Asthma and lower airway disease
Expression of smooth muscle and extracellular matrix proteins in relation to airway function in asthma

https://doi.org/10.1016/j.jaci.2008.02.017Get rights and content

Background

Smooth muscle content is increased within the airway wall in patients with asthma and is likely to play a role in airway hyperresponsiveness. However, smooth muscle cells express several contractile and structural proteins, and each of these proteins may influence airway function distinctly.

Objective

We examined the expression of contractile and structural proteins of smooth muscle cells, as well as extracellular matrix proteins, in bronchial biopsies of patients with asthma, and related these to lung function, airway hyperresponsiveness, and responses to deep inspiration.

Methods

Thirteen patients with asthma (mild persistent, atopic, nonsmoking) participated in this cross-sectional study. FEV1% predicted, PC20 methacholine, and resistance of the respiratory system by the forced oscillation technique during tidal breathing and deep breath were measured. Within 1 week, a bronchoscopy was performed to obtain 6 bronchial biopsies that were immunohistochemically stained for α-SM-actin, desmin, myosin light chain kinase (MLCK), myosin, calponin, vimentin, elastin, type III collagen, and fibronectin. The level of expression was determined by automated densitometry.

Results

PC20 methacholine was inversely related to the expression of α-smooth muscle actin (r = −0.62), desmin (r = −0.56), and elastin (r = −0.78). In addition, FEV1% predicted was positively related and deep inspiration-induced bronchodilation inversely related to desmin (r = −0.60), MLCK (r = −0.60), and calponin (r = −0.54) expression.

Conclusion

Airway hyperresponsiveness, FEV1% predicted, and airway responses to deep inspiration are associated with selective expression of airway smooth muscle proteins and components of the extracellular matrix.

Section snippets

Subjects

This study was performed in the framework of a previously published project.4 Thirteen patients with mild persistent asthma (Global Initiative for Asthma steps 1 and 224) were recruited for this study. All patients had a history of episodic chest tightness or wheezing. Their baseline FEV1 was more than 70% of predicted.25 The PC20 methacholine was less than 8 mg/mL.26 All patients were atopic, as determined by a positive skin prick test result (≥3mm wheal) to 1 or more of 10 common aeroallergen

Smooth muscle protein expression

The density of the smooth muscle protein staining was determined in the whole biopsy section. The mean density (gray value) for each marker is given in Table I. All available sections (2 per patient) were used in the analysis. Fig 1 presents examples of the immunohistochemical staining in the same biopsy section of 1 subject. All markers, except for vimentin, strongly stained the airway smooth muscle cells. Vimentin was negative or weakly expressed in the smooth muscle cells. Outside the smooth

Discussion

Our results demonstrate an inverse association between PC20 methacholine and the level of expression of α-SM-actin, desmin, and elastin in bronchial biopsies in patients with asthma. Also, we showed that FEV1% predicted was positively related, and deep inspiration–induced reduction in respiratory resistance inversely related to calponin, desmin, and MLCK expression. Thus, airway hyperresponsiveness, lung function, and airway responses to deep inspiration are associated with the level of

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    Supported by the Netherlands Asthma Foundation (3.2.02.34).

    Disclosure of potential conflict of interest: J. C. de Jongste has received research support from Aerocrine. K. F. Rabe has consulting arrangements with AstraZeneca, Boehringer Ingelheim, Novartis, Pfizer, Altana, GlaxoSmithKline, and Roche; has received research support from AstraZeneca, Merck, Altana, and Boehringer Ingelheim; and is on the speakers' bureau for AstraZeneca, Boehringer Ingelhim, Novartis, Pfizer, Altana, GlaxoSmithKline, and Roche. P. S. Hiemstra has received research support from AltanaPharma, Novartis, Bayer, AstraZeneca, Pfizer, Merck, Exhale Therapeutics, Boehringer Ingelheim, Roche, and GlaxoSmithKline. The rest of the authors have declared that they have no conflict of interest.

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