The importance of mechanical forces in chronic respiratory diseases

The lung may be the organ whose mechanical environment needs to be most finely tuned to achieve optimal function. These needs have to be fulfilled at multiple scales, from proper force transmission between the chest wall and the parenchyma to reduction of surface tension by surfactants inside the alveoli. In addition, a plethora of mechanical loads and forces takes place within the lung, from the passive stretch withstood by epithelial cells lining the alveoli, to active forces generated by smooth muscle cells to control airway calibre or cilia beating by ciliary cells in the bronchi to clear debris. Furthermore, the acellular structures in the lung are finely tuned in composition and mechanical properties, from the viscoelastic properties of the mucus to trap pathogens, to the collagen- and elastin-rich extracellular matrix that enables the lung to display elastic recoil at resting volumes but stiffen as it approaches total lung capacity. In this review, we describe the mechanical interplay between the cell types found in the lung, as well as cellular responses to their mechanical niche. We further describe how these responses are altered in diseases such as asthma, COPD, pulmonary fibrosis and lung cancer. In addition, key proteins in mechanotransduction events are detailed, stressing their potential role as therapeutical targets for lung diseases. Finally, we also include a sex perspective to lung pathologies and highlight engineered model systems that may be used to advance our understanding of mechanical forces in experimental investigations or towards lung regeneration.