23 results on '"Daalhuisen J"'
Search Results
2. Coagulation Factor IX deficiency does not afford protection from pulmonary fibrosis in the experimental murine bleomycin model: PB 3.74–2
- Author
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Borensztajn, K S, Cong, L, François, C, Crestani, B, Daalhuisen, J, Christophe, O D, and Spek, A
- Published
- 2013
3. Vagus nerve stimulation inhibits activation of coagulation and fibrinolysis during endotoxemia in rats
- Author
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VAN WESTERLOO, D.J., GIEBELEN, I.A.J., MEIJERS, J.C.M., DAALHUISEN, J., DE VOS, A.F., LEVI, M., and VAN DER POLL, T.
- Published
- 2006
- Full Text
- View/download PDF
4. A pivotal role of protease-activated receptor-2 in bleomycin-induced pulmonary fibrosis: OC-WE-105
- Author
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Borensztajn, K S, Bresser, P, von der Thusen, J, van den Blink, B, Groot, A P, Daalhuisen, J, Peppelenbosch, M P, and Spek, A
- Published
- 2009
- Full Text
- View/download PDF
5. Pharmacological targeting of protease-activated receptor 2 affords protection from bleomycin-induced pulmonary fibrosis
- Author
-
Lin, C. (Cong), Thusen, J.H. (Jan) von der, Daalhuisen, J. (Joost), Ten Brink, M. (Marieke), Crestani, B. (Bruno), Poll, T. (Tom) van der, Borensztajn, K. (Keren), Arnold Spek, C. (C.), Lin, C. (Cong), Thusen, J.H. (Jan) von der, Daalhuisen, J. (Joost), Ten Brink, M. (Marieke), Crestani, B. (Bruno), Poll, T. (Tom) van der, Borensztajn, K. (Keren), and Arnold Spek, C. (C.)
- Abstract
Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease that remains refractory to therapy. Despite increasing evidence that protease-activated receptor 2 (PAR-2) contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed whether PAR-2 deficiency persistently reduces bleomycin-induced pulmonary fibrosis or merely delays disease progression and whether pharmacological PAR-2 inhibition limits experimental pulmonary fibrosis. Bleomycin was instilled intranasally into wild-type or PAR-2-deficient mice in the presence/absence of a specific PAR-2 antagonist (P2pal-18S). Pulmonary fibrosis was consistently reduced in PAR-2-deficient mice throughout the fibrotic phase, as evident from reduced Ashcroft scores (29%) and hydroxyproline levels (26%) at d 28. Moreover, P2pal-18S inhibited PAR-2-induced profibrotic responses in both murine and primary human pulmonary fibroblasts (p < 0.05). Once daily treatment with P2pal-18S reduced the severity and extent of fibrotic lesions in lungs of bleomycin-treated wild-type mice but did not further reduce fibrosis in PAR-2-deficient mice. Importantly, P2pal-18S treatment starting even 7 d after the onset of fibrosis limits pulmonary fibrosis as effectively as when treatment was started together with bleomycin instillation. Overall, PAR-2 contributes to the progression of pulmonary fibrosis, and targeting PAR-2 may be a promising therapeutic strategy for treating pulmonary fibrosis.
- Published
- 2015
- Full Text
- View/download PDF
6. Pharmacological Targeting of Protease-Activated Receptor 2 Affords Protection from Bleomycin-Induced Pulmonary Fibrosis
- Author
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Lin, C, von der Thusen, J, Daalhuisen, J, ten Brink, M (Mirian), Crestani, B, van der Poll, T, Borensztajn, K, Spek, CA, Lin, C, von der Thusen, J, Daalhuisen, J, ten Brink, M (Mirian), Crestani, B, van der Poll, T, Borensztajn, K, and Spek, CA
- Abstract
Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease that remains refractory to therapy. Despite increasing evidence that protease-activated receptor 2 (PAR-2) contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed whether PAR-2 deficiency persistently reduces bleomycin-induced pulmonary fibrosis or merely delays disease progression and whether pharmacological PAR-2 inhibition limits experimental pulmonary fibrosis. Bleomycin was instilled intranasally into wild-type or PAR-2-deficient mice in the presence/absence of a specific PAR-2 antagonist (P2pal-18S). Pulmonary fibrosis was consistently reduced in PAR-2-deficient mice throughout the fibrotic phase, as evident from reduced Ashcroft scores (29%) and hydroxyproline levels (26%) at d 28. Moreover, P2pal-18S inhibited PAR-2-induced profibrotic responses in both murine and primary human pulmonary fibroblasts (p < 0.05). Once daily treatment with P2pal-18S reduced the severity and extent of fibrotic lesions in lungs of bleomycin-treated wild-type mice but did not further reduce fibrosis in PAR-2-deficient mice. Importantly, P2pal-18S treatment starting even 7 d after the onset of fibrosis limits pulmonary fibrosis as effectively as when treatment was started together with bleomycin instillation. Overall, PAR-2 contributes to the progression of pulmonary fibrosis, and targeting PAR-2 may be a promising therapeutic strategy for treating pulmonary fibrosis.
- Published
- 2015
7. Protease-activated receptor-2 induces myofibroblast differentiation and tissue factor up-regulation during bleomycin-induced lung injury: Potential role in pulmonary fibrosis
- Author
-
Borensztajn, K. (Keren), Bresser, P. (Paul), Loos, C.M. (Chris) van der, Bot, I. (Ilze), Blink, B. (Bernt) van den, Bakker, M.A. (Michael) den, Daalhuisen, J. (Joost), Groot, A.P. (Angelique), Peppelenbosch, M.P. (Maikel), Thusen, J.H. (Jan) von der, Spek, C.A. (Arnold), Borensztajn, K. (Keren), Bresser, P. (Paul), Loos, C.M. (Chris) van der, Bot, I. (Ilze), Blink, B. (Bernt) van den, Bakker, M.A. (Michael) den, Daalhuisen, J. (Joost), Groot, A.P. (Angelique), Peppelenbosch, M.P. (Maikel), Thusen, J.H. (Jan) von der, and Spek, C.A. (Arnold)
- Abstract
Idiopathic pulmonary fibrosis constitutes the most devastating form of fibrotic lung disorders and remains refractory to current therapies. The coagulation cascade is frequently activated during pulmonary fibrosis, but this observation has so far resisted a mechanistic explanation. Recent data suggest that protease-activated receptor (PAR)-2, a receptor activated by (among others) coagulation factor (F)Xa, plays a key role in fibrotic disease; consequently, we assessed the role of PAR-2 in the development of pulmonary fibrosis in this study.
- Published
- 2010
- Full Text
- View/download PDF
8. Does the extend of the culture time of primary hepatocytes in a bioreactor affect the treatment efficacy of a bioartificial liver?
- Author
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Flendrig, L. M., Maas, M. A., Daalhuisen, J., Ladiges, N. C., la Soe, J. W., te Velde, A. A., Chamuleau, R. A., and Other departments
- Abstract
The purpose of this study was to investigate whether the efficacy of our novel extracorporeal bioartificial liver (BAL) to support rats with complete liver ischemia (LIS) could be improved by extending the culture time of freshly isolated porcine hepatocytes from 14 hours to 38 hours. The results showed that survival as well as porcine hepatocyte integrity improved, the onset of coma delayed, and the ammonia levels decreased in LIS rats of the 38 hour group compared to the 14 hour group, but no statistically significant differences were observed. In the 38 hour group, but not the 14 hour group, the onset of hepatic encephalopathy was significantly delayed and ammonia metabolism significantly improved compared to the LIS rats in control groups that only received a glucose infusion or were connected to a BAL without cells. In conclusion, prolonged hepatocyte recovery favoured all investigated parameters, although not all observed effects were statistically significant. More research is required to find out how long primary hepatocytes should be cultured in a bioreactor for optimal BAL support
- Published
- 1998
9. Commercially available media for flushing extracorporeal bioartificial liver systems prior to connection to the patient's circulation: an in vitro comparative study in two and three dimensional porcine hepatocyte cultures
- Author
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Flendrig, L. M., Sommeijer, D., Ladiges, N. C., te Velde, A. A., Maas, M. A., Jörning, G. G., Daalhuisen, J., Chamuleau, R. A., and Other departments
- Abstract
Extracorporeal bioartificial liver (BAL) systems based on hepatocytes need to be flushed before clinical application, as hepatocyte culture media are not approved for medical use. Commercially available 0.9% NaCl solution and hemofiltration solution (both supplemented with 10% human albumin) were investigated in vitro to test their potential to wash BAL systems with minimal stress for the cultured hepatocytes. After a 2 hour incubation, the lidocaine metabolising capacity and release of liver enzymes were assessed. As hepatocytes have been cultured in bioreactors in either two or three dimensional cell configurations, we tested the media in respectively hepatocyte monolayers cultures and in our newly developed bioreactor in which hepatocytes reorganise as small hepatocyte aggregates. The three dimensional hepatocyte cultures tolerated both media well, and no significant differences were seen compared with hepatocytes cultured in Williams' E (reference hepatocyte culture medium). The two dimensional hepatocyte cultures tolerated the supplemented hemofiltration solution and the reference medium equally well, but the condition of the porcine hepatocytes monolayer cultures was significantly impaired when incubated with the supplemented physiological saline solution. In conclusion, as a supplemented physiological saline solution may have detrimental effects on the condition of the hepatocytes, the more complex hemofiltration solution (bicarbonate buffered, glucose, essential minerals) was considered the better alternative for flushing bioartificial liver systems
- Published
- 1998
10. Therapy-resistant tumor microvascular endothelial cells contribute to treatment failure in glioblastoma multiforme
- Author
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Borovski, T, primary, Beke, P, additional, van Tellingen, O, additional, Rodermond, H M, additional, Verhoeff, J J, additional, Lascano, V, additional, Daalhuisen, J B, additional, Medema, J P, additional, and Sprick, M R, additional
- Published
- 2012
- Full Text
- View/download PDF
11. Mucosal αc4β7+/CD45RBhigh+ T lymphocytes in TNBS induced colitis
- Author
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Camoglio, L, primary, te Velde, A. A., additional, Daalhuisen, J. B, additional, and Hv, S. J., additional
- Published
- 1999
- Full Text
- View/download PDF
12. Memantine, a noncompetitive NMDA receptor antagonist improves hyperammonemia-induced encephalopathy and acute hepatic encephalopathy in rats
- Author
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Vogels, B A, primary, Maas, M A, additional, Daalhuisen, J, additional, Quack, G, additional, and Chamuleau, R A, additional
- Published
- 1997
- Full Text
- View/download PDF
13. Commercially Available Media for Flushing Extracorporeal Bioartificial Liver Systems Prior to Connection to the Patient's Circulation: An in vitroComparative Study in Two and Three Dimensional Porcine Hepatocyte Cultures
- Author
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Flendrig, L.M., Sommeijer, D., Ladiges, N.C.J.J., Te Velde, A.A., Maas, M.A.W., Jörning, G.G.A., Daalhuisen, J., and Chamuleau, R.A.F.M.
- Abstract
Extracorporeal bioartificial liver (BAL) systems based on hepatocytes need to be flushed before clinical application, as hepatocyte culture media are not approved for medical use. Commercially available 0.9% NaCl solution and hemofiltration solution (both supplemented with 10% human albumin) were investigated in vitro to test their potential to wash BAL systems with minimal stress for the cultured hepatocytes. After a 2 hour incubation, the lidocaine metabolising capacity and release of liver enzymes were assessed. As hepatocytes have been cultured in bioreactors in either two or three dimensional cell configurations, we tested the media in respectively hepatocyte monolayers cultures and in our newly developed bioreactor in which hepatocytes reorganise as small hepatocyte aggregates. The three dimensional hepatocyte cultures tolerated both media well, and no significant differences were seen compared with hepatocytes cultured in Williams’ E (reference hepatocyte culture medium). The two dimensional hepatocyte cultures tolerated the supplemented hemofiltration solution and the reference medium equally well, but the condition of the porcine hepatocytes monolayer cultures was significantly impaired when incubated with the supplemented physiological saline solution. In conclusion, as a supplemented physiological saline solution may have detrimental effects on the condition of the hepatocytes, the more complex hemofiltration solution (bicarbonate buffered, glucose, essential minerals) was considered the better alternative for flushing bioartificial liver systems.
- Published
- 1998
- Full Text
- View/download PDF
14. Dabigatran potentiates gemcitabine-induced growth inhibition of pancreatic cancer in mice.
- Author
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Shi K, Damhofer H, Daalhuisen J, Ten Brink M, Richel DJ, and Spek CA
- Abstract
Pancreatic cancer is one of the most lethal solid malignancies with little treatment options. We have recently shown that expression of protease activated receptor (PAR)-1 in the tumor microenvironment drives progression and induces chemoresistance of pancreatic cancer. As thrombin is the prototypical PAR-1 agonist, here we addressed the effect of the direct thrombin inhibitor dabigatran on pancreatic cancer growth and drug resistance in an orthotropic pancreatic cancer model. We show that dabigatran treatment did not affect primary tumor growth whereas it significantly increased tumor dissemination throughout the peritoneal cavity. Increased dissemination was accompanied by intratumoral bleeding and increased numbers of aberrant and/or collapsed blood vessels in the primary tumors. In combination with gemcitabine, dabigatran treatment limited primary tumor growth, did not induce bleeding complications and prevented tumor cell dissemination. Dabigatran was however not as efficient as genetic ablation of PAR-1 in our previous study suggesting that thrombin is not the main PAR-1 agonist in the setting of pancreatic cancer. Overall, we show that dabigatran potentiates gemcitabine-induced growth inhibition of pancreatic cancer but does not affect primary tumor growth when used as a monotherapy.
- Published
- 2017
- Full Text
- View/download PDF
15. Pharmacological Targeting of Protease-Activated Receptor 2 Affords Protection from Bleomycin-Induced Pulmonary Fibrosis.
- Author
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Lin C, von der Thüsen J, Daalhuisen J, ten Brink M, Crestani B, van der Poll T, Borensztajn K, and Spek CA
- Subjects
- Animals, Bleomycin toxicity, Fibroblasts drug effects, Fibroblasts metabolism, Humans, Idiopathic Pulmonary Fibrosis chemically induced, Idiopathic Pulmonary Fibrosis genetics, Mice, Receptor, PAR-2 antagonists & inhibitors, Idiopathic Pulmonary Fibrosis drug therapy, Lipopeptides administration & dosage, Receptor, PAR-2 genetics
- Abstract
Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease that remains refractory to therapy. Despite increasing evidence that protease-activated receptor 2 (PAR-2) contributes to fibrosis, its importance in pulmonary fibrosis is under debate. We addressed whether PAR-2 deficiency persistently reduces bleomycin-induced pulmonary fibrosis or merely delays disease progression and whether pharmacological PAR-2 inhibition limits experimental pulmonary fibrosis. Bleomycin was instilled intranasally into wild-type or PAR-2-deficient mice in the presence/absence of a specific PAR-2 antagonist (P2pal-18S). Pulmonary fibrosis was consistently reduced in PAR-2-deficient mice throughout the fibrotic phase, as evident from reduced Ashcroft scores (29%) and hydroxyproline levels (26%) at d 28. Moreover, P2pal-18S inhibited PAR-2-induced profibrotic responses in both murine and primary human pulmonary fibroblasts (p < 0.05). Once daily treatment with P2pal-18S reduced the severity and extent of fibrotic lesions in lungs of bleomycin-treated wild-type mice but did not further reduce fibrosis in PAR-2-deficient mice. Importantly, P2pal-18S treatment starting even 7 d after the onset of fibrosis limits pulmonary fibrosis as effectively as when treatment was started together with bleomycin instillation. Overall, PAR-2 contributes to the progression of pulmonary fibrosis, and targeting PAR-2 may be a promising therapeutic strategy for treating pulmonary fibrosis.
- Published
- 2015
- Full Text
- View/download PDF
16. Protease-activated receptor (PAR)-2 is required for PAR-1 signalling in pulmonary fibrosis.
- Author
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Lin C, von der Thüsen J, Daalhuisen J, ten Brink M, Crestani B, van der Poll T, Borensztajn K, and Spek CA
- Subjects
- Actins metabolism, Animals, Bleomycin, Blotting, Western, Collagen metabolism, Extracellular Signal-Regulated MAP Kinases metabolism, Fibroblasts drug effects, Fibroblasts metabolism, Humans, Hydroxyproline metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, NIH 3T3 Cells, Peptide Fragments pharmacology, Phosphorylation drug effects, Pulmonary Fibrosis chemically induced, Pulmonary Fibrosis genetics, Receptor, PAR-1 antagonists & inhibitors, Receptor, PAR-1 genetics, Receptor, PAR-2 antagonists & inhibitors, Receptor, PAR-2 genetics, Thrombin pharmacology, Trypsin pharmacology, Pulmonary Fibrosis metabolism, Receptor, PAR-1 metabolism, Receptor, PAR-2 metabolism, Signal Transduction
- Abstract
Idiopathic pulmonary fibrosis is the most devastating diffuse fibrosing lung disease of unknown aetiology. Compelling evidence suggests that both protease-activated receptor (PAR)-1 and PAR-2 participate in the development of pulmonary fibrosis. Previous studies have shown that bleomycin-induced lung fibrosis is diminished in both PAR-1 and PAR-2 deficient mice. We thus have been suggested that combined inactivation of PAR-1 and PAR-2 would be more effective in blocking pulmonary fibrosis. Human and murine fibroblasts were stimulated with PAR-1 and PAR-2 agonists in the absence or presence of specific PAR-1 or PAR-2 antagonists after which fibrotic markers like collagen and smooth muscle actin were analysed by Western blot. Pulmonary fibrosis was induced by intranasal instillation of bleomycin into wild-type and PAR-2 deficient mice with or without a specific PAR-1 antagonist (P1pal-12). Fibrosis was assessed by hydroxyproline quantification and (immuno)histochemical analysis. We show that specific PAR-1 and/or PAR-2 activating proteases induce fibroblast migration, differentiation and extracellular matrix production. Interestingly, however, combined activation of PAR-1 and PAR-2 did not show any additive effects on these pro-fibrotic responses. Strikingly, PAR-2 deficiency as well as pharmacological PAR-1 inhibition reduced bleomycin-induced pulmonary fibrosis to a similar extent. PAR-1 inhibition in PAR-2 deficient mice did not further diminish bleomycin-induced pulmonary fibrosis. Finally, we show that the PAR-1-dependent pro-fibrotic responses are inhibited by the PAR-2 specific antagonist. Targeting PAR-1 and PAR-2 simultaneously is not superior to targeting either receptor alone in bleomycin-induced pulmonary fibrosis. We postulate that the pro-fibrotic effects of PAR-1 require the presence of PAR-2., (© 2015 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
- Published
- 2015
- Full Text
- View/download PDF
17. Targeting protease activated receptor-1 with P1pal-12 limits bleomycin-induced pulmonary fibrosis.
- Author
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Lin C, Duitman J, Daalhuisen J, Ten Brink M, von der Thüsen J, van der Poll T, Borensztajn K, and Spek CA
- Subjects
- Animals, Bleomycin, Cell Differentiation drug effects, Cell Movement drug effects, Cell Proliferation drug effects, Cells, Cultured, Collagen metabolism, Disease Progression, Dose-Response Relationship, Drug, Drug Administration Schedule, Drug Evaluation, Preclinical methods, Fibroblasts cytology, Fibroblasts drug effects, Fibroblasts physiology, Mice, Mice, Inbred C57BL, Peptide Fragments administration & dosage, Peptide Fragments pharmacology, Pulmonary Fibrosis chemically induced, Pulmonary Fibrosis metabolism, Pulmonary Fibrosis pathology, Receptor, PAR-1 administration & dosage, Receptor, PAR-1 physiology, Receptor, PAR-1 therapeutic use, Signal Transduction drug effects, Peptide Fragments therapeutic use, Pulmonary Fibrosis prevention & control, Receptor, PAR-1 antagonists & inhibitors
- Abstract
Background: Idiopathic pulmonary fibrosis is the most devastating fibrotic diffuse parenchymal lung disease which remains refractory to pharmacological therapies. Therefore, novel treatments are urgently required. Protease-activated receptor (PAR)-1 is a G-protein-coupled receptor that mediates critical signalling pathways in pathology and physiology. Bleomycin-induced lung fibrosis has been shown to be diminished in PAR-1-deficient mice. The purpose of this study is to investigate whether pharmacological PAR-1 inhibition is a potential therapeutic option to combat pulmonary fibrosis., Methods: Pulmonary fibrosis was induced by intranasal instillation of bleomycin into wild-type mice with or without a specific PAR-1 antagonist (ie, P1pal-12, a pepducin that blocks the PAR-1/G-protein interaction). Fibrosis was assessed by hydroxyproline analysis, immunohistochemistry, quantitative PCR and western blot for fibrotic markers expression., Results: We first show that P1pal-12 effectively inhibits PAR-1-induced profibrotic responses in fibroblasts. Next, we show that once daily treatment with 0.5, 2.5 or 10 mg/kg P1pal-12 reduced the severity and extent of fibrotic lesions in a dose-dependent manner. These findings correlated with significant decreases in fibronectin, collagen and α smooth muscle actin expression at the mRNA and protein level in treated mice. To further establish the potential clinical applicability of PAR-1 inhibition, we analysed fibrosis in mice treated with P1pal-12 1 or 7 days after bleomycin instillation. Interestingly, when administered 7 days after the induction of fibrosis, P1pal-12 was as effective in limiting the development of pulmonary fibrosis as when administration was started before bleomycin instillation., Conclusions: Overall, targeting PAR-1 may be a promising treatment for pulmonary fibrosis.
- Published
- 2014
- Full Text
- View/download PDF
18. Protease-activated receptor-2 induces myofibroblast differentiation and tissue factor up-regulation during bleomycin-induced lung injury: potential role in pulmonary fibrosis.
- Author
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Borensztajn K, Bresser P, van der Loos C, Bot I, van den Blink B, den Bakker MA, Daalhuisen J, Groot AP, Peppelenbosch MP, von der Thüsen JH, and Spek CA
- Subjects
- Adult, Aged, Animals, Bleomycin, Cells, Cultured, Humans, Lung Injury chemically induced, Lung Injury metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Middle Aged, Myofibroblasts metabolism, Pulmonary Fibrosis pathology, Receptor, PAR-2 genetics, Receptor, PAR-2 metabolism, Thromboplastin metabolism, Up-Regulation genetics, Up-Regulation physiology, Cell Differentiation genetics, Lung Injury genetics, Myofibroblasts physiology, Pulmonary Fibrosis genetics, Receptor, PAR-2 physiology, Thromboplastin genetics
- Abstract
Idiopathic pulmonary fibrosis constitutes the most devastating form of fibrotic lung disorders and remains refractory to current therapies. The coagulation cascade is frequently activated during pulmonary fibrosis, but this observation has so far resisted a mechanistic explanation. Recent data suggest that protease-activated receptor (PAR)-2, a receptor activated by (among others) coagulation factor (F)Xa, plays a key role in fibrotic disease; consequently, we assessed the role of PAR-2 in the development of pulmonary fibrosis in this study. We show that PAR-2 is up-regulated in the lungs of patients with idiopathic pulmonary fibrosis and that bronchoalveolar lavage fluid from these patients displays increased procoagulant activity that triggers fibroblast survival. Using a bleomycin model of pulmonary fibrosis, we show that bleomycin induces PAR-2 expression, as well as both myofibroblast differentiation and collagen synthesis. In PAR-2-/- mice, both the extent and severity of fibrotic lesions are reduced, whereas myofibroblast differentiation is diminished and collagen expression is decreased. Moreover, fibrin deposition in the lungs of fibrotic PAR-2-/- mice is reduced compared with wild-type mice due to differential tissue factor expression in response to bleomycin. Taken together, these results suggest an important role for PAR-2 in the development of pulmonary fibrosis, and the inhibition of the PAR-2-coagulation axis may provide a novel therapeutic approach to treat this devastating disease.
- Published
- 2010
- Full Text
- View/download PDF
19. The cholinergic anti-inflammatory pathway regulates the host response during septic peritonitis.
- Author
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van Westerloo DJ, Giebelen IA, Florquin S, Daalhuisen J, Bruno MJ, de Vos AF, Tracey KJ, and van der Poll T
- Subjects
- Animals, Cytokines physiology, Escherichia coli Infections immunology, Female, Mice, Mice, Inbred C57BL, Nicotine pharmacology, Receptors, Nicotinic drug effects, Receptors, Nicotinic physiology, Vagotomy, Vagus Nerve physiology, Neuroimmunomodulation, Peritonitis immunology, Sepsis immunology
- Abstract
Background: The nervous system, through the vagus nerve, can down-regulate inflammation in vivo by decreasing the release of tumor necrosis factor- alpha by endotoxin-stimulated macrophages. This anti-inflammatory effect is mediated by an interaction between acetylcholine, the principal neurotransmitter of the vagus nerve, and cholinergic nicotinic acetylcholine receptors on macrophages., Methods: We determined the role of this "cholinergic anti-inflammatory pathway" during septic peritonitis induced in mice by intraperitoneal injection of live Escherichia coli. Septic peritonitis was preceded by inhibition of the cholinergic anti-inflammatory pathway by unilateral cervical vagotomy, by stimulation of this pathway by pretreatment of mice with nicotine, or by a combination of both interventions., Results: Initial cytokine release during septic peritonitis was enhanced after previous vagotomy and was decreased after nicotine pretreatment, independently of the integrity of the vagus nerve. Further study established that vagotomy before septic peritonitis resulted in an enhanced influx of neutrophils and a marked increase in proinflammatory cytokine levels and liver damage. Conversely, nicotine pretreatment strongly decreased cell influx, proinflammatory cytokine levels, and liver damage, whereas bacterial clearance and survival were impaired., Discussion: These data provide the first evidence, to our knowledge, of an important role of the vagus nerve in regulating the innate immune response to a severe bacterial infection.
- Published
- 2005
- Full Text
- View/download PDF
20. Therapeutic effects of troglitazone in experimental chronic pancreatitis in mice.
- Author
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van Westerloo DJ, Florquin S, de Boer AM, Daalhuisen J, de Vos AF, Bruno MJ, and van der Poll T
- Subjects
- Actins metabolism, Animals, Cell Differentiation, Ceruletide pharmacology, Chromans pharmacology, Chronic Disease, Collagen metabolism, Disease Models, Animal, Fibrosis, Inflammation, Interleukin-6 blood, Ligands, Mice, Mice, Inbred C57BL, Muscle, Smooth metabolism, PPAR gamma metabolism, Pancreatitis metabolism, Platelet Aggregation Inhibitors pharmacology, Platelet Aggregation Inhibitors therapeutic use, Receptors, Tumor Necrosis Factor, Type I metabolism, Sodium Chloride pharmacology, Thiazolidinediones pharmacology, Transforming Growth Factor beta metabolism, Transforming Growth Factor beta1, Troglitazone, Chromans therapeutic use, Pancreatitis drug therapy, Thiazolidinediones therapeutic use
- Abstract
Peroxisome proliferator-activated receptor (PPAR)-gamma controls growth, differentiation, and inflammation. PPAR-gamma agonists exert anti-inflammatory effects in vitro and inhibit the activation of pancreas stellate cells, implicated in the formation and progression of fibrosis. We determined the influence of troglitazone, a ligand for PPAR-gamma, on pancreatic damage and fibrosis in experimental chronic pancreatitis. Mice received six hourly intraperitoneal injections with 50 microg/kg of cerulein or saline, three times a week for 6 weeks. One week after the last injection all mice were sacrificed. Untreated mice were compared with mice treated with troglitazone either during weeks 1 to 6 or weeks 4 to 6. All mice that received cerulein injections displayed histopathological signs of chronic pancreatitis at week 7. Troglitazone treatment improved all markers for severity of pancreatitis. Moreover, early and postponed troglitazone treatments were equally effective in diminishing intrapancreatic fibrosis as quantified by Sirius red staining, hydroxyproline content, and laminin staining as well as the increased number of pancreatic stellate cells and pancreas levels of transforming growth factor-beta. Thus, troglitazone attenuated pancreatic damage and inflammation in experimental chronic pancreatitis and remained beneficial in a therapeutic setting when given after initial damage had been established.
- Published
- 2005
- Full Text
- View/download PDF
21. Evaluation of a novel bioartificial liver in rats with complete liver ischemia: treatment efficacy and species-specific alpha-GST detection to monitor hepatocyte viability.
- Author
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Flendrig LM, Chamuleau RA, Maas MA, Daalhuisen J, Hasset B, Kilty CG, Doyle S, Ladiges NC, Jörning GG, la Soe JW, Sommeijer D, and te Velde AA
- Subjects
- Animals, Equipment Design, Evaluation Studies as Topic, Immunoenzyme Techniques methods, Isomerism, Male, Rats, Rats, Wistar, Species Specificity, Swine, Glutathione Transferase analysis, Ischemia surgery, Liver Circulation physiology, Liver, Artificial standards
- Abstract
Background/aims: There is an urgent need for an effective bioartificial liver system to bridge patients with fulminant hepatic failure to liver transplantation or to regeneration of their own liver. Recently, we proposed a bioreactor with a novel design for use as a bioartificial liver (BAL). The reactor comprises a spirally wound nonwoven polyester fabric in which hepatocytes are cultured (40 x 10(6) cells/ml) as small aggregates and homogeneously distributed oxygenation tubing for decentralized oxygen supply and CO2 removal. The aims of this study were to evaluate the treatment efficacy of our original porcine hepatocyte-based BAL in rats with fulminant hepatic failure due to liver ischemia (LIS) and to monitor the viability of the porcine hepatocytes in the bioreactor during treatment. The latter aim is novel and was accomplished by applying a new species-specific enzyme immunoassay (EIA) for the determination of porcine alpha-glutathione S-transferase (alpha-GST), a marker for hepatocellular damage., Methods: Three experimental groups were studied: the first control group (LIS Control, n = 13) received a glucose infusion only; a second control group (LIS No-Cell-BAL, n = 8) received BAL treatment without cells; and the treated group (LIS Cell-BAL, n = 8) was connected to our BAL which had been seeded with 4.4 x 10(8) viable primary porcine hepatocytes., Results/conclusions: In contrast to previous comparable studies, BAL treatment significantly improved survival time in recipients with LIS. In addition, the onset of hepatic encephalopathy was significantly delayed and the mean arterial blood pressure significantly improved. Significantly lower levels of ammonia and lactate in the LIS Cell-BAL group indicated that the porcine hepatocytes in the bioreactor were metabolically activity. Low pig alpha-GST levels suggested that our bioreactor was capable of maintaining hepatocyte viability during treatment. These results provide a rationale for a comparable study in LIS-pigs as a next step towards potential clinical application.
- Published
- 1999
- Full Text
- View/download PDF
22. Does the extend of the culture time of primary hepatocytes in a bioreactor affect the treatment efficacy of a bioartificial liver?
- Author
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Flendrig LM, Maas MA, Daalhuisen J, Ladiges NC, La Soe JW, Te Velde AA, and Chamuleau RA
- Subjects
- Ammonia blood, Animals, Cell Culture Techniques, Glutathione Transferase blood, Hepatic Encephalopathy blood, Male, Rats, Rats, Sprague-Dawley, Rats, Wistar, Swine, Time Factors, Bioreactors, Hepatic Encephalopathy therapy, Liver cytology, Liver, Artificial
- Abstract
The purpose of this study was to investigate whether the efficacy of our novel extracorporeal bioartificial liver (BAL) to support rats with complete liver ischemia (LIS) could be improved by extending the culture time of freshly isolated porcine hepatocytes from 14 hours to 38 hours. The results showed that survival as well as porcine hepatocyte integrity improved, the onset of coma delayed, and the ammonia levels decreased in LIS rats of the 38 hour group compared to the 14 hour group, but no statistically significant differences were observed. In the 38 hour group, but not the 14 hour group, the onset of hepatic encephalopathy was significantly delayed and ammonia metabolism significantly improved compared to the LIS rats in control groups that only received a glucose infusion or were connected to a BAL without cells. In conclusion, prolonged hepatocyte recovery favoured all investigated parameters, although not all observed effects were statistically significant. More research is required to find out how long primary hepatocytes should be cultured in a bioreactor for optimal BAL support.
- Published
- 1998
23. Commercially available media for flushing extracorporeal bioartificial liver systems prior to connection to the patient's circulation: an in vitro comparative study in two and three dimensional porcine hepatocyte cultures.
- Author
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Flendrig LM, Sommeijer D, Ladiges NC, Te Velde AA, Maas MA, Jörning GG, Daalhuisen J, and Chamuleau RA
- Subjects
- Animals, Artificial Organs, Aspartate Aminotransferases metabolism, Cells, Cultured, Chromatography, High Pressure Liquid, L-Lactate Dehydrogenase metabolism, Lidocaine analogs & derivatives, Lidocaine metabolism, Liver enzymology, Male, Organ Culture Techniques methods, Swine, Culture Media pharmacology, Liver cytology
- Abstract
Extracorporeal bioartificial liver (BAL) systems based on hepatocytes need to be flushed before clinical application, as hepatocyte culture media are not approved for medical use. Commercially available 0.9% NaCl solution and hemofiltration solution (both supplemented with 10% human albumin) were investigated in vitro to test their potential to wash BAL systems with minimal stress for the cultured hepatocytes. After a 2 hour incubation, the lidocaine metabolising capacity and release of liver enzymes were assessed. As hepatocytes have been cultured in bioreactors in either two or three dimensional cell configurations, we tested the media in respectively hepatocyte monolayers cultures and in our newly developed bioreactor in which hepatocytes reorganise as small hepatocyte aggregates. The three dimensional hepatocyte cultures tolerated both media well, and no significant differences were seen compared with hepatocytes cultured in Williams' E (reference hepatocyte culture medium). The two dimensional hepatocyte cultures tolerated the supplemented hemofiltration solution and the reference medium equally well, but the condition of the porcine hepatocytes monolayer cultures was significantly impaired when incubated with the supplemented physiological saline solution. In conclusion, as a supplemented physiological saline solution may have detrimental effects on the condition of the hepatocytes, the more complex hemofiltration solution (bicarbonate buffered, glucose, essential minerals) was considered the better alternative for flushing bioartificial liver systems.
- Published
- 1998
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