Steroids augment relengthening of contracted airway smooth muscle: potential additional mechanism of benefit in asthma

Abstract

Breathing (especially deep breathing) antagonises 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 antagonises 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. It has previously been demonstrated that FFIR is physiologically regulated through the p38 mitogen-activated protein kinase (MAPK) signalling pathway. While the beneficial effects of corticosteroids have been attributed to suppression of airway inflammation, the current authors hypothesised that alternatively they might exert their action directly on ASM by augmenting FFIR as a result of inhibiting p38 MAPK signalling.This possibility was tested in the present study by measuring relengthening in contracted canine tracheal smooth muscle (TSM) strips.The results indicate that dexamethasone treatment significantly augmented FFIR of contracted canine TSM. Canine tracheal ASM cells treated with dexamethasone demonstrated increased MAPK phosphatase-1 expression and decreased p38 MAPK activity, as reflected in reduced phosphorylation of the p38 MAPK downstream target, heat shock protein 27.These results suggest that corticosteroids may exert part of their therapeutic effect through direct action on airway smooth muscle, by decreasing p38 mitogen-activated protein kinase activity and thus increasing force fluctuation-induced relengthening.

The secret life of steroids in asthma

“…This is exactly the angle that LAKSER et al [17] chose in the current issue of the European Respiratory Journal. Here one recognises a physiological approach.…”

“…This inactivates p38 MAPK, thereby enhancing the stretch of precontracted airway smooth muscle by periodic strain. The data show that [17], first, incubation of isotonicly shortened canine tracheal smooth muscle strips with dexamethasone prior to and during force fluctuations significantly augment muscle relengthening. Secondly, dexamethasone increases the expression of MKP-1 in cultured canine tracheal smooth muscle cells, which is accompanied by a decrease in phosphorylation of a downstream target of p38 MAPK, heat shock protein 27 [17].…”

“…The data show that [17], first, incubation of isotonicly shortened canine tracheal smooth muscle strips with dexamethasone prior to and during force fluctuations significantly augment muscle relengthening. Secondly, dexamethasone increases the expression of MKP-1 in cultured canine tracheal smooth muscle cells, which is accompanied by a decrease in phosphorylation of a downstream target of p38 MAPK, heat shock protein 27 [17]. In short, steroids promote the re-lengthening of smooth muscle by cyclic stretch and also inhibit a suppressor signalling pathway of this, fitting in with each other.…”

“…LAKSER et al [17] reasoned that if this is the key abnormality of airway function in asthma (as opposed to airway inflammation per se), the re-lengthening of smooth muscle by force fluctuations should be steroid sensitive. The hypothesis was that steroids inactivate a potential suppressor of force fluctuation-induced relengthening, p38 mitogen-activated protein kinase (MAPK) [21], by increasing the expression of MAPK phosphatase-1 (MKP-1).…”

Association of Childhood Asthma and Pediatric Obstructive Sleep Apnea: A Retrospective Cohort Study from a Nationwide Population-based Database

“…Second, the deformable pharyngeal airway duration inspiration and the active contraction of respiratory muscles during forced exhalation in an asthma attack could promote the collapse of the upper airway at night [21]. Third, corticosteroid therapy may affect the pharyngeal airway and render pharyngeal dilators more floppy, thus reducing their ability to protect the upper airway patency during sleep [22,23]. More clinical trials or animal studies should be performed to confirmed these mechanisms or pathophysiology.…”