Plantier et al this disease. In this review, we will successively assess the evidence (1) that alveolar regeneration systems are functional in the mammalian lung and have the potential to regrow lost alveoli, (2) that cigarette smoke, the main etiologic factor of emphysema, inhibits those systems under experimental conditions, and (3) that alveolar regeneration systems are dysfunctional in the human emphysematous lung and may be a target for therapeutic intervention in this disease. Special emphasis will be put on the role of alveolar ﬁbroblasts in those processes. Effective alveolar regeneration systems are functional in the adult mammalian lung The potential for alveolar generation and regeneration in adult mammals was only recently demonstrated in rodents but also in larger animals. This phenomenon could be observed after alveolar depletion was induced either diffusely by starvation or locally by the surgical resection of lung parenchyma. Alveolar regeneration has been observed in mice fed a normal diet after a starvation period. Starvation has long been known to induce the loss of pulmonary alveoli and the subsequent development of emphysema-like lesions in the lung as was recently shown in humans with anorexia nervosa (Coxson et al 2004). There are no data regarding the potential reversibility of these lesions in humans, however the return to a normal diet induces the complete resolution of starvation- associated emphysema in mice (Massaro et al 2004). This phenomenon represents a truly regenerative process as the restoration of normal numbers and surface of alveoli is accompanied by a sharp elevation of DNA synthesis in the lung, indicating cellular replication (Massaro et al 2007). Alveolar regeneration was also demonstrated after a local- ized resection of lung parenchyma. Indeed, the knowledge that the remaining lung undergoes adaptative changes and compensatory alveolar generation after lung resection was acquired several decades ago (Cagle and Thurlbeck 1988). In rats, resection of the upper and middle lobes of the right lung (25% of the total lung volume) induces a sharp increase in the volume of the remaining lobes, while microscopically alveolar size and surface are close to those of unoperated animals, indicating the de novo generation of alveoli (Wandel et al 1983). In mice, post-resection alveolar generation involves all cellular components of the lung as epithelial, endothelial and mesenchymal cells proliferate (Voswinckel et al 2004). It must be emphasized that in this context the newly formed alveolar tissue seems to be functional and to participate in ventilation. 464 Of major interest, compensatory alveolar generation after lung resection was also evidenced in growth–arrested species, albeit to a lesser degree than in rodents. In dogs as well as in humans, the intensity of post-pneumonectomy alveolar generation seems to depend on age. In young dogs, after left pneumonectomy removing less than 45% of total lung parenchyma, compensatory alveolar generation occurs vigorously and leads to the restoration of alveolar numbers similar to that of unoperated animals (Takeda et al 1999). By contrast, in fully adult dogs, a stronger stimulus such as right pneumonectomy (removing 55% or more of parenchyma) is needed to induce a weaker and incomplete response (Hsia et al 1994). In humans, post- pneumonectomy alveolar generation and lung growth do not seem to occur in adults but indirect clues point towards the existence of such phenomenon in children and to a lesser degree in adolescents. In particular, the ventilatory function at adulthood of patients pneumonectomized before the age of 4 is close to that of unoperated subjects, most likely indicating that the formation of new alveoli com- pensated for resected ones (Laros and Westermann 1987). Patients operated upon between 6 and 20 years of age still had better lung function parameters than those of patients who underwent pneumonectomy at adulthood (Laros and Westermann 1987). Altogether, those results indicate that alveolar regeneration systems are present in the lung of growth-arrested mammals such as humans, and that those systems are accessible to stimulation. Mechanisms of alveolar regeneration, role of alveolar ﬁbroblasts Alveolar cells of every type (epithelial, endothelial, and mesenchymal) participate in alveolar multiplication and regeneration events since those require their equilibrated proliferation. Moreover, all three main cell types seem to possess the ability to drive lung growth since the administra- tion of growth factors targeted towards either type leads to the acceleration of alveolar generation after lung resection. The hepatocyte growth factor (HGF), the ﬁrst such agent that was identiﬁed as stimulating lung growth after lung resection (Yanagita et al 1993), targets both epithelial and endothelial cells. The epidermal growth factor (EGF) (Kaza et al 2000), activates mainly epithelial cells, whereas the platelet–derived growth factor-BB (PDGF-BB) (Yuan et al 2002) is a mitogen primarily for mesenchymal cells. While both the keratinocyte growth factor (KGF) (Kaza et al 2002), and the vascular endothelial growth factor (VEGF) (Sakurai et al 2006) International Journal of COPD 2007:2(4)