| 2020 | Measurement of Bradykinin Formation and Degradation in Blood Plasma: Relevance for Acquired Angioedema Associated With Angiotensin Converting Enzyme Inhibition and for Hereditary Angioedema Due to Factor XII or Plasminogen Gene Variants. | Front Med (Lausanne) | Bradykinin (BK)-mediated angioedema (AE) states are rare acquired or hereditary conditions involving localized edema of the subcutaneous and submucosal tissues. Citrated plasma from healthy volunteers or patients with hereditary angioedema (HAE) with normal level of C1-inhibitor (C1-INH) was used to investigate pathways of BK formation and breakdown relevant to AE physiopathology. The half-life of BK (100 nM) added to normal plasma was 34 s, a value that was increased ~12-fold when the angiotensin converting enzyme (ACE) inhibitor enalaprilat (130 nM) was added (enzyme immunoassay measurements). The BK half-life was similarly increased ~5-fold following 2 daily oral doses of enalapril maleate in healthy volunteers, finding of possible relevance for the most common form of drug-associated AE. We also addressed the kinetics of immunoreactive BK (iBK) formation and decline, spontaneous or under three standardized stimuli: tissue kallikrein (KLK-1), the particulate material Kontact-APTT™ and tissue plasminogen activator (tPA). Relative to controls, iBK production was rapid (10-20 min) and very intense in response to tPA in plasma of female heterozygotes for variants in gene coding for factor XII (FXII) (p.Thr328Lys, 9 patients; p.Thr328Arg, one). An increased response to Kontact-APTT™ and an early tPA-induced cleavage of anomalous FXII (immunoblots) were also observed. Biotechnological inhibitors showed that the early response to tPA was dependent on plasmin, FXIIa and plasma kallikrein. Results from post-menopausal and pre-menopausal women with HAE-FXII were indistinguishable. The iBK production profiles in seven patients with the plasminogen p.Lys330Glu variant (HAE-PLG) did not significantly differ from those of controls, except for an unexpected, rapid and lanadelumab-resistant potentiation of KLK-1 effect. This enzyme did not cleave plasminogen or factor XII, suggesting a possible idiosyncratic interaction of the plasminogen pathogenic variant with KLK-1 activity. KLK-1 abounds in salivary glands and human saliva, hypothetically correlating with the clinical presentation of HAE-PLG that includes the swelling of the tongue, lips and contiguous throat tissues. Samples from HAE patients with normal C1-INH levels and gene did not produce excessive iBK in response to stimuli. The approach provides physiopathological insight into AE states and supports the heterogeneous physiopathology of HAE with normal C1-INH. |
| 2020 | An update on the genetics and pathogenesis of hereditary angioedema. | Genes Dis | Hereditary angioedema (HAE) is an uncommon genetic disorder characterized by recurrent episodes of edema involving subcutaneous tissue and submucosa. The pathogenesis of HAE reflects an intricate coordinated regulation of components of complement, kinin and hemostatic pathway. Till date, mutations in 4 different genes have been identified to cause HAE which includes serine protease inhibitor G1 (), factor XII (), plasminogen () and angiopoietin 1 (). These mutations lead to increased bradykinin 2 receptor mediated signalling via increased production of bradykinin except mutations in gene that disturbs the cytoskeletal assembly of vascular endothelial cells. In this review we aim to summarize the recent advances in the pathogenesis and genetics of HAE. We also provide an overview of possible future prospects in the identification of new genetic defects in HAE. |
| 2019 | Effect of Diosmin Administration in Patients with Chronic Venous Disorders on Selected Factors Affecting Angiogenesis. | Molecules | Diosmin is a natural compound with a wide range of biological activity, e.g., it improves lymphatic drainage, supports microcirculation, and increases venous tone, and venous elasticity, hence, it is applied in the pharmacotherapy of chronic venous disorders (CVD). The aim of this study was to assess the correlation between diosmin administration (2 × 600 mg daily) in patients suffering from CVD and the levels of selected factors influencing angiogenesis, which are involved in CVD pathophysiology. Thirty-five CVD patients were examined. Levels of plasma tumor necrosis factor alpha (TNF alpha), vascular endothelial growth factor (VEGF-A and VEGF-C); angiostatin, interleukin 6 (IL-6), fibroblast growth factor 2 (FGF2); and plasminogen (PLG) were measured with an Elisa assay before and after three months of diosmin administration. The clinical symptoms of CVD were monitored using ultrasound images, echo Doppler assay, visual analogue scale (VAS), and measurement of the leg circumference. The average content of TNF alpha, VEGF-C, VEGF-A IL-6, and FGF2 decreased after the therapy with diosmin in a significant manner; with < 0.001, < 0.05, < 0.05, < 0.01, and < 0.01, respectively, and a significant ( < 0.05) increase in the plasma angiostatin level after the three-month treatment was found. A significant ( < 0.05) decrease in edema and the average leg circumference of the patients was observed after the therapy. Diosmin influences the angiogenic and inflammatory mechanisms involved in the pathophysiology of edema presented in patients with a different class of CVD. |
| 2018 | iTRAQ-Based Quantitative Proteomics Reveals the New Evidence Base for Traumatic Brain Injury Treated with Targeted Temperature Management. | Neurotherapeutics | This study aimed to investigate the effects of targeted temperature management (TTM) modulation on traumatic brain injury (TBI) and the involved mechanisms using quantitative proteomics technology. SH-SY5Y and HT-22 cells were subjected to moderate stretch injury using the cell injury controller (CIC), followed by incubation at TTM (mild hypothermia, 32°C), or normothermia (37°C). The real-time morphological changes, cell cycle phase distribution, death, and cell viability were evaluated. Moderate TBI was produced by the controlled cortical impactor (CCI), and the effects of TTM on the neurological damage, neurodegeneration, cerebrovascular histopathology, and behavioral outcome were determined in vivo. Results showed that TTM treatment prevented TBI-induced neuronal necrosis in the brain, achieved a substantial reduction in neuronal death both in vitro and in vivo, reduced cortical lesion volume and neuronal loss, attenuated cerebrovascular histopathological damage, brain edema, and improved behavioral outcome. Using an iTRAQ proteomics approach, proteins that were significantly associated with TTM in experimental TBI were identified. Importantly, changes in four candidate molecules (plasminogen [PLG], antithrombin III [AT III], fibrinogen gamma chain [FGG], transthyretin [TTR]) were verified using TBI rat brain tissues and TBI human cerebrospinal fluid (CSF) samples. This study is one of the first to investigate the neuroprotective effects of TTM on the proteome of human and experimental models of TBI, providing an overall landscape of the TBI brain proteome and a scientific foundation for further assessment of candidate molecules associated with TTM for the promotion of reparative strategies post-TBI. |
| 2010 | Evaluation of the phototoxic potential of plants used in oriental medicine. | J Ethnopharmacol | Phototoxicity can be either harmful or beneficial. Yet the phototoxicity of oriental medicinal plants is an understudied area. The purpose of this study is to fill in this gap.The phototoxic potential of oriental medicinal plants was examined in vitro using photohemolysis and the Candida albicans test. Seventeen medicinal plants [Acorus gramineus (ACG), Panax ginseng C.A. (PAG), Platycodon grandiflorum (PLG), Aractylodes japonica (ATJ), Xanthium strumarium (XAS), Dioscorea batatas (DIB), Anemarrhena asphodeloides (ANA), Polygonatum sibiricum Red (PSR), Cocculus trilobus (COT), Ficus carica (FIC), Chelidonium majus var. asiaticum (CMA), Pulsatilla koreana (PUK), Agrimonia pilosa (AGP), Zanthoxylum schinifolium (ZAS), Angelica gigas (ANG), Ledebouriella seseloides (LES), and Cnidium officinale (CNO)] were selected because they showed strong fluorescence in one of our previous studies of 62 plants. We further evaluated in vivo phototoxicity in mice. 0.75 mL/kg of seed oil for Xanthium strumarium (XAS, ), or 1.25 mL/kg of extracted solutions of Atractylodes japonica (ATJ, ), Chelidonium majus var. asiaticum (CMA, ), Zanthoxylum schinifolium (ZAS, ), and Ledebouriella seseloides (LES, ) were given once, and evaluated for sunburn edema, formation of sunburn cell, decrease of epidermal Langerhans cells and local suppression of contact hypersensitivity by UVA irradiation.Sixteen out of the 17 plants tested except COT showed significant photohemolysis, and 5 of those exhibited phototoxic killing of Candida albicans. The phototoxicity of oriental medicines using those 5 plants was then studied in mice. The 5 plants increased sunburn edema and formation of sunburn cell, and suppressed immune responses locally by decreasing epidermal Langerhans cells and contact hypersensitivity by UVA irradiation.More than a quarter of oriental medicinal plants can be phototoxic, and strong fluorescence measured by absorption and fluorescence spectra can be an easier way to screen for phototoxicity. On the other hand, the phototoxicity of the plants may also be used therapeutically. Further studies regarding the phototoxicity of active components extracted from both live and dried oriental medicinal plants are necessary. |
| 2009 | Microglial low-density lipoprotein receptor-related protein 1 mediates the effect of tissue-type plasminogen activator on matrix metalloproteinase-9 activity in the ischemic brain. | J Cereb Blood Flow Metab | Studies in animal models of cerebral ischemia indicate that besides its thrombolytic effect, treatment with tissue-type plasminogen activator (tPA) also induces an increase in matrix metalloproteinase-9 (MMP-9) activity in the ischemic tissue associated with the development of cerebral edema. Earlier, we had shown that the low-density lipoprotein receptor-related protein 1 (LRP1) is a substrate for tPA in the brain. In this study, we investigated the effect of the interaction between tPA and microglial LRP1 on MMP-9 activity after middle cerebral artery occlusion (MCAO). We found that exposure to oxygen-glucose deprivation (OGD) conditions increases MMP-9 activity in wild-type (Wt) and plasminogen-deficient (Plg(-/-)) microglia, but not in tPA (tPA(-/-)) or LRP1-deficient (macLRP-) cells. Treatment with tPA increases MMP-9 expression in tPA(-/-) but not in macLRP- microglia. Middle cerebral artery occlusion increases MMP-9 expression and activity in Wt but not in tPA(-/-) or macLRP- mice, and treatment with tPA increases MMP-9 activity in tPA(-/-) mice but not in macLRP- animals. Finally, MCAO-induced ischemic edema and degradation of the interendothelial right junction protein claudin-5 were significantly attenuated in tPA(-/-) and macLRP- mice. The results of our study indicate that the interaction between tPA and microglial LRP1 increases MMP-9 expression and activity resulting in the degradation of claudin-5 and development of cerebral edema. |
| 2009 | Osteochondral defect repair after implantation of biodegradable scaffolds: indirect magnetic resonance arthrography and histopathologic correlation. | Acta Radiol | Biodegradable scaffolds have become an important option in the treatment of osteochondral defects. Therefore, accurate and reproducible monitoring of scaffold repair tissue is crucial.To assess the feasibility of indirect magnetic resonance (MR) arthrography in determining the quality of osteochondral repair after scaffold implantation using an MR imaging (MRI) scoring and grading system with histology as reference.Osteochondral defects created at ovine condylar facets were treated with either a commercial poly (DL-lactide-co-glycolide) (PLG) scaffold or a modified softer one (n=6/group; 87% and 55% of the elastic modulus of ovine subchondral bone, respectively). Empty defects at the contralateral condyle served as control group. A 1.5T MRI scan was performed after 6 months with proton density (PD)-weighted (w) fat-saturated (fs) fast spin-echo (FSE), T1-w two-dimensional (2D), and 3D fs gradient echo (GE) sequences 30 min after intravenous Gd-DTPA administration and passive joint movement. Two independent radiologists evaluated the repair tissue. The MR findings were correlated with histological findings.MRI and histological grading correlated well (10/12 cases). The stiff-scaffold group showed significantly superior repair in comparison to the control group (P<0.05). The 3D fs GE sequence proved to be most valuable in evaluating morphologic status. Complete defect filling and integration, intact surface and isointense signal to the adjacent native cartilage, subchondral incorporation with bone marrow edema, and graft plug enhancement were associated with a good histological outcome. Histologically, we found a smooth fibrocartilaginous layer and osseous replacement of the scaffold. Incomplete cartilage repair and irregular subchondral structures on the MRI correlated histologically with fibrocartilage-like repair and subchondral sclerosis, due to substantial degradation of the scaffold.Indirect MR arthrography is an accurate, noninvasive monitoring tool in the follow-up of scaffold implants. The MRI scoring and grading system allows reliable assessment of normal and pathological repair, with high correlation to histological findings. |
| 2008 | Lack of plasminogen does not alter the early inflammatory response following a tympanic membrane perforation: a study in plasminogen-deficient mice. | Acta Otolaryngol | The results of the present study show that the early inflammatory response in plasminogen (plg)-deficient mice is not altered compared to that in wild-type (wt) mice. Therefore the chronicity of the perforation in the long-term healing experiment cannot be explained by an impairment of the early inflammatory response, but rather by an impairment in activation of the inflammatory cells. These findings give further insight into the mechanisms resulting in a clinically seen chronic tympanic membrane (TM) perforation and thus possible therapeutic strategies to replace today's conventional surgical treatment of these perforations.Plg has been shown to play an essential role in the healing of TM perforations. In plg-deficient mice a completely arrested healing reaction was seen, resulting in a chronic TM perforation. The mechanisms involved seem to be an abundant neutrophil recruitment, an accumulation of macrophages, an arrested keratinocyte migration, and a massive deposition of fibrin along the TM tissue. However, the exact functional role of plg in the early inflammatory response during healing of TM perforation remains unclear. This study aimed to evaluate the early inflammatory response, mainly the occurrence of macrophages and neutrophils, during the first 48 h following a perforation in the pars tensa (PT) of the TM, in mice lacking the plasminogen gene compared to the corresponding response in wt mice.The TMs were perforated in 45 plg-deficient and 39 wt mice. Otomicroscopic evaluation was performed at 3, 6, 9, 12, 18, 24, and 48 h after the perforation was made. Mice were harvested at all time points and prepared for morphology including immunohistochemistry (IHC). IHC was performed with antibodies targeting macrophages, neutrophils, T and B cells, cytokeratin, and fibrin(ogen). Morphometry was performed regarding the volume percentage of TM tissue occupied by the different inflammatory cells.Perforation of the TM resulted in early otomicroscopic changes of the pars flaccida (PF) in both genotypes. Infiltration of inflammatory cells to PF and the presence of edema occurred as early as 6 h after the perforation was made, in both plg-deficient and wt mice. Morphometry did not reveal any significant differences between the genotypes concerning the occurrence of inflammatory cells. In contrast to the PF, the PT showed only sparse reactions during the experimental period. Furthermore, the migration pattern of keratinocytes did not differ between the genotypes throughout the experimental period. |
| 2003 | Tissue-type plasminogen activator induces opening of the blood-brain barrier via the LDL receptor-related protein. | J Clin Invest | The regulation of cerebrovascular permeability is critical for normal brain homeostasis, and the "breakdown" of the blood-brain barrier (BBB) is associated with the development of vasogenic edema and intracranial hypertension in a number of neurological disorders. In this study we demonstrate that an increase in endogenous tissue-type plasminogen activator (tPA) activity in the perivascular tissue following cerebral ischemia induces opening of the BBB via a mechanism that is independent of both plasminogen (Plg) and MMP-9. We also show that injection of tPA into the cerebrospinal fluid in the absence of ischemia results in a rapid dose-dependent increase in vascular permeability. This activity is not seen with urokinase-type Plg activator (uPA) but is induced in Plg-/- mice, confirming that the effect is Plg-independent. However, the activity is blocked by antibodies to the LDL receptor-related protein (LRP) and by the LRP antagonist, receptor-associated protein (RAP), suggesting a receptor-mediated process. Together these studies demonstrate that tPA is both necessary and sufficient to directly increase vascular permeability in the early stages of BBB opening, and suggest that this occurs through a receptor-mediated cell signaling event and not through generalized degradation of the vascular basement membrane. |
| 2001 | Protein-Losing Enteropathy and Gastropathy. | Curr Treat Options Gastroenterol | The diagnosis of protein-losing enteropathy (PLE) should be considered in all patients with hypoalbuminemia and edema without other known causes, and established by plasma alpha(1)-antitrypsin (alpha(1)-AT) clearance or nuclear studies. The therapy for PLE should focus principally on the treatment of the underlying disease after it has been identified. Therapeutic goals should include improvement of hypoalbuminemia, edema, and lymphopenia. The existing primary literature for therapy of PLE syndromes consists mainly of case reports and expert opinions, subject to substantial reporting bias and unknown rates of spontaneous remission; the rarity of and the diversity among this set of diseases make future large randomized trials unlikely. Therapeutic choices, therefore, must involve clinical acumen, empiricism, and understanding of the pathophysiology of the underlying disease process, and must be tailored to each individual patient's syndrome. Dietary interventions including hypolipidic, high-protein regimens, supplemented by medium-chain triglycerides (MCTs), are extremely useful, particularly in protein loss due to increased lymphatic pressure. Corticosteroids can be very useful in certain cases of PLE (though not without substantial long-term toxicity) when clinical serologic or histologic markers of inflammatory disease are present. Octreotide is a well tolerated drug that has been demonstrated to improve PLE in some patients, and is worth consideration. Octreotide is a well tolerated drug that has been demonstrated to improve PLE in some patients, and is worth consideration. Surgery finds its best role in treating gastrointestinal protein loss from neoplasia, inflammatory bowel disease, and hypertrophic gastritis. Most other PLEs are distributed too widely for surgical intervention. Protein-losing gastropathy (PLG) behaves somewhat differently from the general group of PLE, marked by excellent responses to elimination of Helicobacter pylori, antisecretory therapy, and surgical resection. Protein-losing enteropathy stemming from cardiovascular disease is best treated by medical or surgical cardiovascular interventions; however, some patients may respond to mucosa-directed therapy. |
| 1988 | Transient protein-losing gastropathy (Menetrier's disease) in childhood. | Pediatr Radiol | Two cases of transient protein-losing gastropathy (PLG) or Menetrier's disease in childhood are described. Both cases presented with an abrupt onset of edema due to hypoalbuminemia and were diagnosed by an upper gastrointestinal series. One of the cases was further diagnosed and followed by ultrasound. We believe that this is the first description of the ultrasonic picture of transient PLG in children. In both cases complete recovery was evident after a few weeks. |
| 1984 | Current status of pulmonary thromboembolism--incidence, diagnosis, classification, pathogenesis, and treatment. | Jpn Circ J | The incidence of pulmonary thromboembolism in the total autopsied cases and the actual reported cases of pulmonary thromboembolism in Japan has gradually increased. Since there is no part of the history, physical examination or noninvasive laboratory findings that is specific, a tentative criteria for diagnosis of pulmonary thromboembolism is proposed based a scoring system. Pulmonary thromboembolism can be classified into 5 different types: (1) massive pulmonary thromboembolism, (2) recurrent or occult pulmonary thromboembolism, (3) diffuse pulmonary microthromboembolism, (4) submassive pulmonary thromboembolism, (5) pulmonary infarction. We have carried out a series of model experiments in order to clarify the mechanism of the development of pulmonary microthromboembolism and the production of pulmonary infarction. On the basis of this data, we suspect that hyperfibrinolysis, endothelial damages and activated permeability factors lead to the interstitial and alveolar edema in pulmonary microthromboembolism or severe hemorrhage in pulmonary infarction. The combination therapy of UK (480,000 units) and DS (3,000 mg) had two advantages: (1) inhibition of shortening of APTT, (2) economy of UK dosage. Laboratory monitoring for effective UK therapy showed a markedly reduced alpha 2PI to under 50% of normal levels and fibrinolysis associated with fibrinogenolysis. The therapeutic effects of heparin were assessed by prolonged APTT (45-250 sec) and elevated Anti-FXa activity (0.2-1.2 u/ml of plasma heparin concentration) as an indicator for the evaluation of anticoagulation activity and by normalized FPA, Fbg, FDP, Plg and AT III as an indicator for evaluation of antithrombolic activity. |
| 1982 | [Effect of combined use of dextran sulfate and urokinase in cases of preeclampsia-behavior of blood coagulation-fibrinolysis and inhibitor systems]. | Nihon Sanka Fujinka Gakkai Zasshi | In the severe cases of toxemia of pregnancy, the coagulation-fibrinolysis pattern and the morphological findings of the kidney suggest participation of chronic DIC. Accordingly, it is considered that management of mother and fetus by administration of drugs with anticoagulant and fibrinolytic activities may be useful.For 17 cases of preeclampsia (gestosis index, 9.1 +/- 1.5) daily dose of 3,000-1,500mg DS and 48,000 IU of UK were administered intravenously by one shot or drip (10-30 minutes) twice daily. The following clinical and laboratory examinations were done: Gestosis index (GI), blood pressure (BP), edema, urine volume, urine protein, Ccr (ml/min), platelet counts, PT, PTT, PRT, TT, factors XII, IX, VIII, X, VII, V, II and XIII, Fbg, ELT, eug + SKLA(Std), Plg, SFMC, serum and urine FDP, AT-III, C1-INA, alpha 2-PI, alpha 2-M and alpha 1-AT.In the preeclamptic women, increases in intrinsic coagulating factors, marked decreases in the extrinsic coagulating factors, depletion of ELT, rise in SFMC, marked increases in blood and urine FDP, and decreases in AT-III and alpha 2-PI were observed, suggesting the presence of chronic DIC. After administration of DS and UK, improvement of clinical findings such as a fall of BP, disappearance of edema, reduction in urine protein, and increase in Ccr were observed. In addition, normalization of the intrinsic system, recovery of the extrinsic system, ELT and serum FDP to normal levels, increasing tendency of Plg, AT-III, alpha 2-PI, alpha 2-M, alpha 1-AT, and disappearance of urine FDP were demonstrated at the same time. It is therefore concluded that this treatment for severe preeclampsia seems to be effective. |