Small airway hyperresponsiveness in COPD: Relationship between structure and function in lung slices

Harm Maarsingh*, Cecile M. Bidan, Bindi S. Brook, Annet B. Zuidhof, Carolina R. S. Elzinga, Marieke Smit, Anouk Oldenburger, Reinoud Gosens, Wim Timens, Herman Meurs

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

21 Citations (Scopus)
268 Downloads (Pure)


The direct relationship between pulmonary structural changes and airway hyperresponsiveness (AHR) in chronic obstructive pulmonary disease (COPD) is unclear. We investigated AHR in relation to airway and parenchymal structural changes in a guinea pig model of COPD and in COPD patients. Precision-cut lung slices (PCLS) were prepared from guinea pigs challenged with lipopolysaccharide or saline two times weekly for 12 wk. Peripheral PCLS were obtained from patients with mild to moderate COPD and non-COPD controls. AHR to methacholine was measured in large and small airways using video-assisted microscopy. Airway smooth muscle mass and alveolar airspace size were determined in the same slices. A mathematical model was used to identify potential changes in biomechanical properties underlying AHR. In guinea pigs, lipopolysaccharide increased the sensitivity of large (> 150 mu m) airways toward methacholine by 4.4-fold and the maximal constriction of small airways (> 150 mu m) by 1.5-fold. Similarly increased small airway responsiveness was found in COPD patients. In both lipopolysaccharide-challenged guinea pigs and patients, airway smooth muscle mass was unaltered, whereas increased alveolar airspace correlated with small airway hyperresponsiveness in guinea pigs. Fitting the parameters of the model indicated that COPD weakens matrix mechanical properties and enhances stiffness differences between the airway and the parenchyma, in both species. In conclusion, this study demonstrates small airway hyperresponsiveness in PCLS from COPD patients. These changes may be related to reduced parenchymal retraction forces and biomechanical changes in the airway wall. PCLS from lipopolysaccharide-exposed guinea pigs may be useful to study mechanisms of small airway hyperresponsiveness in COPD.

Original languageEnglish
Pages (from-to)L537-L546
Number of pages10
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Issue number3
Early online date10-Jan-2019
Publication statusPublished - Mar-2019


  • airway constriction
  • airway remodeling
  • biomechanical modeling
  • emphysema
  • human lung

Cite this