RESUMO
We determined the time-specific effects of FasL overexpression on perinatal alveolar type II cell growth kinetics. To achieve temporal overexpression of respiratory epithelium-specific FasL expression, tetracycline inducible CCSP-rtTA/FasL-TetOp transgenic mice were given doxycycline (Dox) from gestational d 14 (E14) to E19 (antenatal treatment group), from postnatal d 1 (P1) to P7 (postnatal group), or from E14 to P7 (combined antenatal and postnatal group). Antenatal Dox administration induced an increase of pulmonary FasL mRNA levels in double transgenic animals up to >300-fold over single transgenic littermate controls, associated with massive fetal respiratory epithelial apoptosis and excessive postnatal lethality. Although animals from the combined antenatal/postnatal Dox treatment group continued to display evidence of increased apoptosis, there was a paradoxical increase in alveolar type II cell proliferation, resulting in a net increase in type II cell density, elevated pulmonary surfactant protein C levels and improved postnatal survival. Postnatal Dox administration was also associated with increased type II cell density, although FasL up-regulation was more variable. In conclusion, these results, and our previous studies, suggest that FasL signaling has dual timing-dependent proapoptotic and proproliferative effects on postcanalicular type II cell kinetics.
Assuntos
Proteína Ligante Fas/metabolismo , Alvéolos Pulmonares/citologia , Alvéolos Pulmonares/embriologia , Alvéolos Pulmonares/crescimento & desenvolvimento , Animais , Animais Recém-Nascidos , Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Proliferação de Células/efeitos dos fármacos , Doxiciclina/farmacologia , Proteína Ligante Fas/genética , Camundongos , Camundongos Transgênicos , Alvéolos Pulmonares/efeitos dos fármacos , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Taxa de SobrevidaRESUMO
Preterm infants are at risk for bronchopulmonary dysplasia (BPD), a chronic lung disease characterized by disrupted alveolar remodeling and microvascular dysangiogenesis. The pathogenesis of BPD is multifactorial, with contributions from antenatal and/or postnatal infection and inflammation. The potential role of dendritic cells, critical immune regulatory cells with potent angiogenic activities, remains undetermined. We studied the prevalence and topography of dendritic cells in postmortem lungs of short- and long-term ventilated preterm infants born between 23 and 29 weeks in gestation. Controls were age-matched infants who had lived less than 12 hours. Dendritic cells were identified by anti-DC-SIGN immunohistochemistry and were co-localized with endothelial and smooth muscle cells by double immunofluorescence. Lungs of early and late control infants without evidence of antenatal infection contained scattered DC-SIGN-positive dendritic cells in the peripheral lung parenchyma. Lungs of early control infants with a history of chorioamnionitis/antenatal infection and lungs of short- or long-term ventilated preterm infants showed a dramatic (more than 3-fold) increase in dendritic cells. Double labeling highlighted a close association between dendritic cells and small- or medium-sized pulmonary vessels. In conclusion, we demonstrated that dendritic cells are an integral component of normal postcanalicular lung development. Antenatal infection and ventilation/BPD are associated with significant pulmonary recruitment of dendritic cells. The recently described angiogenic effects of dendritic cells and their intimate association with the pulmonary microvasculature indicate that dendritic cells may participate in BPD-associated dysangiogenesis. Elucidation of the role of this immunovascular axis may lead to novel therapeutic approaches to BPD.