Extracellular matrix mechanics in lung parenchymal diseases

Abstract

In this review, we examine how the extracellular matrix (ECM) of the lung contributes to the overall mechanical properties of the parenchyma, and how these properties change in disease. The connective tissues of the lung are composed of cells and ECM, which includes a variety of biological macromolecules and water. The macromolecules that are most important in determining the mechanical properties of the ECM are collagen, elastin, and proteoglycans. We first discuss the various components of the ECM and how their architectural organization gives rise to the mechanical properties of the parenchyma. Next, we examine how mechanical forces can affect the physiological functioning of the lung parenchyma. Collagen plays an especially important role in determining the homeostasis and cellular responses to injury because it is the most important load-bearing component of the parenchyma. We then demonstrate how the concept of percolation can be used to link microscopic pathologic alterations in the parenchyma to clinically measurable lung function during the progression of emphysema and fibrosis. Finally, we speculate about the possibility of using targeted tissue engineering to optimize treatment of these two major lung diseases.

Figure 1

Stress–strain curve of collagen in tendon. Large crimps and unfolding result in little stress in the “toe” region. Nonlinearity characterized by the “heel” region originates from the crimps (a) unfolding with stretching (with permission from Fratzl et al. (1998)).

Figure 2

Two-dimensional elastic network model of the lung parenchyma. Line elements are nonlinear springs and their folding is resisted by angular springs. When the angular spring (bond-bending) constant is low (left), the uniaxial stretching in the vertical direction results in large changes in angle. When the angular spring constant is high (right), macroscopic stretching lengthens the line elements rather than folding them, which results in higher forces and hence more red color. The microscopic deformation is not affine, it does not follow the macroscopic deformation leading to significant heterogeneity both in structure and force distribution (color) which also depend on the bond-bending to line element stiffness ratio. The black bonds at the top and bottom boundaries are rigid (based on Cavalcante et al. (2005)). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)

Figure 3

Schematic diagram of force transmission from the level of the whole lung to single cell with various feedback mechanisms influencing ECM composition and lung mechanics. Dotted lines show external or internal influences as well as various possible feedback loops in disease states.

Figure 4

Simulation of the progression of pulmonary fibrosis. The solid line shows the bulk modulus B of the elastic network as a function of the fraction of springs c randomly stiffened by a factor of 100. If all of 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. Shown at the top are the network configurations obtained when c =0, c = 0.5 and c = 0.67 with thick line showing stiff springs (with permission from Bates et al. (2007)).

Figure 5

Simulation of the progression of emphysema. The curve shows the bulk modulus B of the elastic network (normalized to the modulus of the network when fully intact) as a function of the fraction of springs c cut on the basis of the amount of force they carry. Shown at the top are the network configurations obtained at three points along this process. The forces in the individual springs are indicated by colors with yellow indicating high stress and decreasing stress corresponding to progressively darker shades of blue (with permission from Bates et al. (2007)). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of the article.)