Rationale: Activation of the platelet-derived growth factor receptors-α and -β (PDGF-Rα and -Rβ) is critical in the formation of secondary crests/septa during alveologenesis, and its regulation has been found to be disrupted in rat lung injury models. Objective: To determine whether the process of secondary septation can occur after transient pharmacologic inhibition of PDGF-R action during postnatal days (P)1 – 7 in rats. Hypothesis: The initial process of secondary crest formation is time-limited and, if missed, will result in a permanent loss of alveoli. Methods: Imatinib mesylate, a PDGF-R inhibitor, was injected intraperitoneally from P1 – 7. Pups were sacrificed on P2, 4, 8, 14, 28 and 65 for studies of alveolar development. Main results: The injection of imatinib inhibited PDGF-R action, resulting in a permanent decrease in alveolar number in treated rats. Conclusions: Inhibition of secondary septation during the first 7 days of life resulted in a decrease in alveolar number lasting into early adult life. This is consistent with a critical time window for secondary septation, which, if disrupted, results in long-term adverse effects on lung development.

Rationale: Activation of the platelet-derived growth factor receptors-α and -β (PDGF-Rα and -Rβ) is critical in the formation of secondary crests/septa during alveologenesis, and its regulation has been found to be disrupted in rat lung injury models. Objective: To determine whether the process of secondary septation can occur after transient pharmacologic inhibition of PDGF-R action during postnatal days (P)1 – 7 in rats. Hypothesis: The initial process of secondary crest formation is time-limited and, if missed, will result in a permanent loss of alveoli. Methods: Imatinib mesylate, a PDGF-R inhibitor, was injected intraperitoneally from P1 – 7. Pups were sacrificed on P2, 4, 8, 14, 28 and 65 for studies of alveolar development. Main results: The injection of imatinib inhibited PDGF-R action, resulting in a permanent decrease in alveolar number in treated rats. Conclusions: Inhibition of secondary septation during the first 7 days of life resulted in a decrease in alveolar number lasting into early adult life. This is consistent with a critical time window for secondary septation, which, if disrupted, results in long-term adverse effects on lung development.

Les m?canismes de l?emphys?me pulmonaire, caract?ris? par la destruction des alv?oles pulmonaire, sont incompl?tement connus. L?hypoth?se d?fendue par cette th?se est qu?une alt?ration des syst?mes d?alv?olog?n?se et de r?paration alv?olaire port?s par les fibroblastes pulmonaires contribue au d?veloppement des l?sions au cours de cette maladie. Les travaux pr?sent?s ici ont permis d??tablir que les fibroblastes pulmonaires cultiv?s in vitro ? partir de poumon emphys?mateux pr?sentaient un ph?notype alt?r? dans le sens d?une perte de leur capacit? ? participer ? la r?g?n?ration et ? la r?paration des alv?oles : Ces cellules s?cr?taient ? un niveau faible ou non stimulable le Hepatocyte Growth Factor et le Keratinocyte Growth Factor (KGF), qui ciblent les cellules ?pith?liales et endoth?liales de l?alv?ole. De plus, l?expression par ces cellules de l??lastine, le composant majeur de la matrice extracellulaire pulmonaire, n??tait pas induite par l?acide tout-trans r?tino?que, stimulus central de l?alv?olog?n?se, du fait d?une faible expression de Cellular Retinoic Acid Binding Protein 2 (CRABP2). Le r?le du KGF dans l?hom?ostasie de l?alv?ole a ?t? d?montr? dans le mod?le d?emphys?me induit par l??lastase in vivo : Les souris trait?es par le KGF avant l?instillation d??lastase ?taient prot?g?es de l?emphys?me. Les souris dont le g?ne de CRABP2 ?tait inactiv? de fa?on globale n??taient pas sensibilis?es vis-?-vis de l?emphys?me dans ce mod?le. Les donn?es physiopathologiques pr?sent?es dans ce m?moire pourraient contribuer ? l?identification de nouvelles cibles th?rapeutiques pour l?emphys?me. / The mechanisms of pulmonary emphysema, characterized by the destruction of alveolar walls, remain incompletely understood. Our hypothesis is that a deficiency in fibroblast-borne alveolar repair systems accounts partly for the constitution of lesions in this disease. In our experiments, we show that fibroblasts isolated in vitro from human emphysematous lung express the Hepatocyte Growth Factor and the Keratinocyte Growth Factor (KGF), which target alveolar epithelial and endothelial cells, at low or unstimulable levels. Additionally, emphysema fibroblasts did not increase their expression of elastin, the main component of the pulmonary extracellular matrix, in response to retinoic acid, due to a low expression of Cellular Retinoic Acid Binding Protein 2 (CRABP2). The role of KGF In alveolar homeostasis was demonstrated in vivo in the elastase-induced emphysema model: Mice treated with KGF before elastase instillation were protected against emphysema. CRABP2- knockout mice were not protected against emphysema in this model. Our pathophysiological data may help in the identification of novel therapeutic targets for emphysema.