Studies on change in airway hyperresponsiveness at bronchial asthma using the technique of RhoA gene manipulation

• Project/Area Number: 15590236
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General pharmacology
• Research Institution: Hoshi University
• Principal Investigator: MISAWA Miwa Hoshi University, Department of Pharmacology, School of Pharmacy, 薬理学教室, 教授 (20061294)
• Co-Investigator(Kenkyū-buntansha): CHIBA Yoshihiko Hoshi University, Department of Pharmacology, School of Pharmacy, 薬理学教室, 講師 (00287848)
• Project Period (FY): 2003 – 2005
• Project Status: Completed (Fiscal Year 2005)
• Budget Amount: ¥3,600,000 (Direct Cost: ¥3,600,000); Fiscal Year 2005: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 2004: ¥700,000 (Direct Cost: ¥700,000); Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
• Keywords: bronchial asthma / airway hyperresponsiveness / Ca^<2+> sensitization / RhoA / CPI-17 / rhoA mRNA / cpi-17 mRNA / membrane tranlocation / 膜translacetion / endothelin / TNFα / 転写因子

Research Abstract

(1)The authors have found for the first time that expression of rhoA mRNA and upregulation of RhoA protein in bronchial smooth muscle of airway hyperresponsive (AHR) rats which received repeated antigen-challenge. We propose that enhanced Ca^<2+> sensitization induced by such RhoA protein activation may evoke the AHR. (2)Transcriptional factors involved in RhoA protein expression were investigated by protein/DNA array. Stat5,CDP,HSE,SBE,SIE and CBF were observed to be activated at AHR state. (3)TNF-a detected in broncho-alveolar fluid of asthmatics enhanced the bronchosonstriction by ACh, which accompanied with increases in rhoA mRNA and protein. (4)Translocation of RhoA protein from cytosol to plasma membrane was observed after ACh stimulation of bronchial cells, suggesting an activation of RhoA by ACh. (5)Another protein CPI-17 involved in Ca^<2+> sensitization as well as RhoA was also increased in the AHR bronchial smooth muscle. Therefore, RhoA/Rho-kinase/CPI-17 cross-pathway might work at Ca^<2+> sensitization of bronchial smooth muscle of AHR rats.

Research Products

• [Journal Article] Uteroglobin-related protein 1 expression suppesses allergic airway inflammation in mice (2006)
  • Author(s): Chiba, Y., Kurotani.R., Kusakabe, T., Miura, T., Link, B.W., Misawa, M., Kimura, S.
  • Journal Title: Am. J. Respir. Crit. Care Med. 173 Pages: 958-964
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Uteroglobin-related protein 1 expression suppesses allergic airway inflammation in mice (2006)
  • Author(s): Chiba, Y., Kurotani, R., Kusakabe, T., Miura, T., Link, B.W., Misawa, M., Kimura, S.
  • Journal Title: Am.J.Respir.Crit.Care Med. 173 Pages: 958-964
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Acetylcholine-induced phosphorylation of CPI-17 in rat bronchial smooth muscle : roles of rho-kinase and protein kinase C (2005)
  • Author(s): Sakai, H., Hirano, T., Takeyama, H., Chiba, Y., Misawa, M.
  • Journal Title: Can. J. Physiol. Pharmacol. 83 Pages: 375-381
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Acetylcholine-induced phosphorylation and membrane translocation of CPI-17 in bronchial smooth muscle of rats (2005)
  • Author(s): Sakai, H., Hirano, T., Chiba, Y., Misawa, M.
  • Journal Title: Am. J. Physiol. Lung Cell. Mol. Physiol. 289
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effect of sodium azulene sulfonate on capsaicin-induced pharyngitis in rats (2005)
  • Author(s): Sakai, H., Misawa, M.
  • Journal Title: Basic Clin. Pharmacol. Toxicol. 96 Pages: 54-59
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Involvement of RhoA-mediated Ca^<2+> sensitization in antigen-induced bronchial smooth muscle hyperresponsiveness in mice (2005)
  • Author(s): Chiba, Y., Ueno, A., Shinozaki, K., Takeyama, H., Sakai, H., Misawa, M.
  • Journal Title: Respir. Res. 6(#4) Pages: 1-11
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Possible involvement of CPI-17 in augmented bronchial smooth muscle contraction in antigen-induced airway hyperresponsiveness rats (2005)
  • Author(s): Sakai, H., Hirano, T., Takeyama, H., Chiba, Y., Misawa, M.
  • Journal Title: Mol. Pharmacol. 68 Pages: 145-151
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Involvement of M_3 muscarinic receptors in ACh-induced increase in membrane-associated RhoA of rat bronchial smooth muscle (2005)
  • Author(s): Sakai, H., Hirano, T., Takeyama, H., Chiba, Y., Misawa, M.
  • Journal Title: Biol. Pharm. Bull. 28 Pages: 625-628
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effects of repeated antigen exposure on endothelin-1-induced bronchial smooth muscle contraction and activation of RhoA in sensitized rats (2005)
  • Author(s): Chiba, Y., Sakai, H., Yu, Y-Y, Misawa, M.
  • Journal Title: J. Biochem. (Tokyo) 137 Pages: 751-756
  • NAID: 10017345755
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Effect of cigarette smoke exposure in vivo on bronchial smooth muscle contractility in vitro in rats (2005)
  • Author(s): Chiba, Y., Murata, M., Ushikubo, H., Saitoh, A., Sakai, H., Kamei, J., Misawa, M.
  • Journal Title: Am. J. Respir. Cell. Mol. Biol. 33 Pages: 574-581
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Endothelin-1-induced translocation of RhoA is mediated by endothelin ET_A receptors in rat bronchial smooth muscle (2005)
  • Author(s): Chiba, Y., Sakai, H., Misawa, M.
  • Journal Title: Eur. J. Pharmacol. 517 Pages: 182-185
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Difference in the effects of cigarette smoke exposure on bronchial smooth muscle contractility in rats (2005)
  • Author(s): Chiba, Y., Murata, M., Yoshikawa, Y., Saitoh, A., Sakai, H., Kamei, J., Misawa, M.
  • Journal Title: Med. Hypothesis Res. 2 Pages: 597-603
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Acetylcholine-induced phosphorylation of CPI-17 in rat bronchial smooth muscle : roles of Rho-kinase and protein kinase C (2005)
  • Author(s): Sakai, H., Hirano, T., Takeyama, H., Chiba, Y., Misawa, M.
  • Journal Title: Can.J.Physiol.Pharmacol. 83 Pages: 375-381
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Acetylcholine-induced phosphorylation and membrane translocation of CPI-17 in bronchial smooth muscle of rats (2005)
  • Author(s): Sakai, H., Hirano, T., Chiba, Y., Misawa, M.
  • Journal Title: Am.J.Physiol.Lung Cell.Mol.Physiol. 289
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effect of sodium azulene sulfonate on capsaicin-induced pharyngitis in rats (2005)
  • Author(s): Sakai, H., Misawa, M.
  • Journal Title: Basic Clin.Pharmacol.Toxicol. 96 Pages: 54-59
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of RhoA-mediated Ca^<2+> sensitization in antigen-induced bronchial smooth muscle hyperresponsiveness in mice (2005)
  • Author(s): Chiba, Y., Ueno, A., Shinozaki, K., Takeyama, H., Sakai, H., Misawa, M.
  • Journal Title: Respir.Res. 6(#4) Pages: 1-11
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Possible involvement of CPI-17 in augmented bronchial smooth muscle contraction in antigen-induced airway hyperresponsiveness rats (2005)
  • Author(s): Sakai, H., Hirano, T., Takeyama, H., Chiba, Y., Misawa, M.
  • Journal Title: Mol.Pharmacol. 68 Pages: 145-151
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of M_3 muscarinic receptors in ACh-induced increase in membrane-associated RhoA of rat bronchial smooth muscle (2005)
  • Author(s): Sakai, H., Hirano, T., Takeyama, H., Chiba, Y., Misawa, M.
  • Journal Title: Biol.Pharm.Bull. 28 Pages: 625-628
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effects of repeated antigen exposure on endothelin-1-induced bronchial smooth muscle contraction and activation of RhoA in sensitized rats (2005)
  • Author(s): Chiba, Y., Sakai, H., Yu, Y-Y., Misawa, M.
  • Journal Title: J.Biochem.(Tokyo) 137 Pages: 751-756
  • NAID: 10017345755
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Effect of cigarette smoke exposure in vivo on bronchial smooth muscle contractility in vitro in rats (2005)
  • Author(s): Chiba, Y., Murata, M., Ushikubo, H., Saitoh, A., Sakai, H., Kamei, J., Misawa, M.
  • Journal Title: Am.J.Respir.Cell.Mol.Biol. 33 Pages: 574-581
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Endothelin-1-induced translocation of RhoA is mediated by endothelin ET_A receptors in rat bronchial smooth muscle (2005)
  • Author(s): Chiba, Y., Sakai, H., Misawa, M.
  • Journal Title: Eur.J.Pharmacol. 517 Pages: 182-185
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Difference in the effects of cigarette smoke exposure on bronchial smooth muscle contractility in rats (2005)
  • Author(s): Chbia, Y., Murata, M., Yoshikawa, Y., Saitoh, A., Sakai, H., Kamei, J., Misawa, M.
  • Journal Title: Med.Hypothesis Res. 2 Pages: 597-603
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Acetylcholine-induced phosphorylation of CPI-17 in rat bronchial smooth muscle : the roles of Rho-kinase and protein kinase C (2005)
  • Author(s): Sakai, H., Hirano, T., Takeyama, H., Chiba, Y., Misawa, M.
  • Journal Title: Can.J.Physiol.Pharmacol. 83 Pages: 375-381
• [Journal Article] Effect of sodium azulene sulfonate on capsaicin-induced pharyngitis in rats (2005)
  • Author(s): Sakai, Misawa, M.
  • Journal Title: Basic Clin.Pharmacol.Toxicol. 96 Pages: 54-59
• [Journal Article] Involvement of RhoA-mediated Ca^<2+> sensitization in antigen-induced bronchial smooth muscle hyperresponsiveness in mice (2005)
  • Author(s): Chiba, Y., Ueno, A., Shinozaki, K., Takeyama, H., Sakai, H., Misawa M.
  • Journal Title: Respir.Res. 6(4) Pages: 1-11
• [Journal Article] Possible involvement of CPI-17 in augmented bronchial smooth muscle contraction in antigen-induced airway hyperresponsive rats (2005)
  • Author(s): Sakai, H., Hirano, T., Chiba, Y., Takeyama, H., Misawa, M.
  • Journal Title: Mol.Pharmacol. 68 Pages: 145-151
• [Journal Article] Involvement of M_3 muscarinic receptors in ACh-induced increase in membrane-associated RhoA of rat bronchial smooth muscle (2005)
  • Author(s): Sakai, H., Shirai, T., Yamamoto, M., Chiba, Y., Misawa, M.
  • Journal Title: Biol.Pharm.Bull. 28 Pages: 625-628
• [Journal Article] Effects of repeated antigen exposure on endothelin-1-induced bronchial Smooth muscle contraction and activation of RhoA in sensitized rats. (2005)
  • Author(s): Chiba, Y., Sakai, H., Yu, Y., Misawa, M.
  • Journal Title: J.Biochem.(Tokyo) 137 Pages: 751-756
  • NAID: 10017345755
• [Journal Article] Effect of cigarette smoke exposure in vivo on bronchial smooth muscle contractility in vitro in rats (2005)
  • Author(s): Chiba, Y., Murata, M., Ushikubo, H., Yoshikawa, Y., Saitoh, A., Sakai, H., Kamei, J., Misawa, M.
  • Journal Title: Am.J.Respir.Cell.Mol.Biol. 33 Pages: 574-581
• [Journal Article] Difference in the effects of cigarette smoke exposure on bronchial smooth muscle contractility in rats (2005)
  • Author(s): Chiba, Y., Murata, M., Yoshikawa, Y., Saitoh, A., Sakai, H., Kamei J., Misawa M.
  • Journal Title: Med.Hypothesis Res. 2 Pages: 597-603
• [Journal Article] Involvement of RhoA-mediated Ca^<2+> sensitization in antigen-induced bronchial smooth muscle hyperresponsiveness in mice (2005)
  • Author(s): Chiba, Y., Ueno, A., Shinozaki, K., Takayama, H., Sakai, H., Misawa, M.
  • Journal Title: Respir.Res. 6(accepted)
• [Journal Article] Involvement of M_3 muscarinic receptors in Ach-induced increase in membrane-associated RhoA of rat bronchial smooth muscle (2005)
  • Author(s): Sakai, H., Shirai, T., Yamamoto, M., Chiba, Y., Misawa, M.
  • Journal Title: Biol.Pharm.Bull. 28(accepted)
• [Journal Article] Acetylcholine-induced phosphorylation of CPI-17 in rat bronchial smooth muscle : roles of Rho kinase and protein kinase C (2005)
  • Author(s): Sakai, H., Hirano, T., Takeyama, H., Chiba, Y., Misawa, M.
  • Journal Title: Can.J.Physiol.Pharmacol. (accepted)
• [Journal Article] Effect of sodium azulene sulfonate on capsaicin-induced pharyngitis in rats (2005)
  • Author(s): Sakai, H., Misawa, M.
  • Journal Title: Basic Clin.Pharmacol.Toxical. 96 Pages: 54-59
• [Journal Article] The role of RhoA-mediated Ca^2+ sensitization of bronchial smooth muscle contraction in airway hyperresponsiveness (2004)
  • Author(s): Chiba, Y., Misawa, M.
  • Journal Title: J. Smooth Muscle Res. 40 Pages: 155-167
  • NAID: 110002952048
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Hyperresponsiveness of bronchial but not tracheal smooth muscle in a murine model of allergic bronchial asthma (2004)
  • Author(s): Chiba, Y., Ueno, A., Sakai, H., Misawa, M.
  • Journal Title: Inflamm. Res. 53 Pages: 636-642
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Acetylcholine-induced translocation of RhoA in freshly isolated single smooth muscle cells of rat bronchi (2004)
  • Author(s): Chiba, Y., Uchida, T., Sakai, H., Oku, T., Ito, S., Tsuji, T., Misawa, M.
  • Journal Title: J. Pharmacol. Sci. 95 Pages: 479-482
  • NAID: 10014165998
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Involvement of p42/44 MAPK and RhoA protein in the augmentation of ACh-induced bronchial smooth muscle contraction by TNF-α in rats (2004)
  • Author(s): Sakai, H., Otogoto, S., Chiba, Y., Abe, K., Misawa, M.
  • Journal Title: J. Appl. Physiol. 97 Pages: 2154-2159
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] TNF-α augments the expression of RhoA in rat bronchus (2004)
  • Author(s): Sakai, H., Otogoto, S., Chiba, Y., Abe, K., Misawa, M.
  • Journal Title: J. Smooth Muscle Res. 40 Pages: 25-34
  • NAID: 110002912889
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] The role of RhoA-mediate Ca^<2+> sensitization of bronchial smooth muscle contraction in airway hyperresponsiveness (2004)
  • Author(s): Chiba, Y., Misawa, M.
  • Journal Title: J.Smooth Muscle Res. 40 Pages: 155-167
  • NAID: 110002952048
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hyperresponsiveness of bronchial but not tracheal smooth muscle in a murine model of allergic bronchial asthma (2004)
  • Author(s): Chiba, Y., Ueno, A., Sakai, H., Misawa, M.
  • Journal Title: Inflamm.Res. 53 Pages: 636-642
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Acetylcholine-induced translocation of RhoA in freshly isolated single smooth muscle cells of rat bronchi (2004)
  • Author(s): Chiba, Y., Uchida, T., Sakai, H., Oku, T., Ito, S., Tsuji, T., Misawa, M.
  • Journal Title: J.Pharmacol.Sci. 95 Pages: 479-482
  • NAID: 10014165998
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Involvement of p42/44 MARK and RhoA protein in the augmentation of ACh-induced bronchial smnooth muscle contraction by TNF-α in rats (2004)
  • Author(s): Sakai, H., Otogotom, S., Chiba, Y., Abe, K., Misawa, M.
  • Journal Title: J.Appl.Physiol. 97 Pages: 2154-2159
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TNF-α augments the expression of RhoA in rat bronchus (2004)
  • Author(s): Sakai, H., Otogoto, S., Chiba, Y., Abe, K., Misawa, M.
  • Journal Title: J.Smooth Muscle Res. 40 Pages: 25-34
  • NAID: 110002912889
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] TNF-α augment the expression of RhoA in rat bronchus (2004)
  • Author(s): Sakai, H., Otogoto, S., Chiba, Y., Abe, K., Misawa, M.
  • Journal Title: J.Smooth Muscle Res. 40 Pages: 25-34
  • NAID: 110002912889
• [Journal Article] Involvement of p42/44 MAPK and RhoA protein in augmentation of ACh-induced bronchial smooth muscle contraction by TNF-α (2004)
  • Author(s): Sakai, H., Otogoto, S., Chiba, Y., Abe, K., Misawa, M.
  • Journal Title: J.Appl.Physiol. 97 Pages: 2154-2159
• [Journal Article] Acetylcholine-induced translocation of RhoA in freshly isolated single smooth muscle cells of rat bronchi (2004)
  • Author(s): Chiba, Y., Uchida, T., Sakai, H., Oku, T., Itoh, S., Tsuji, T., Misawa, M.
  • Journal Title: J.Pharmacol.Sci. 95 Pages: 479-482
  • NAID: 10014165998
• [Journal Article] Involvement of L-type Ca^<2+> channels in the induction of long-term potentiation in the basolateral amygdala-dendate gyrus pathway of anesthetized rats (2004)
  • Author(s): Niikura, Y., Abe, K., Misawa, M.
  • Journal Title: Brain Res. 1017 Pages: 218-221
• [Journal Article] GABA_A receptor-mediated inhibition by ethanol of long-term potentiation in the basolateral amygdala-dendate gyrus pathway in vivo (2004)
  • Author(s): Abe, K., Niikura, Y., Misawa M.
  • Journal Title: Neuroscience 125 Pages: 113-117
• [Journal Article] Hyperresponsiveness of bronchial but not tracheal smooth muscle in a murine model of allergic bronchial asthma (2004)
  • Author(s): Chiba, Y., Ueno, A., Sakai, H., Misawa, M.
  • Journal Title: Inflam.Res. 53 Pages: 636-642
• [Journal Article] The role of RhoA-mediated Ca^<2+>- sensitization of bronchial smooth muscle contraction in airway hyperresponsiveness (2004)
  • Author(s): Chiba, Y., Misawa, M.
  • Journal Title: J.Smooth Muscle Res. 40 Pages: 155-167
  • NAID: 110002952048
• [Journal Article] Upregulation of rhoA mRNA in bronchial smooth muscle of antigen-induced airway hyperresponsive rats (2003)
  • Author(s): Chiba, Y., Sakai, H., Wachi, H., Sugitani, H., Seyama, Y., Misawa, M.
  • Journal Title: J. Smooth Muscle Res. 39 Pages: 221-228
  • NAID: 110002912882
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Upregulation of rhoA mRNA in bronchial smooth muscle of antigen-induced airway hyperresponsive rats (2003)
  • Author(s): Chiba, Y., Sakai, H., Wachi, H., Sugitani, H., Sayama, Y., Misawa, M.
  • Journal Title: J.Smooth Muscle Res. 39 Pages: 221-228
  • NAID: 110002912882
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Astrocyte stellation induced by Rho kinase inhibitors in culture (2003)
  • Author(s): Abe, K., Misawa, M.
  • Journal Title: Brain Res.Dev.Brain Res. 143 Pages: 99-104
• [Book] カッツング薬理学(原著9版)(監訳) (2005)
  • Author(s): 三澤美和ら
  • Total Pages: 1270
  • Publisher: 丸善
  • Description: 「研究成果報告書概要(和文)」より
• [Book] カッシング薬理学(原著9版) (2005)
  • Author(s): 三澤美和ら(監訳)
  • Total Pages: 1270
  • Publisher: 丸善
• [Publications] Chiba, Y., Sakai, H., Wachi, H., Sugitani, H., Seyama, Y., Misawa, M.: "Upregulation of RhoA mRNA in bronchial smooth muscle of antigen-induced airway hyperresponsive rats"J.Smooth Muscle Res. 39. 221-228 (2003)
• [Publications] Abe, K., Misawa, M.: "Amyloid β protein enhances the clearance of extracellular L-glutamate by cultured rat cortical astrocytes"Neurosci Res. 45. 25-31 (2003)
• [Publications] Abe, K., Niikura, Y., Misawa, M.: "The induction of long-term potentiation at amygdalo-hippocampal synapses in vivo"Biol.Pharm Bull. 26. 1560-1562 (2003)
• [Publications] Abe, K., Misawa, M.: "The extracellular signal-regulated kinase cascade suppresses amyloid β protein-induced promotion of glutamate clearance"Brain Res. 979. 179-187 (2003)
• [Publications] Abe, K., Hisatomi, R., Misawa, M.: "Amyloid β peptide specifically promotes phosphorylation and nuclear translocation of the ESR kinase in cultured astrocytes"J.Pharmacol Sci. 93. 272-278 (2003)