Recent advances and new opportunities in lung mechanobiology

Abstract

Lung function is inextricably linked to mechanics. On short timescales every breath generates dynamic cycles of cell and matrix stretch, along with convection of fluids in the airways and vasculature. Perturbations such airway smooth muscle shortening or surfactant dysfunction rapidly alter respiratory mechanics, with profound influence on lung function. On longer timescales, lung development, maturation, and remodeling all strongly depend on cues from the mechanical environment. Thus mechanics has long played a central role in our developing understanding of lung biology and respiratory physiology. This concise review focuses on progress over the past 5 years in elucidating the molecular origins of lung mechanical behavior, and the cellular signaling events triggered by mechanical perturbations that contribute to lung development, homeostasis, and injury. Special emphasis is placed on the tools and approaches opening new avenues for investigation of lung behavior at integrative cellular and molecular scales. We conclude with a brief summary of selected opportunities and challenges that lie ahead for the lung mechanobiology research community.

Figure 1

(A) Micro-CT images of rat lung airways at inflation volumes of (a) functional residual capacity (FRC) and (b) total lung capacity (TLC). Same-direction arrows indicate the same airways. Scale bar, 500 μm. Adapted with permission from (Sera et al. 2004). (B) The same rat lung alveolus imaged with intravital microscopy at transpulmonary inflation pressures of 5 cmH2O (green pseudocolor) and 20 cmH2O (red pseudocolor). Numbers in baseline image label two perimeter segments. An overlay of the images demonstrates inflation-induced alveolar expansion, which increased total alveolar perimeter length, L and alveolar diameter, D by 13 and 15%, respectively. Adapted with permission from (Perlman and Bhattacharya 2007).

Figure 2

(A) Representative stiffness maps of normal and fibrotic (14 days post bleomycin treatment) mouse lung parenchyma. Colorbar indicates shear modulus. AFM force-indentation profiles were acquired in a 16×16 sample grid separated by 5 μm spatially covering 80×80 μm area. Shear modulus at each point on the grid was calculated from fitting force-indentation data using a Hertz sphere model and resulting shear modulus data were plotted in a contour map (unpublished data). (B) Simulation of the progression of pulmonary fibrosis (a) and emphysema (b) based on percolation of sequential alveolar wall stiffening or rupture. (a) The curve shows the bulk modulus of the elastic network versus the fraction of springs randomly stiffened by a factor of 100. If all the spring constants were uniformly stiffened in a gradual manner from the baseline value of 1 to 100, the modulus would follow the dashed diagonal line. Top: Network configurations obtained when 0, 50, and 67% of the springs have been stiffened. (b) The curve shows the bulk modulus of the elastic network versus the fraction of springs cut on the basis of the amount of tension they carry. Top: Network configurations obtained at three points along this process. The stresses in the individual springs are indicated by color coding, with yellow indicating high stress and decreasing stress corresponding to progressively darker shades of blue. Adapted with permission from (Bates et al 2007).

Figure 3

(A) Schematic of bronchial epithelial cells cultured at air-liquid interface on a microporous substrate. The lateral cellular surfaces express pro-ligands of the EGF family and their cognate EGFR receptors, forming a local autocrine circuit. (B) Compressive stress (apical to basal transcellular pressure gradient) shrinks the lateral intercellular space between neighboring bronchial epithelial cells, visualized by two-photon imaging of extracellular fluorescent dextran. Sequential images at baseline (0 seconds), 60 and 600 seconds after initiation of continuous compressive stress illustrate the gradual decline in intercellular gap distance. (C) Chronic intermittent exposure to compressive stress daily for 14 days enhances expression of a mucus secretory phenotype, visualized by immunofluorescent staining of MUC5AC (green). Nuclear counterstain is shown in red.