R E V I E W Defect of alveolar regeneration in pulmonary emphysema: Role of lung ﬁbroblasts Laurent Plantier1,2 Jorge Boczkowski1,3 Bruno Crestani1,4 1INSERM, U700, Faculté Xavier Bichat, Paris, France; 2Assistance Publique- Hôpitaux de Paris, Hôpital Bichat, Service de Pneumologie B, Paris, France; 3Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, CIC 07, Paris, France; 4Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, Service de Pneumologie A, Paris, France Correspondence: Bruno Crestani Service de Pneumologie A, Hôpital Bichat, 16 rue Henri Huchard, 75877, Paris Cedex 18, France Tel +33 1 40256800 Fax +33 1 40258818 Email bruno.crestani@bch.aphp.fr Abstract: Pulmonary emphysema is characterized by the irreversible loss of pulmonary alveoli. Despite recent advances in the understanding this disease, its treatment remains palliative. In this review, we will successively review the data suggesting (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. Keywords: emphysema, repair, regeneration, HGF, ﬁbroblasts Introduction Pulmonary emphysema is characterized by the progressive destruction of pulmonary alveoli. It is one of the most common diseases worldwide (Halbert et al 2006) and its incidence keeps growing along with the large diffusion of its main etiologic factor, tobacco smoking. The ever-increasing use of tobacco in the developing world allows for the prediction of a huge increase in the number of cases in the near and distant future. The prognosis of pulmonary emphysema is poor, with airﬂow limitation progressing to chronic respiratory insufﬁciency, disability and premature death. To this day, therapeutic options for pulmonary emphysema are few and scarcely effective. Patients who stop smoking do beneﬁt in terms of lung function and survival, but the decline in lung function is not reversed, merely slowed. Apart from long-term oxygen therapy, pharmacological intervention is unsatisfactory and is mainly limited to the control of symptoms related to frequently-associated chronic bronchitis (Sutherland and Cherniack 2004). Lung volume reduction surgery can be of interest in selected patients (Fishman et al 2003) as may be the implantation of endobronchial one-way valves (Wood et al 2007) but those techniques do not remedy the underlying condition. Lung transplantation, while beneﬁcial in terms of symptoms-related quality of life, does not improve survival in patients with pulmonary emphysema (Hosenpud et al 1998). Overall, treatment of pulmonary emphysema is palliative. Most studies of the pathogenesis of emphysema focused on the mechanisms involved in chronic injury induced by cigarette smoke to the pulmonary parenchyma. In particular, the role of protease-antiprotease imbalance, persistent inﬂammation, oxi- dative stress and excessive apoptosis of alveolar cells was demonstrated (Barnes et al 2003). However, while great advances were made towards the comprehension of those phenomenons, they have not translated into new therapeutic prospects until now. Alveolar regeneration systems may be important actors in the course of emphysema. On the one hand, alterations or defects in those systems may account for the deﬁciency in tissue repair which is observed in the emphysematous lung. On the other hand, the induction of alveolar regeneration would be an interesting therapeutic target in International Journal of COPD 2007:2(4) 463–469 © 2007 Dove Medical Press Limited. All rights reserved 463