Use of human airway smooth muscle in vitro and ex vivo to investigate drugs for the treatment of chronic obstructive respiratory disorders

Abstract

Isolated airway smooth muscle has been extensively investigated since 1840 to understand the pharmacology of airway diseases. There has been often poor predictability from murine experiments to drugs evaluated in patients with asthma or chronic obstructive pulmonary disease (COPD). However, the use of isolated human airways represents a sensible strategy to optimise the development of innovative molecules for the treatment of respiratory diseases. This review aims to provide updated evidence on the current uses of isolated human airways in validated in vitro methods to investigate drugs in development for the treatment of chronic obstructive respiratory disorders. This review also provides historical notes on the pioneering pharmacological research on isolated human airway tissues, the key differences between human and animal airways, as well as the pivotal differences between human medium bronchi and small airways. Experiments carried out with isolated human bronchial tissues in vitro and ex vivo replicate many of the main anatomical, pathophysiological, mechanical and immunological characteristics of patients with asthma or COPD. In vitro models of asthma and COPD using isolated human airways can provide information that is directly translatable into humans with obstructive lung diseases. Regardless of the technique used to investigate drugs for the treatment of chronic obstructive respiratory disorders (i.e. isolated organ bath systems, videomicroscopy, wire myography), the most limiting factors to produce high‐quality and repeatable data remain closely tied to the manual skills of the researcher conducting experiments and the availability of suitable tissue.

Precision cut lung slices: an integrated ex vivo model for studying lung physiology, pharmacology, disease pathogenesis and drug discovery

“…Additionally, PCLS has enabled investigators to translate their findings to clinically measurable respiratory parameters that are typically measured in obstructive lung diseases like asthma and COPD. For example, the luminal area of the small airways in PCLS correlates with the forced expiratory flow between 25% and 75% (FEF25-75), which serves to predict small airways obstruction that is characteristic of asthma and COPD (as reviewed in [ 138 ]).…”

“…In addition to differential responsiveness to bronchoconstrictors, many studies highlight the substantial differences between mice and human lungs in terms of the physiology, anatomy, and immunology of each species. Studies have also highlighted that the preclinical results obtained from mouse studies failed to accurately model airways diseases in humans (as reviewed in [ 138 ]). Despite the limitations of mouse models in the study of airways diseases, rodent strains offer the opportunity to genetically modify the animal to assess the function of cell-specific gene deficiency on the development and progression of lung diseases.…”