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National Institute of Environmental Health Sciences

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Publication Detail

Title: Abrogation of airway hyperresponsiveness but not inflammation by rho kinase insufficiency.

Authors: Kasahara, David I; Ninin, Fernanda M C; Wurmbrand, Alison P; Liao, James K; Shore, Stephanie A

Published In Clin Exp Allergy, (2015 Feb)

Abstract: Major features of allergic asthma include airway hyperresponsiveness (AHR), eosinophilic inflammation, and goblet cell metaplasia. Rho kinase (ROCK) is a serine/threonine protein kinase that regulates the actin cytoskeleton. By doing so, it can modulate airway smooth muscle cell contraction and leucocyte migration and proliferation. This study was designed to determine the contributions of the two ROCK isoforms, ROCK1 and ROCK2, to AHR, inflammation and goblet cell metaplasia in a mast cell-dependent model of allergic airways disease.Repeated intranasal challenges with OVA caused AHR, eosinophilic inflammation, and goblet cell hyperplasia in wild-type (WT) mice. OVA-induced AHR was partially or completely abrogated in mice haploinsufficient for ROCK2 (ROCK2(+/-) ) or ROCK1 (ROCK1(+/-) ), respectively. In contrast, there was no effect of ROCK insufficiency on allergic airways inflammation, although both ROCK1 and ROCK2 insufficiency attenuated mast cell degranulation. Goblet cell hyperplasia, as indicated by PAS staining, was not different in ROCK1(+/-) vs. WT mice. However, in ROCK2(+/-) mice, goblet cell hyperplasia was reduced in medium but not large airways. Maximal acetylcholine-induced force generation was reduced in tracheal rings from ROCK1(+/-) and ROCK2(+/-) vs. WT mice. The ROCK inhibitor, fasudil, also reduced airway responsiveness in OVA-challenged mice, without affecting inflammatory responses.In a mast cell model of allergic airways disease, ROCK1 and ROCK2 both contribute to AHR, likely through direct effects on smooth muscle cell and effects on mast cell degranulation. In addition, ROCK2 but not ROCK1 plays a role in allergen-induced goblet cell hyperplasia.

PubMed ID: 25323425 Exiting the NIEHS site

MeSH Terms: Allergens/immunology; Animals; Bronchoalveolar Lavage Fluid/immunology; Cytokines/metabolism; Disease Models, Animal; Enzyme Activation/genetics; Female; Goblet Cells/metabolism; Goblet Cells/pathology; Immunoglobulin E/blood; Immunoglobulin E/immunology; Immunoglobulin G/blood; Immunoglobulin G/immunology; Inflammation Mediators/metabolism; Mast Cells/immunology; Mast Cells/metabolism; Mice; Mice, Knockout; Ovalbumin/immunology; Respiratory Hypersensitivity/enzymology*; Respiratory Hypersensitivity/genetics; Respiratory Hypersensitivity/immunology; Respiratory Hypersensitivity/physiopathology; Th2 Cells/immunology; Th2 Cells/metabolism; rho-Associated Kinases/genetics; rho-Associated Kinases/metabolism*

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