Bronchoconstriction

Asthma is characterized by airway hyperresponsiveness and airway remodeling, which are largely attributed to increased airway smooth muscle contractility and cell proliferation. It is known that both chemical and mechanical stimulation regulates smooth muscle contraction. Recent studies suggest that contractile activation and mechanical stretch induce actin cytoskeletal remodeling in smooth muscle. However, the mechanisms that control actin cytoskeletal reorganization are not completely elucidated. This review summarizes our current understanding regarding how actin-associated proteins may regulate remodeling of the actin cytoskeleton in airway smooth muscle. In particular, there is accumulating evidence to suggest that Abelson tyrosine kinase (Abl) plays a critical role in regulating airway smooth muscle contraction and cell proliferation in vitro, and airway hyperresponsiveness and remodeling in vivo. These studies indicate that Abl may be a novel target for the development of new therapy to treat asthma.

BackgroundIt is widely recognized that deep inspiration (DI), either before methacholine (MCh) challenge (Bronchoprotection, BP) or after MCh challenge (Bronchodilation, BD) protects against this challenge in healthy individuals, but not in asthmatics. Sulforaphane, a dietary antioxidant and antiinflammatory phytochemical derived from broccoli, may affect the pulmonary bronchoconstrictor responses to MCh and the responses to DI in asthmatic patients.MethodsForty-five moderate asthmatics were administered sulforaphane (100 μmol daily for 14 days), BP, BD, lung volumes by body-plethsmography, and airway morphology by computed tomography (CT) were measured pre- and post sulforaphane consumption.ResultsSulforaphane ameliorated the bronchoconstrictor effects of MCh on FEV1 significantly (on average by 21 %; p = 0.01) in 60 % of these asthmatics. Interestingly, in 20 % of the asthmatics, sulforaphane aggravated the bronchoconstrictor effects of MCh and in a similar number was without effect, documenting the great heterogeneity of the responsiveness of these individuals to sulforaphane. Moreover, in individuals in whom the FEV1 response to MCh challenge decreased after sulforaphane administration, i.e., sulforaphane was protective, the activities of Nrf2-regulated antioxidant and anti-inflammatory genes decreased. In contrast, individuals in whom sulforaphane treatment enhanced the FEV1 response to MCh, had increased expression of the activities of these genes. High resolution CT scans disclosed that in asthmatics sulforaphane treatment resulted in a significant reduction in specific airway resistance and also increased small airway luminal area and airway trapping modestly but significantly.ConclusionThese findings suggest the potential value of blocking the bronchoconstrictor hyperresponsiveness in some types of asthmatics by phytochemicals such as sulforaphane.

Airway remodelling, including smooth muscle remodelling, is a primary cause of airflow limitation in asthma. Recent evidence links bronchoconstriction to airway remodelling in asthma. The mechanisms involved are poorly understood. A possible player is the multifunctional cytokine TGF-β, which plays an important role in airway remodelling. Guinea pig lung slices were used as an in vitro model to investigate mechanisms involved in bronchoconstriction-induced airway remodelling. To address this aim, mechanical effects of bronchoconstricting stimuli on contractile protein expression and TGF-β release were investigated. Lung slices were viable for at least 48 h. Both methacholine and TGF-β1 augmented the expression of contractile proteins (sm-α-actin, sm-myosin, calponin) after 48 h. Confocal fluorescence microscopy showed that increased sm-myosin expression was enhanced in the peripheral airways and the central airways. Mechanistic studies demonstrated that methacholine-induced bronchoconstriction mediated the release of biologically active TGF-β, which caused the increased contractile protein expression, as inhibition of actin polymerization (latrunculin A) or TGF-β receptor kinase (SB431542) prevented the methacholine effects, whereas other bronchoconstricting agents (histamine and KCl) mimicked the effects of methacholine. Collectively, bronchoconstriction promotes the release of TGF-β, which induces airway smooth muscle remodelling. This study shows that lung slices are a useful in vitro model to study mechanisms involved in airway remodelling.

IntroductionThe forced oscillation technique (FOT) complements spirometry in assessing lung function, with higher sensitivity to small airway dysfunction. Systemic inflammation is thought to influence lung development and exercise-induced bronchoconstriction (EIB), but its relationship to circulating inflammatory proteins in adolescents is unclear.ObjectiveTo investigate associations between systemic inflammatory biomarkers and baseline lung function and post-exercise airway responses in adolescents.MethodsIn 143 adolescents (13-15 years) from a population-based cohort, baseline spirometry, FOT, and baseline blood samples were obtained. Participants completed an exercise challenge to assess EIB via changes in forced expiratory volume in 1 s (FEV1), resistance at 5 Hz (R5), and reactance at 5 Hz (X5). Plasma protein levels were measured using the proximity extension assay technique (Olink Target Inflammation and Immune Response panels). Associations with lung function (FEV1% predicted, R5, and X5 z-scores) and post-exercise responses (∆FEV1, ∆R5, ∆X5) were analyzed using linear regression with false discovery rate correction. Interaction with atopy was also examined.ResultsHigher plasma levels of C-C motif chemokine 19 (CCL19) were significantly associated with lower FEV1% predicted and lower X5 z-scores at baseline, indicating reduced lung function and impaired small airway function. No proteins were associated with post-exercise airway responses after correction. Five proteins showed significant interactions with atopy in relation to EIB.ConclusionElevated CCL19 may reflect systemic inflammatory processes contributing to impaired lung function in early adolescence. The observed atopy-related interactions suggest the need to consider atopy in studies of systemic inflammation and airway physiology.