Alveolar septal patterning during compensatory lung growth: Part II the effect of parenchymal pressure gradients.

In most mammals, compensatory lung growth occurs after the removal of one lung (pneumonectomy). Although the mechanism of alveolar growth is unknown, the patterning of complex alveolar geometry over organ-sized length scales is a central question in regenerative lung biology. Because shear forces appear capable of signaling the differentiation of important cells involved in neoalveolarization (fibroblasts and myofibroblasts), interstitial fluid mechanics provide a potential mechanism for the patterning of alveolar growth. The movement of interstitial fluid is created by two basic mechanisms: 1) the non-uniform motion of the boundary walls, and 2) parenchymal pressure gradients external to the interstitial fluid. In a previous study (Haber et al., Journal of Theoretical Biology 400: 118-128, 2016), we investigated the effects of non-uniform stretching of the primary septum (associated with its heterogeneous mechanical properties) during breathing on generating non-uniform Stokes flow in the interstitial space. In the present study, we analyzed the effect of parenchymal pressure gradients on interstitial flow. Dependent upon lung microarchitecture and physiologic conditions, parenchymal pressure gradients had a significant effect on the shear stress distribution in the interstitial space of primary septa. A dimensionless parameter δ described the ratio between the effects of a pressure gradient and the influence of non-uniform primary septal wall motion. Assuming that secondary septa are formed where shear stresses were the largest, it is shown that the geometry of the newly generated secondary septa was governed by the value of δ. For δ smaller than 0.26, the alveolus size was halved while for higher values its original size was unaltered. We conclude that the movement of interstitial fluid, governed by parenchymal pressure gradients and non-uniform primary septa wall motion, provides a plausible mechanism for the patterning of alveolar growth.

Interstitial fluid flow of alveolar primary septa after pneumonectomy.

Neoalveolation is known to occur in the remaining lung after pneumonectomy. While compensatory lung growth is a complex process, stretching of the lung tissue appears to be crucial for tissue remodeling. Even a minute shear stress exerted on fibroblasts in the interstitial space is known to trigger cell differentiation into myofibroblast that are essential to building new tissues. We hypothesize that the non-uniform motion of the primary septa due to their heterogeneous mechanical properties under tidal breathing induces a spatially unique interstitial flow and shear stress distribution in the interstitial space. This may in turn trigger pulmonary fibroblast differentiation and neoalveolation. In this study, we developed a theoretical basis for how cyclic motion of the primary septal walls with heterogeneous mechanical properties affects the interstitial flow and shear stress distribution. The velocity field of the interstitial flow was expressed by a Fourier (complex) series and its leading term was considered to induce the basic structure of stress distribution as long as the dominant length scale of heterogeneity is the size of collapsed alveoli. We conclude that the alteration of mechanical properties of the primary septa caused by pneumonectomy can develop a new interstitial flow field, which alters the shear stress distribution. This may trigger the differentiation of resident fibroblasts, which may in turn induce spatially unique neoalveolation in the remaining lung. Our example illustrates that the initial forming of new alveoli about half the size of the original ones.