Lung regeneration and translational implications of the postpneumonectomy model

Lung regeneration research is yielding data with increasing translational value. The classical models of lung development, postnatal alveolarization, and postpneumonectomy alveolarization have contributed to a broader understanding of the cellular participants including stem-progenitor cells, cell-cell signaling pathways, and the roles of mechanical deformation and other physiologic factors that have the potential to be modulated in human and animal patients. Although recent information is available describing the lineage fate of lung fibroblasts, genetic fate mapping, and clonal studies are lacking in the study of lung regeneration and deserve further examination. In addition to increasing knowledge concerning classical alveolarization (postnatal, postpneumonectomy), there is increasing evidence for remodeling of the adult lung after partial pneumonectomy. Though limited in scope, compelling data have emerged describing restoration of lung tissue mass in the adult human and in large animal models. The basis for this long-term adaptation to pneumonectomy is poorly understood, but investigations into mechanisms of lung regeneration in older animals that have lost their capacity for rapid re-alveolarization are warranted, as there would be great translational value in modulating these mechanisms. In addition, quantitative morphometric analysis has progressed in conjunction with developments in advanced imaging, which allow for longitudinal and nonterminal evaluation of pulmonary regenerative responses in animals and humans. This review focuses on the cellular and molecular events that have been observed in animals and humans after pneumonectomy because this model is closest to classical regeneration in other mammalian systems and has revealed several new fronts of translational research that deserve consideration.