Steroids Augment Relengthening of Contracted Airway Smooth Muscle: Potential Additional Mechanism of Benefit in Asthma

¹ Depts of paediatrics
² Depts of paediatrics; and Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL 60637
³ Medicine, Section of Pulmonary and Critical Care Medicine, The University of Chicago, Chicago, IL 60637
⁴ Dept of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208

^* To whom correspondence should be addressed. E-mail: olakser{at}peds.bsd.uchicago.edu.

	Abstract

Breathing (especially deep breathing) antagonizes development and persistence of airflow obstruction during bronchoconstrictor stimulation. Force fluctuations imposed on contracted airway smooth muscle (ASM) in vitro result in its relengthening, a phenomenon called force fluctuation-induced relengthening (FFIR). Because breathing imposes similar force fluctuations on contracted ASM within intact lungs, FFIR represents a likely mechanism by which breathing antagonizes bronchoconstriction. While this bronchoprotective effect appears to be impaired in asthma, corticosteroid treatment can restore the ability of deep breaths to reverse artificially induced bronchoconstriction in asthmatic subjects. We previously demonstrated that FFIR is physiologically regulated through the p38 MAPK signaling pathway. While the beneficial effects of corticosteroids have been attributed to suppression of airway inflammation, we hypothesized that alternatively they might exert their action directly on ASM by augmenting FFIR as a result of inhibiting p38 MAPK signaling.

We tested this possibility in the present study by measuring relengthening in contracted canine tracheal smooth muscle (TSM) strips.

Our results indicate that dexamethasone treatment significantly augmented FFIR of contracted canine TSM. Canine tracheal ASM cells treated with dexamethasone demonstrated increased MAP kinase phosphatase (MKP)-1 expression and decreased p38 MAPK activity, as reflected in reduced phosphorylation of the p38 MAPK downstream target, HSP27.

These results suggest that corticosteroids may exert part of their therapeutic effect through direct action on ASM, by decreasing p38 MAPK activity and thus increasing FFIR.