| Thorax. 2002 June; 57(6): 524–527. doi: 10.1136/thorax.57.6.524. | PMCID: PMC1746359 |
Suppression of airway hyperresponsiveness induced by ovalbumin sensitisation and RSV infection with Y-27632, a Rho kinase inhibitor K Hashimoto, R Peebles, J Sheller, K Jarzecka, J Furlong, D Mitchell, T Hartert, and B Graham Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN 37232-2582, USA. Abstract Background: Smooth muscle contraction is one of the hallmarks of asthma. A recently developed pyridine derivative, Y-27632, a selective Rho kinase inhibitor, has been reported to inhibit the smooth muscle contraction of human and animal trachea in ex vivo systems but its effect in animal models of airway hyperresponsiveness (AHR) has not been examined. The purpose of this study was to evaluate the effect of Y-27632 in a murine model of allergic and virally induced AHR. Methods: Baseline lung resistance and methacholine induced AHR were measured in mice sensitised to ovalbumin (OVA) and also in mice infected with respiratory syncytial virus (RSV) following ovalbumin sensitisation (OVA/RSV). Results: Time course and dose ranging experiments indicated that 30 mg/kg Y-27632 given by gavage 2 hours before methacholine challenge significantly reduced baseline lung resistance and prevented AHR in OVA sensitised mice. Y-27632 also suppressed AHR induced by the bronchospastic agent serotonin in OVA sensitised mice and prevented methacholine induced AHR in OVA/RSV mice. Conclusions: These results suggest that the signalling pathway mediated through Rho kinase may have an important role in bronchial smooth muscle tone in allergen induced and virus induced AHR and should be considered as a novel target for asthma treatment. Full Text The Full Text of this article is available as a PDF (166K). These references are in PubMed. This may not be the complete list of references from this article. - Kamm, KE; Stull, JT. The function of myosin and myosin light chain kinase phosphorylation in smooth muscle. Annu Rev Pharmacol Toxicol. 1985;25:593–620. [PubMed]
- Kitazawa, T; Masuo, M; Somlyo, AP. G protein-mediated inhibition of myosin light-chain phosphatase in vascular smooth muscle. Proc Natl Acad Sci U S A. 1991 Oct 15;88(20):9307–9310. [PubMed]
- Kitazawa, T; Kobayashi, S; Horiuti, K; Somlyo, AV; Somlyo, AP. Receptor-coupled, permeabilized smooth muscle. Role of the phosphatidylinositol cascade, G-proteins, and modulation of the contractile response to Ca2+. J Biol Chem. 1989 Apr 5;264(10):5339–5342. [PubMed]
- Gong, MC; Iizuka, K; Nixon, G; Browne, JP; Hall, A; Eccleston, JF; Sugai, M; Kobayashi, S; Somlyo, AV; Somlyo, AP. Role of guanine nucleotide-binding proteins--ras-family or trimeric proteins or both--in Ca2+ sensitization of smooth muscle. Proc Natl Acad Sci U S A. 1996 Feb 6;93(3):1340–1345. [PubMed]
- Kureishi, Y; Kobayashi, S; Amano, M; Kimura, K; Kanaide, H; Nakano, T; Kaibuchi, K; Ito, M. Rho-associated kinase directly induces smooth muscle contraction through myosin light chain phosphorylation. J Biol Chem. 1997 May 9;272(19):12257–12260. [PubMed]
- Hirata, K; Kikuchi, A; Sasaki, T; Kuroda, S; Kaibuchi, K; Matsuura, Y; Seki, H; Saida, K; Takai, Y. Involvement of rho p21 in the GTP-enhanced calcium ion sensitivity of smooth muscle contraction. J Biol Chem. 1992 May 5;267(13):8719–8722. [PubMed]
- Fu, X; Gong, MC; Jia, T; Somlyo, AV; Somlyo, AP. The effects of the Rho-kinase inhibitor Y-27632 on arachidonic acid-, GTPgammaS-, and phorbol ester-induced Ca2+-sensitization of smooth muscle. FEBS Lett. 1998 Nov 27;440(1-2):183–187. [PubMed]
- Ishizaki, T; Uehata, M; Tamechika, I; Keel, J; Nonomura, K; Maekawa, M; Narumiya, S. Pharmacological properties of Y-27632, a specific inhibitor of rho-associated kinases. Mol Pharmacol. 2000 May;57(5):976–983. [PubMed]
- Uehata, M; Ishizaki, T; Satoh, H; Ono, T; Kawahara, T; Morishita, T; Tamakawa, H; Yamagami, K; Inui, J; Maekawa, M; Narumiya, S. Calcium sensitization of smooth muscle mediated by a Rho-associated protein kinase in hypertension. Nature. 1997 Oct 30;389(6654):990–994. [PubMed]
- Kureishi, Y; Kobayashi, S; Amano, M; Kimura, K; Kanaide, H; Nakano, T; Kaibuchi, K; Ito, M. Rho-associated kinase directly induces smooth muscle contraction through myosin light chain phosphorylation. J Biol Chem. 1997 May 9;272(19):12257–12260. [PubMed]
- Kimura, K; Ito, M; Amano, M; Chihara, K; Fukata, Y; Nakafuku, M; Yamamori, B; Feng, J; Nakano, T; Okawa, K; Iwamatsu, A; Kaibuchi, K. Regulation of myosin phosphatase by Rho and Rho-associated kinase (Rho-kinase). Science. 1996 Jul 12;273(5272):245–248. [PubMed]
- Nakahara, T; Moriuchi, H; Yunoki, M; Sakamato, K; Ishii, K. Y-27632 potentiates relaxant effects of beta 2-adrenoceptor agonists in bovine tracheal smooth muscle. Eur J Pharmacol. 2000 Feb 11;389(1):103–106. [PubMed]
- Yoshii, A; Iizuka, K; Dobashi, K; Horie, T; Harada, T; Nakazawa, T; Mori, M. Relaxation of contracted rabbit tracheal and human bronchial smooth muscle by Y-27632 through inhibition of Ca2+ sensitization. Am J Respir Cell Mol Biol. 1999 Jun;20(6):1190–1200. [PubMed]
- Yamagata, S; Ichinose, M; Sugiura, H; Koarai, A; Koike, K; Shirato, K. Effect of a calcium sensitization modulator, Y-27632, on isolated human bronchus and pulmonary artery. Pulm Pharmacol Ther. 2000;13(1):25–29. [PubMed]
- Johnston, SL; Pattemore, PK; Sanderson, G; Smith, S; Lampe, F; Josephs, L; Symington, P; O'Toole, S; Myint, SH; Tyrrell, DA, et al. Community study of role of viral infections in exacerbations of asthma in 9-11 year old children. BMJ. 1995 May 13;310(6989):1225–1229. [PubMed]
- Rakes, GP; Arruda, E; Ingram, JM; Hoover, GE; Zambrano, JC; Hayden, FG; Platts-Mills, TA; Heymann, PW. Rhinovirus and respiratory syncytial virus in wheezing children requiring emergency care. IgE and eosinophil analyses. Am J Respir Crit Care Med. 1999 Mar;159(3):785–790. [PubMed]
- Sigurs, N; Bjarnason, R; Sigurbergsson, F; Kjellman, B; Björkstén, B. Asthma and immunoglobulin E antibodies after respiratory syncytial virus bronchiolitis: a prospective cohort study with matched controls. Pediatrics. 1995 Apr;95(4):500–505. [PubMed]
- Peebles, RS, Jr; Sheller, JR; Johnson, JE; Mitchell, DB; Graham, BS. Respiratory syncytial virus infection prolongs methacholine-induced airway hyperresponsiveness in ovalbumin-sensitized mice. J Med Virol. 1999 Feb;57(2):186–192. [PubMed]
- Graham, BS; Perkins, MD; Wright, PF; Karzon, DT. Primary respiratory syncytial virus infection in mice. J Med Virol. 1988 Oct;26(2):153–162. [PubMed]
- Chen, XS; Sheller, JR; Johnson, EN; Funk, CD. Role of leukotrienes revealed by targeted disruption of the 5-lipoxygenase gene. Nature. 1994 Nov 10;372(6502):179–182. [PubMed]
- Barnes, PJ; Chung, KF; Page, CP. Inflammatory mediators of asthma: an update. Pharmacol Rev. 1998 Dec;50(4):515–596. [PubMed]
- Thirstrup, S. Control of airway smooth muscle tone. I--electrophysiology and contractile mediators. Respir Med. 2000 Apr;94(4):328–336. [PubMed]
- Daum, PR; Downes, CP; Young, JM. Histamine stimulation of inositol 1-phosphate accumulation in lithium-treated slices from regions of guinea pig brain. J Neurochem. 1984 Jul;43(1):25–32. [PubMed]
- Hunter, JC; Goedert, M; Pinnock, RD. Mammalian tachykinin-induced hydrolysis of inositol phospholipids in rat brain slices. Biochem Biophys Res Commun. 1985 Mar 15;127(2):616–622. [PubMed]
- Mong, S; Hoffman, K; Wu, HL; Crooke, ST. Leukotriene-induced hydrolysis of inositol lipids in guinea pig lung: mechanism of signal transduction for leukotriene-D4 receptors. Mol Pharmacol. 1987 Jan;31(1):35–41. [PubMed]
- Hirshman, CA; Lande, B; Croxton, TL. Role of M2 muscarinic receptors in airway smooth muscle contraction. Life Sci. 1999;64(6-7):443–448. [PubMed]
- Pastey, MK; Crowe, JE, Jr; Graham, BS. RhoA interacts with the fusion glycoprotein of respiratory syncytial virus and facilitates virus-induced syncytium formation. J Virol. 1999 Sep;73(9):7262–7270. [PubMed]
|
This article has been