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論文
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Juanjuan, Zhao ; Okamoto, Yasuo ; Takuwa, Yoh
概要:
The lysophospholipid mediator sphingosine-1-phosphate (S1P) exerts diverse biological activities including the regulatio
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n of leukocyte migration and vascular barrier integrity, suggesting that S1P signaling could be involved in inflammatory fibrotic diseases. Pulmonary fibrosis is a devastating disease characterized by fibroblast accumulation and extracellular matrix deposition in lungs, and bleomycin–induced pulmonary fibrosis is the most widely used experimental model. We studied the effects of the S1P–specific receptor S1P2 on the phenotypes of lung fibroblasts isolated from bleomycin- and saline-administered wild-type and S1P2–null (S1pr2-/-) mice. The lung fibroblasts from bleomycin-administered wild-type and S1pr2-/- mice failed to proliferate in the presence of serum, unlike fibroblasts from saline-administered mice. The fibroblasts from bleomycin-administered mice also showed the enlarged and flattened morphology compared with fibroblasts from control mice. Bleomycin administration increased the protein expression of the cell cycle inhibitor p16INK4a in fibroblasts and the number of senescence–associated β-galactosidase (SA-β-gal)-positive fibroblasts. In S1pr2-/- fibroblasts, bleomycin administration-induced increases in p16INK4a protein expression and SA–β-gal–positive cells were augmented. Furthermore, bleomycin increased mRNA expression of interleukin-6 and matrix metalloproteinases in S1pr2-/- fibroblasts compared with wild-type fibroblasts. In addition, the activation of Akt in response to platelet–derived growth factor and S1P was enhanced in S1pr2-/- fibroblasts compared with wild-type fibroblasts. These results indicate that S1P2 deletion enhances bleomycin administration–induced cellular senescence of lung fibroblasts, which may lead to inhibition of lung fibrosis through the mechanisms involving increased matrix metalloproteinases expression. Thus, S1P2 may be a novel therapeutic target for lung fibrosis.
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| 2.
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論文
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Cui, Hong ; Okamoto, Yasuo ; Yoshioka, Kazuaki ; Du, Wa ; Takuwa, Noriko ; Zhang, Wei ; Asano, Masahide ; Shibamoto, Toshishige ; Takuwa, Yoh
概要:
Background: Sphingosine-1-phosphate receptor 2 (S1P2) is expressed in vascular endothelial cells (ECs). However, the rol
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e of S1P2 in vascular barrier integrity and anaphylaxis is not well understood. Endothelial nitric oxide synthase (eNOS) generates nitric oxide to mediate vascular leakage, compromising survival in patients with anaphylaxis. We recently observed that endothelial S1P2 inhibits Akt, an activating kinase of eNOS. Objective: We tested the hypothesis that endothelial S1P2 might suppress eNOS, exerting a protective effect against endothelial barrier disruption and anaphylaxis. Methods: Mice deficient in S1P2 and eNOS underwent antigen challenge or platelet-activating factor (PAF) injection. Analyses were performed to examine vascular permeability and the underlying mechanisms. Results: S1pr2 deletion augmented vascular leakage and lethality after either antigen challenge or PAF injection. PAF injection induced activation of Akt and eNOS in the aortas and lungs of S1pr2-null mice, which were augmented compared with values seen in wild-type mice. Consistently, PAF-induced increase in cyclic guanosine monophosphate levels in the aorta was enhanced in S1pr-null mice. Genetic Nos3 deletion or pharmacologic eNOS blockade protected S1pr2-null mice from aggravation of barrier disruption after antigen challenge and PAF injection. ECs isolated from S1pr2-null mice exhibited greater stimulation of Akt and eNOS, with enhanced nitric oxide production in response to sphingosine-1-phosphate or PAF, compared with that seen in wild-type ECs. Moreover, S1pr2-deficient ECs showed more severe disassembly of adherens junctions with augmented S-nitrosylation of β-catenin in response to PAF, which was restored by pharmacologic eNOS blockade. Conclusion: S1P2 diminishes harmful robust eNOS stimulation and thereby attenuates vascular barrier disruption, suggesting potential usefulness of S1P2 agonists as novel therapeutic agents for anaphylaxis. © 2013 American Academy of Allergy, Asthma & Immunology.
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| 3.
論文 |
論文
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Cui, Hong ; Okamoto, Yasuo ; Yoshioka, Kazuaki ; Du, Wa ; Takuwa, Noriko ; Zhang, Wei ; Asano, Masahide ; Shibamoto, Toshishige ; Takuwa, Yoh
概要:
Background Sphingosine-1-phosphate receptor 2 (S1P2) is expressed in vascular endothelial cells (ECs). However, the role
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of S1P 2 in vascular barrier integrity and anaphylaxis is not well understood. Endothelial nitric oxide synthase (eNOS) generates nitric oxide to mediate vascular leakage, compromising survival in patients with anaphylaxis. We recently observed that endothelial S1P2 inhibits Akt, an activating kinase of eNOS. Objective We tested the hypothesis that endothelial S1P 2 might suppress eNOS, exerting a protective effect against endothelial barrier disruption and anaphylaxis. Methods Mice deficient in S1P2 and eNOS underwent antigen challenge or platelet-activating factor (PAF) injection. Analyses were performed to examine vascular permeability and the underlying mechanisms. Results S1pr2 deletion augmented vascular leakage and lethality after either antigen challenge or PAF injection. PAF injection induced activation of Akt and eNOS in the aortas and lungs of S1pr2-null mice, which were augmented compared with values seen in wild-type mice. Consistently, PAF-induced increase in cyclic guanosine monophosphate levels in the aorta was enhanced in S1pr-null mice. Genetic Nos3 deletion or pharmacologic eNOS blockade protected S1pr2-null mice from aggravation of barrier disruption after antigen challenge and PAF injection. ECs isolated from S1pr2-null mice exhibited greater stimulation of Akt and eNOS, with enhanced nitric oxide production in response to sphingosine-1-phosphate or PAF, compared with that seen in wild-type ECs. Moreover, S1pr2-deficient ECs showed more severe disassembly of adherens junctions with augmented S-nitrosylation of β-catenin in response to PAF, which was restored by pharmacologic eNOS blockade. Conclusion S1P2 diminishes harmful robust eNOS stimulation and thereby attenuates vascular barrier disruption, suggesting potential usefulness of S1P2 agonists as novel therapeutic agents for anaphylaxis. © 2013 American Academy of Allergy, Asthma & Immunology.
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