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1 Departments of Pulmonary and Critical Care Medicine, and Cell Biology, The Cleveland Clinic Foundation, Cleveland, OH, USA
2 Department of Pediatric Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, USA
* To whom correspondence should be addressed. E-mail: thomasm{at}ccf.org.
GM-CSF is critically implicated in lung homeostasis in the GM-CSF knockout mouse model. These animals develop an isolated lung lesion reminiscent of pulmonary alveolar proteinosis seen in patients. The development of the adult form of human alveolar proteinosis is not due to the absence of a GM-CSF gene or receptor defect, but due to the development of an anti-GM-CSF autoimmunity. The role of GM-CSF in the development of PAP is unknown. Studies in the GM-CSF knockout mouse have shown that lack of PU.1 protein expression in alveolar macrophages correlated with decreased maturation, differentiation and surfactant catabolism. This study investigates PU.1 expression in vitro and in vivo in human PAP alveolar macrophages as well as the regulation of PU.1 by GM-CSF. We show for the first time that PU.1 mRNA expression in PAP bronchoalveolar lavage (BAL) cells is deficient as compared to healthy controls. PU.1 dependent terminal differentiation markers CD32 (FC
II), mannose receptor and M-CSFR are decreased in PAP alveolar macrophages. In vitro studies demonstrated that exogenous GM-CSF treatment up-regulated PU.1 and M-CSFR gene expression in PAP alveolar macrophages. Finally, in vivo studies showed that, PAP patients treated with GM-CSF therapy have higher levels of PU.1 and M-CSFR expression in alveolar macrophages as compared to healthy control and PAP patients prior to GM-CSF therapy. These observations suggest that PU.1 is critical in the terminal differentiation of human alveolar macrophages.
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