Bronchopulmonary dysplasia (BPD) is a chronic lung disease of infants born extremely preterm and characterized by inflammation and simplification of the distal lung structure with fewer, larger alveoli. A number of studies have demonstrated elevated macrophage and neutrophil numbers in the diseased lung, and it is becoming apparent that there is a connection between impaired alveolarization and the preceding inflammatory process. As macrophages play key role in tissue remodeling, lung injury and repair, we focused on the role of macrophages in the pathogenesis of BPD. Using a mouse model of BPD that relies on hyperoxia (HYX) and two transgenic mouse lines (CCR2 KO and MAFIA (Macrophage Fas-Induced Apoptosis)) functional roles of different alveolar macrophages (AM), namely resident (rAM) and exudate (ExAM) were studied. It was found that WT mice had a population of rAM (CD11c+/SiglecF+/CD11b-) in NOX group which was gone in HYX-exposed mice; and recruitment of neutrophils (Gr-1+) and ExAM (CD11c+/CD11b+/MHCIIinterm) upon HYX exposure. CCR2 KO mice had neutrophil recruited upon HYX exposure, but no ExAM recruitment. MAFIA mice lacked rAM populations in NOX, had no influx of neutrophils in HYX, but had clear populations of ExAM both in NOX and HYX groups. Lung structures analysis revealed that WT mice had 2.1 ± 0.067 million alveoli and a septa of 9.53 ± 0.2 microm in NOX group and reduced alveolar number (1.07 ± 0.056 million) and thicker septa (10.90 ± 1.0 microm) in HYX-exposed mice. CCR2 KO mice had a small alveolarization improvement (1.48 ± 0.95 million) in HYX group and no septal thickness improvement, whereas MAFIA mice had a great improvement in the lung structure of HYX exposed pups (1.8 ± 0.11 million alveoli and 8.66 ± 0.27 microm septa). No alveolar number improvement after depleting neutrophils alone in HYX-exposed WT mice, was observed. Further analysis showed that a population of CD11c+/SiglecF+/CD11b+/MHCIIhigh cells (Pop3) was significantly increased in WT and neutrophil-depleted mice upon HYX exposure and completely depleted in MAFIA mice. Pop3 sorting followed by cytospin and H&E staining and rtPCR analysis with CD68-specific primers demonstrated that Pop3 is a population of macrophages. These data suggest a novel role of rAM in the development of BPD and demonstrates that rAM might change phenotype upon HYX exposure and this population of activated macrophages (SiglecF+/CD11b+/MHCIIhigh) might contribute greatly to the alveolarization arrest observed in BPD.
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