potential regenerative effect of HGF and KGF in the lung, a low secretion of this factor by lung ﬁbroblasts may play a role in the pathogenesis of emphysema. Altogether, those results indicate an altered phenotype of pulmonary ﬁbroblasts which may partly contribute to the absence of alveolar regeneration observed in emphysema. Alveolar regeneration systems are therapeutic targets for emphysema The therapeutic manipulation of alveolar regeneration sys- tems would represent a tremendous advance for the treat- ment of emphysema as well as other diseases characterized by the destruction of alveoli. Such results were obtained in animal models of emphysema through the administration of pharmacological agents, gene therapy or the implantation of mesenchymal stem cells, raising hope that such an effect may be attainable in human patients. The proof of concept that alveolar regeneration was a possible therapeutical goal in emphysema was brought by the pioneering work by Donald and Gloria Massaro (Massaro and Massaro 1997). In this study, all-trans retinoic acid induced partial alveolar regeneration 20 days after emphysema was induced in rats with the tracheal instillation of elastase. This result was reproduced by some groups (Ishizawa et al 2004), while others did not (Tepper et al 2000; Lucey et al 2003; Fujita et al 2004; March et al 2004). The strong regenerative effect of exogenous HGF was shown in the elastase-induced emphysema model in mice. Its effect was associated to the engraftment into the lung of cells derived from the circulation (Ishizawa et al 2004). This effect was reproduced in rats transfected intravenously with the human HGF gene seven days after the instilla- tion of elastase (Shigemura et al 2005). Adrenomedullin, an angiogenic factor, has been shown to possess alveolar regenerative properties in the same model, albeit at a lesser degree than HGF (Murakami et al 2005). Interestingly, an angiogenic stimulus seems necessary for the induction of alveolar regeneration in the emphysematous lung as KGF, which targets mainly epithelial cells, was not found to exert such an effect, even though its cytoprotective properties allowed it to fully prevent the constitution of emphysema in mice instilled with elastase (Plantier et al 2006). All of the studies cited so far relied on the administration of soluble factors, either directly or by gene transfection. Another approach to the development of alveolar regenera- tive therapeutics has been the transplantation into the lung of mesenchymal stem cells obtained from adipose tissue (Shigemura et al 2006a, 2006b). Adipose-tissue derived International Journal of COPD 2007:2(4) Alveolar regeneration in pulmonary emphysema stromal cells were obtained from inguinal subcutaneous fat and applicated to the elastase-injured lung, resulting in alveolar regeneration and higher levels of PaO2 and maximal oxygen consumption. Interestingly, adipose-tissue derived stromal cells secrete particularly high levels of HGF. Their regenerative effect in the emphysematous lung may be related to this characteristic as their engraftment into the lung was not reported. Overall, the feasibility of inducing alveolar regeneration in rodents with elastase-induced emphysema has been thoroughly demonstrated. Alveolar regeneration in human emphysema? Whether alveolar regeneration may be obtained in pulmonary emphysema patients in the near future remains unsure. To this day, a single study has been devoted to the exploration of the effect of a regenerative agent in this disease, namely reti- noic acid (Roth et al 2006). In this crossover study, all-trans retinoic acid, 13-cis retinoic acid or placebo were administered for 6 months to 148 patients with moderate-to-severe COPD and a predominant component of emphysema. Despite the fact that high plasma levels of retinoic acid were obtained in treated patients, no difference in pulmonary function or quality of life was observed between groups in this study. Among the candidate drugs for regeneration therapy in the lung, HGF seems to be of particular interest. While the use of this factor for the treatment of lung disease has not been reported to date, encouraging preliminary results have been obtained in the treatment of peripheral arterial disease where HGF is well tolerated in the short term and induces an increase in distal perfusion (Morishita et al 2004). However, HGF has been reported to facilitate the growth of tumors in various organs, including the lung (Stabile et al 2006). Since patients with pulmonary emphysema are most frequently smokers or ex-smokers at a high risk of lung cancer, whether HGF itself is a good candidate for the long-term treatment of this disease remains to be evaluated. Conclusion Alveolar regeneration can be induced in animal models of dif- fuse or localized alveolar loss and can be repressed by exposure to cigarette smoke. Defects in alveolar regeneration systems have been identiﬁed in the human emphysematous lung and may play an important role in the course of this disease which is characterized by alveolar loss. Restoration and/or induction of these systems in emphysematous patients may represent a major advance in the treatment of pulmonary emphysema, a disease characterized by the loss of pulmonary alveoli. 467