stimulate post-pneumonectomy alveolar multiplication, the former induces proliferation exclusively in epithelial cells while the latter essentially targets the endothelium. Alto- gether, those results suggest that the induction of proliferation in a particular cell population of alveoli may be accompanied by the simultaneous expansion of the other neighboring cell types, possibly through paracrine mechanisms. However, some elements indicate that mesenchymal cells may be ﬁrst among equals and may play a leading part in those processes. Indeed, pulmonary ﬁbroblasts are the main contributors to the synthesis and maintenance of the alveolar extracellular matrix which is the essential scaffold over which other cells proliferate and differentiate and which provides the lung with its essential mechanical characteristic, elasticity. Moreover, alveolar ﬁbroblasts secrete growth factors targeting alveolar epithelial and endothelial cells. Pulmonary ﬁbroblasts are the main cell type responsible for the synthesis and secretion of the main components of the alveolar extracellular matrix, proteoglycan, collagen and elastin. Elastin in particular is an essential component of the alveolar extracellular matrix as it provides the lung with the elasticity needed for ventilation, and it is probable that elastin synthesis is an essential step in alveolar growth and regeneration. Supporting this hypothesis, Koh and colleagues (Koh et al 1996) showed that tropoelastin mRNA was sharply overexpressed in the lung of rats after pneumonectomy, and that its expression was localized to the ends, bends and junc- tions of alveolar walls, indicating that the de novo synthesis of elastic ﬁbers was part of the process of alveolar growth and multiplication. In this study, the localization of lung elastin mRNA expression after pneumonectomy differed slightly from that observed in developing animals as in the latter case elastin mRNA expression was observed at the end and bend of alveolar walls but was not observed at the junctions of alveolar walls. In addition to their role as extracellular matrix providers, alveolar fibroblasts seem to participate in the complex cellular interactions that lead to alveolar growth and mul- tiplication both in the fetal lung (Warburton and Bellusci 2004) and in the adult lung. Fibroblasts interact both with endothelial cells and epithelial cells through the secretion of soluble factors that act in a paracrine fashion. In particu- lar, ﬁbroblasts are the main if not the only source of KGF in the distal lung and contribute greatly to the elevation of lung HGF levels in response to alveolar injury (Stern et al 2000; Marchand-Adam et al 2003, 2005; Cohen et al 2006). Moreover, although this point has not been demonstrated in adult animals so far, lipid-laden interstitial ﬁbroblasts, International Journal of COPD 2007:2(4) Alveolar regeneration in pulmonary emphysema a subpopulation of alveolar ﬁbroblasts, are the main source of retinoic acid in the lungs of rodents undergoing alveolar septation (McGowan and Torday 1997). In adult animals, retinoic acid, the active metabolite of vitamin A, increases post-pneumonectomy lung growth in rodents (Kaza et al 2001) and enhances alveolar capillary formation after right pneumonectomy in dogs (Yan et al 2004). Interestingly, the role of ﬁbroblasts in the regulation of cell-cell interactions in alveoli may not be limited to the secretion of paracrine signal molecules as cytoplasmic expan- sions originating in those cells reach alveolar endothelial and epithelial cells through their respective underlying basement membranes (Sirianni et al 2003). Overall, ﬁbroblasts seem to play a central role in alveolar multiplication and regeneration and it may be assumed that the realization of such phenomenon requires proliferating and metabolically active ﬁbroblasts. Cigarette smoke represses ﬁbroblast functions implicated in alveolar regeneration and repair Cigarette smoke is responsible for an overwhelming majority of cases of pulmonary emphysema. The mechanisms by which chronic smoke exposure induces chronic lung injury leading to emphysema have been exhaustively described and include chronic inﬂammation (Hoidal and Niewoehner 1982), protease/antiprotease imbalance (Carp and Janoff 1978), oxidative stress (Church and Pryor 1985) and excessive death of bronchiolar and alveolar epithelial and endothelial cells (Jung et al 2000; Tuder et al 2000; Wickenden et al 2003). However, the role of cigarette smoke in the pathogenesis of emphysema does not seem to be limited to its participation in chronic injury to the lung. Indeed, cigarette smoke has been shown to reduce viability in human lung ﬁbroblasts and to inhibit a number of ﬁbroblast functions closely linked to alveolar regeneration, at least in vitro. Cigarette smoke possesses cytotoxic properties towards lung fibroblasts as cigarette smoke extract reduces the viability of those cells in vitro (Ishii et al 2001). This effect has been linked to the induction of apoptosis (Carnevali et al 2003; Baglole et al 2006). Additionally, cigarette smoke inhibits lung ﬁbroblast proliferation and their capacity to migrate (Nakamura et al 1995; Nobukuni et al 2002). More- over, lung ﬁbroblasts chronically exposed to cigarette smoke display a senescent phenotype characterized by an enlarged morphology and cell cycle arrest (Nyunoya et al 2006). Altogether, those results indicate that cigarette smoke proba- bly induces a reduction in the number of metabolically active 465