title: Stretching mechanotransduction from the lung to the lab: approaches and physiological relevance in drug discovery.
abstract: Recent years have shown a great deal of interest and research into the understanding of the biological and physiological roles of mechanical forces on cellular behavior. Despite these reports, in vitro screening of new molecular entities for lung ailments is still performed in static cell culture models. Failure to incorporate the effects of mechanical forces during early stages of screening could significantly reduce the success rate of drug candidates in the highly expensive clinical phases of the drug discovery pipeline. The objective of this review is to expand our current understanding of lung mechanotransduction and extend its applicability to cellular physiology and new drug screening paradigms. This review covers early in vivo studies and the importance of mechanical forces in normal lung development, use of different types of bioreactors that simulate in vivo movements in a controlled in vitro cell culture environment, and recent research using dynamic cell culture models. The cells in lungs are subjected to constant stretching (mechanical forces) in regular cycles due to involuntary expansion and contraction during respiration. The effects of stretch on normal and abnormal (disease) lung cells under pathological conditions are discussed. The potential benefits of extending dynamic cell culture models (screening in the presence of forces) and the associated challenges are also discussed in this review. Based on this review, the authors advocate the development of dynamic high throughput screening models that could facilitate the rapid translation of in vitro biology to animal models and clinical efficacy. These concepts are translatable to cardiovascular, digestive, and musculoskeletal tissues and in vitro cell systems employed routinely in drug-screening applications.
authors.affiliation: School of Engineering, The University of Kansas, Lawrence, Kansas 66160, USA. vsnirmalan@hotmail.com
authors.forename: Sarah
authors.initials: S
authors.lastname: Schmitt
authors.forename: Peter
authors.initials: P
authors.lastname: Hendricks
authors.forename: Josh
authors.initials: J
authors.lastname: Weir
authors.forename: Raj
authors.initials: R
authors.lastname: Somasundaram
authors.forename: G Sitta
authors.initials: GS
authors.lastname: Sittampalam
authors.forename: Victor Sanjit
authors.initials: VS
authors.lastname: Nirmalanandhan
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D055808:Drug Discovery / Q000379:methods*; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008168:Lung / Q000502:physiology*; D040542:Mechanotransduction, Cellular / Q000502:physiology*; D011661:Pulmonary Stretch Receptors / Q000502:physiology; D015656:Respiratory Mechanics / Q000502:physiology; D013314:Stress, Mechanical