Premium
Abrogation of airway hyperresponsiveness but not inflammation by rho kinase insufficiency
Author(s) -
Kasahara David I.,
Ninin Fernanda M. C.,
Wurmbrand Alison P.,
Liao James K.,
Shore Stephanie A.
Publication year - 2015
Publication title -
clinical and experimental allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.462
H-Index - 154
eISSN - 1365-2222
pISSN - 0954-7894
DOI - 10.1111/cea.12438
Subject(s) - rho associated protein kinase , goblet cell , inflammation , degranulation , immunology , fasudil , mast cell , hyperplasia , medicine , rock2 , pathology , kinase , biology , microbiology and biotechnology , epithelium , receptor
Summary Background 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, ROCK 1 and ROCK 2, to AHR , inflammation and goblet cell metaplasia in a mast cell‐dependent model of allergic airways disease. Methods and Results 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 ROCK 2 ( ROCK 2 +/‐ ) or ROCK 1 ( ROCK 1 +/− ), respectively. In contrast, there was no effect of ROCK insufficiency on allergic airways inflammation, although both ROCK 1 and ROCK 2 insufficiency attenuated mast cell degranulation. Goblet cell hyperplasia, as indicated by PAS staining, was not different in ROCK 1 +/− vs. WT mice. However, in ROCK 2 +/− mice, goblet cell hyperplasia was reduced in medium but not large airways. Maximal acetylcholine‐induced force generation was reduced in tracheal rings from ROCK 1 +/− and ROCK 2 +/− vs. WT mice. The ROCK inhibitor, fasudil, also reduced airway responsiveness in OVA ‐challenged mice, without affecting inflammatory responses. Conclusion In a mast cell model of allergic airways disease, ROCK 1 and ROCK 2 both contribute to AHR , likely through direct effects on smooth muscle cell and effects on mast cell degranulation. In addition, ROCK 2 but not ROCK 1 plays a role in allergen‐induced goblet cell hyperplasia.