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Rebuilding the lung: signals for a complex architectural task.

WHAT A REMARKABLE ORGAN THE human lung is! At the end of a deep breath, the vast majority of its volume (80%) is air. More than half of the remaining volume (10%) is blood. These two phases have to be separated strictly but also brought into close contact over a large surface to allow efficient gas exchange. However, what about those remaining 10% that serves this function: the “real” lung tissue? Those few hundred grams of tissue consist of more than 40 cell types, originating from all 3 germ layers, and a sophisticated connective tissue network. Together they form an organ with a complex architecture optimized to serve its main function. The branching airway and vascular trees come in close proximity in the parenchymal region where gas exchange is facilitated by a minimized barrier thickness over a maximized surface area. This delicate parenchymal structure is stabilized by two factors: the surface tension modifying properties of the pulmonary surfactant system and the lung’s connective tissue “backbone.” A continuous network of connective tissue, consisting of collagenous and elastic fibers and the fibroblasts that produce them, forms a tensegrity structure in the lung (15). This network, however, appears as “focal” (as it is often described in cases of proliferation, e.g., in idiopathic pulmonary fibrosis, although it is actually a highly interconnected reticulum; Ref. 3) in thin histological sections, which underscores the importance of qualitative and quantitative threedimensional information for proper characterization of lung structure in health and disease. Mechanical signals that act within and on the lung are translated into biochemical signals that lead to effects at the cellular level, e.g., inducing secretion, tissue growth, or remodeling, which, in turn, affect lung mechanics (for review, see e.g., Ref. 16). One example specific to the lung is the stimulation of surfactant secretion by mechanical distension of surfactant-producing type II alveolar epithelial cells or their neighboring type I cells (reviewed in Ref. 5). An interesting and relevant model to study the effects of mechanical forces on lung structure and function is compensatory lung growth following pneumonectomy. Moreover, compensatory lung growth is a paradigmatic example for the structural plasticity of the adult lung. Can the mechanical stimuli that induce compensatory lung growth after pneumonectomy, tissue expansion vs. microvascular perfusion, be dissected? A study by Ravikumar et al. (12) in this issue of the Journal of Applied Physiology elegantly demonstrates that this is possible. In adult dogs, the right lung was replaced by an inflated silicone prosthesis for 4 mo. Then, the prosthesis was either kept inflated or deflated for another 8 mo (long-term cohort). This study design was complemented by a short-term cohort with right pneumonectomy, prosthesis inflation for 1 mo, and immediate analysis either with or without deflation. This setting allowed the temporal separation of expansion- and perfusion-related stimuli for compensatory lung growth. A comprehensive quantitative analysis of lung structure was undertaken. Noninvasive chest imaging by high-resolution computed tomography was performed before and after pneumonectomy in the inflation and deflation groups. This was followed by post mortem morphometric analysis by light and electron microscopic stereology. The prosthesis prevented mediastinal shift and lateral expansion of the left lung but allowed some caudal elongation. Capillary blood volume increased and microvascular congestion was noted at low inflation. This was accompanied by an increase in alveolar septal volume but not surface area. Subsequent deflation led to an immediate mediastinal shift and lateral expansion of the remaining left lung which, in the long-term cohort, further increased lung and alveolar septal tissue volume and surface area in comparison to the inflation group. These quantitative data demonstrate that lung tissue expansion and microvascular perfusion contribute nearly