlated with arterial oxygen (Pa,O2) (r = -0.6, p = 0.04), alveolar-arterial oxygen difference (r = 0.8, p = 0.01), and Ppa (r = 0.6, p = 0.04) in ILD patients, but not in those with emphysema. In brief, the results of this study suggest that arterial endothelin-1 is markedly increased in interstitial lung disease and emphysema patients, and that, it is related to the exercise-induced exacerbation of pulmonary hypertension in patients with interstitial lung disease, but not in those with emphysema.