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In a Murine Model of Bronchopulmonary Dysplasia, Lung CD103+ Dendritic Cells Display Accelerated Developmental Expansion and Acquire a Secretory Phenotype that Promotes Hypoalveolarization
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A6106 - In a Murine Model of Bronchopulmonary Dysplasia, Lung CD103+ Dendritic Cells Display Accelerated Developmental Expansion and Acquire a Secretory Phenotype that Promotes Hypoalveolarization
Author Block: T. X. Cui, C. Fulton, A. P. Popova; Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, United States.
Rationale: Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth and is characterized by hypoalveolarization, interstitial thickening and dysmorphic microvasculature. We have shown that hyperoxic exposure of immature mice (a model of BPD) increases the number of activated CD103+ dendritic cells (DCs). We also showed CD103+ DCs are required for hyperoxia-induced hypoalveolarization (Am J Respir Crit Care Med 195: A7181, 2017). We hypothesize that hyperoxic exposure modulates the development of lung CD103+ DCs by stimulating DC growth factor expression. We also hypothesize that hyperoxic exposure induces lung CD103+ DC secretory phenotype that mediates hypoalveolarization.
Methods: 2 day-old C57BL/6J mice were exposed to normoxia or 75% oxygen for up to 14 days or inoculated intranasally with recombinant Saa3 or CXCL9 on DOL 2, 5, 7 and 9. Lung gene expression was analyzed by qPCR and ELISA. Lung myeloid cells were analyzed by flow cytometry. CD103+ DCs were flow-sorted. E16 fetal lungs were microdissected and cultured in transwell plates.
Results: Normoxia-exposed immature mice showed a gradual increase in whole lung mRNA and protein levels of the DC growth factor FMS-like tyrosine kinase 3 ligand (Flt3L) as well as in CD103+ DC numbers between day of life 3 and 16. Compared to normoxic mice, whole lung Flt3L levels were higher on day 1 and 7 of hyperoxic exposure, followed by a significant increase in lung CD103+ DC number after 14 days of hyperoxia. Flow-sorted lung CD103+ DCs from hyperoxic lungs showed higher mRNA expression of the acute phase protein associated with fibrosis Serum Amyloid A3 (Saa3) and angiostatic chemokine CXCL9. Similar increases in Saa3 and CXCL9 mRNA and protein were observed in whole lungs after hyperoxia. In E16 fetal lung explants, Saa3 decreased Pdgfra and Cd31 mRNA expression, CXCL9 decreased Wnt2 and Cd31 mRNA expression and combined Saa3 and CXCL9 treatment had an additive effect in decreasing Wnt2 and Cd31 expression. Immature mice inoculated with Saa3 or CXCL9 showed larger alveoli and a significant increase in alveolar chord length.
Conclusions: In normoxia-exposed mice during early life, the number of lung CD103+ DCs gradually increases and correlates with an increase in lung Flt3L expression. This process is accelerated by hyperoxic exposure. CD103+ DCs and their secretory products represent new targets for BPD prevention and treatment.
Author Block: T. X. Cui, C. Fulton, A. P. Popova; Pediatrics and Communicable Diseases, University of Michigan Medical School, Ann Arbor, MI, United States.
Rationale: Bronchopulmonary dysplasia (BPD) is a common complication of preterm birth and is characterized by hypoalveolarization, interstitial thickening and dysmorphic microvasculature. We have shown that hyperoxic exposure of immature mice (a model of BPD) increases the number of activated CD103+ dendritic cells (DCs). We also showed CD103+ DCs are required for hyperoxia-induced hypoalveolarization (Am J Respir Crit Care Med 195: A7181, 2017). We hypothesize that hyperoxic exposure modulates the development of lung CD103+ DCs by stimulating DC growth factor expression. We also hypothesize that hyperoxic exposure induces lung CD103+ DC secretory phenotype that mediates hypoalveolarization.
Methods: 2 day-old C57BL/6J mice were exposed to normoxia or 75% oxygen for up to 14 days or inoculated intranasally with recombinant Saa3 or CXCL9 on DOL 2, 5, 7 and 9. Lung gene expression was analyzed by qPCR and ELISA. Lung myeloid cells were analyzed by flow cytometry. CD103+ DCs were flow-sorted. E16 fetal lungs were microdissected and cultured in transwell plates.
Results: Normoxia-exposed immature mice showed a gradual increase in whole lung mRNA and protein levels of the DC growth factor FMS-like tyrosine kinase 3 ligand (Flt3L) as well as in CD103+ DC numbers between day of life 3 and 16. Compared to normoxic mice, whole lung Flt3L levels were higher on day 1 and 7 of hyperoxic exposure, followed by a significant increase in lung CD103+ DC number after 14 days of hyperoxia. Flow-sorted lung CD103+ DCs from hyperoxic lungs showed higher mRNA expression of the acute phase protein associated with fibrosis Serum Amyloid A3 (Saa3) and angiostatic chemokine CXCL9. Similar increases in Saa3 and CXCL9 mRNA and protein were observed in whole lungs after hyperoxia. In E16 fetal lung explants, Saa3 decreased Pdgfra and Cd31 mRNA expression, CXCL9 decreased Wnt2 and Cd31 mRNA expression and combined Saa3 and CXCL9 treatment had an additive effect in decreasing Wnt2 and Cd31 expression. Immature mice inoculated with Saa3 or CXCL9 showed larger alveoli and a significant increase in alveolar chord length.
Conclusions: In normoxia-exposed mice during early life, the number of lung CD103+ DCs gradually increases and correlates with an increase in lung Flt3L expression. This process is accelerated by hyperoxic exposure. CD103+ DCs and their secretory products represent new targets for BPD prevention and treatment.
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