Plantier et al ﬁbroblasts available for alveolar growth and multiplication in the emphysematous lung. In addition to its cytotoxic and antiproliferative effects, cigarette smoke inhibits key ﬁbroblastic functions associated with alveolar growth and multiplication. In particular, elastin synthesis and cross-linking seem to be especially sensitive to exposure to cigarette smoke. While no data are available regarding adult lung ﬁbroblasts, cigarette smoke extract down regulates tropoelastin mRNA in rat fetal lung ﬁbroblasts (Gao et al 2005). In an acellular model, cigarette smoke inhibits elastin cross-linking (Laurent et al 1983), while the transcrip- tion of lysyl oxidase, a key effector of elastin cross-linking is reduced in fetal rat lung ﬁbroblasts exposed to cigarette smoke extract (Gao et al 2005). Whether cigarette smoke exposure antagonizes alveolar growth and multiplication in vivo has not been demonstrated directly. To our knowledge, no study has been dedicated to the description of the effect of cigarette smoke on post- pneumonectomy lung growth. However, data obtained in a different model of alveolar depletion, elastase-induced emphysema, indicate that cigarette smoke exposure may indeed induce a defect in elastin synthesis and cross-linking, alveolar growth, multiplication and/or repair. Indeed, while elastase instillation in the trachea induces a sharp elevation in elastin synthesis in the lung, this response is reduced by 40% in the lung of hamsters exposed to cigarette smoke for one week (Osman et al 1985). This reduction in elastin synthesis is accompanied by a seven-fold reduction in lysyl oxidase activity in the lung of those animals. This reduc- tion in elastin synthesis and cross-linking may be of great pathophysiological signiﬁcance as emphysema lesions are exaggerated in hamsters exposed to cigarette smoke after elastase instillation (Hoidal and Niewoehner 1983). Are alveolar regeneration and repair systems defective in human emphysema? Abnormal phenotype of ﬁbroblasts Whether a defect in alveolar regeneration systems plays a role in cigarette smoke induced emphysema in humans remains unclear but some elements indicate that such systems do get activated in the course of this disease. For instance, contrary to what is observed in the normal lung (Shapiro et al 1991), a high elastin turnover is observed in the emphysematous lung (Stone et al 1995; Gottlieb et al 1996; Vlahovic et al 1999), indicating that in parallel with the excessive degradation of elastic ﬁbers which is observed in this disease, elastin 466 synthesis occurs in the lung. Interestingly, in line with a high rate of extracellular matrix synthesis associated with a high rate of extracellular matrix degradation, a high rate of cellular proliferation is associated with the elevated apoptosis of alveolar cells in the emphysematous lung (Imai et al 2005), adding more substance to the hypothesis that alveolar regen- eration systems do get activated in the emphysematous lung even though they are probably not functional as the alveolar architecture is not restored. While an alteration of alveolar regeneration systems has not been directly evidenced in the emphysematous lung (Bonay et al 2005), it must be put for- ward that alveolar ﬁbroblasts exhibit a defective phenotype in the emphysematous lung. Available data regarding the in situ phenotype of pulmonary ﬁbroblasts in emphysema are limited to the obser- vations by Sirianni and coworkers (Sirianni et al 2006). These authors showed that direct intercellular contacts between alveolar ﬁbroblasts and alveolar epithelial cells or capillary endothelial cells are greatly reduced in the emphysematous lung. Those results suggest that pulmonary emphysema ﬁbroblasts may lack the capacity to participate in the direct intercellular communications which play an essential role in fetal lung development and probably during lung repair in the lung (Warburton et al 2001; Parker et al 2004; Warburton and Bellusci 2004). The abnormal phenotype of alveolar fibroblasts in pulmonary emphysema was described more extensively in vitro on primary lines of pulmonary ﬁbroblasts obtained following the explant culture technique. First, pulmonary emphysema ﬁbroblasts show signs of premature senescence. When compared to ﬁbroblasts obtained from normal human lung, ﬁbroblasts obtained from emphysematous lung have a markedly reduced proliferation rate. Indeed, emphysema ﬁbroblast proliferation was described as 50%–60% of con- trols (Nobukuni et al 2002; Noordhoek et al 2003; Holz et al 2004). In one study, those cells were shown to express senescence-associated beta-galactosidase (SA-beta-Gal), a marker of cellular senescence (Muller et al 2006). Moreover, in some studies emphysema ﬁbroblasts did not exhibit the typical spindle-shaped microscopic appearance of ﬁbroblasts and expressed smooth-muscle actin, indicating a degree of differentiation towards the myoﬁbroblast phenotype. Secondly, in addition to premature senescence of pulmonary emphysema ﬁbroblasts precluding an elevation of their num- ber, those cells seem to secrete low levels of growth factors. In particular, HGF secretion by those cells is sharply reduced compared to normal lung ﬁbroblasts and they poorly respond to exogenously added KGF (Plantier et al 2005). Given the International Journal of COPD 2007:2(4)