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- Title
Allergic sensitization enhances the contribution of Rho-kinase to airway smooth muscle contraction.
- Authors
Schaafsma, Dedmer; Gosens, Reinoud; Bos, I. Sophie T.; Meurs, Herman; Zaagsma, Johan; Nelemans, S. Adriaan
- Abstract
1. Repeated allergen challenge has been shown to increase the role to Rho-kinase in airway smooth muscle (ASM) contraction. We considered the possibility that active allergic sensitization by itself, that is, without subsequent allergen exposure, could be sufficient in enhance Rho-kinase mediated ASM contraction. 2. Guinea pigs were actively IgE-sensitized to ovalbumin (OA), using A(OH)3 as adjuvant. Contractile responses in G4-coupled receptor agoniosts (methacholine, histamine or PGF2) was investigated in tracheal rings. No effect of sensitization was observed on basal- and methacholine-induced myogenic tone. In contrast, potency of histamne and PGF2 increased, without effect on maximal contraction (Emax). 3. Basal tone in preparations from both control and OA-sensitized animals was strongly decreased in the presence of the Rho-kinase inhibitor (+)-(R)-trans-(1-aminoethyl)-N-(4-pyridyl) cyclohexine carboximide (Y-27632) (1 µM). In control preparations, the Emax and potency of histamine were unaffected by Y-27632, but were decreased for PGF2, (by 38.2% and 2.0-fold, respectively,\). However, in preparations from OA-sensitized animals, Y-27632 induced a significant reduction in Emax (33.5%) and potency (2.3-fold) of histamine and of PGF2, (48.3% and 6.6-fold, respectively), normalizing the OA-sensitization-induced increase in selectivity toward these agonists. 4. We also investigated the contribution of Rho-kinase in vivo by measuring airway responsiveness toward inhaled histamine in permanently instrumented, unanaesthesized control and OA-sentized guinea-pigs. Treatment with Y-27632 inhalation was significantly smaller in OA-sensitized animals. However, the histamine PC100 ratio pre/post Y-27632 inhalation was significantly smaller in OA-sensitized animals as compared to control animals, indicating an enhanced contribution of Rho-kinase. 5. Expression of Rho-A, an upstream activator of Rho-kinase, was significantly increased (2.6-fold) in lung homogenates of OA-sensitized guinea pigs compared to control animals, as determined by Western analysis. 6. In conclusion the results show a receptor-dependent role of Rho-kinase in agonist-induced ASM contraction. The contribution of Rho-kinase to contractile airway responsiveness, both in vivo and ex vivo, is augmented after active allergic sensitization, as a consequence of increased expression of RhoA presumably. Inhibition of the RhoA, Rho-kinase pathway may be considered a useful pharmacother-apeutical target in allergy and asthma.
- Subjects
ALLERGY desensitization; MUSCLE contraction; SMOOTH muscle; AIRWAY (Anatomy); ASTHMA; ALLERGIES
- Publication
British Journal of Pharmacology, 2004, Vol 143, Issue 4, p477
- ISSN
0007-1188
- Publication type
Article
- DOI
10.1038/sj.bjp.0705903