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Repeated Allergen Inhalation Induces Cytoskeletal Remodeling in Smooth Muscle from Rat Bronchioles

King's College London School of Medicine, MRC and Asthma UK Centre in Allergic Mechanisms of Asthma, Division of Asthma, Allergy and Lung Biology; Experimental Studies Unit, National Heart and Lung Institute, Imperial College, London, United Kingdom; and Woolcock Institute of Medical Research, Sydney, and Discipline of Pharmacology, University of Sydney, Sydney, New South Wales, Australia

Correspondence and requests for reprints should be addressed to Stuart J. Hirst, Ph.D., King's College London School of Medicine, MRC & Asthma UK Centre in Allergic Mechanisms of Asthma, Thomas Guy House, Guy's Hospital Campus, London SE1 9RT, UK. E-mail: stuart.hirst{at}kcl.ac.uk.

Airway hyperresponsiveness (AHR) is associated with airway wall structural remodeling and alterations in airway smooth muscle (ASM) function. Previously, in bronchioles from Brown Norway rats challenged by repeated ovalbumin (OVA) inhalation, we have reported increased force generation and depletion of smooth muscle contractile proteins. Here, we investigated if cytoskeletal changes in smooth muscle could account for this paradox. Sensitized rats (n = 5/group) were repeatedly challenged with OVA or saline, and the lungs were removed 24 h after the last challenge. Levels of globular (G) and filamentous (F) actin in bronchioles were determined by DNase I inhibition and contraction assessed in intact small bronchioles using a myograph. DNase I inhibition assays showed that G-actin monomers were more abundant ( 1F:2G) in extracts from resting small bronchioles from OVA- or saline-challenged animals. However, while contractile protein levels in bronchioles were reduced by OVA (P < 0.05), the proportion of F:G actin was 1.8-fold greater compared with saline challenge (P < 0.05). Consistent with induction of F-actin after OVA challenge, increases in maximum tension development to carbachol or KCl in small bronchioles from OVA-challenged animals were abrogated (P < 0.01) by actin cytoskeleton disruption with 0.5 µM latrunculin A. Cytoskeletal stabilization of F-actin with 0.1 µM jasplakinolide potentiated maximum contractions to carbachol or KCl (P < 0.05) in bronchioles from OVA- but not saline-treated rats. We conclude that alterations in the composition and/or arrangement of the contractile apparatus after OVA exposure confer enhanced contractile responses, possibly as a result of increased F-actin content. Such a mechanism may have relevance for AHR found in allergic asthma.

Key Words: airway hyperresponsiveness • airway smooth muscle • asthma • cytoskeleton

CLINICAL RELEVANCE Allergen exposure in rats reduces airway smooth muscle contractile proteins, but enhances force generation. We examined this paradox and found that F-actin is doubled. Our data suggest that increased F-actin levels after chronic allergen exposure confer enhanced contractions.