| First Author | Rochford I | Year | 2021 |
| Journal | Am J Physiol Lung Cell Mol Physiol | Volume | 321 |
| Issue | 4 | Pages | L686-L702 |
| PubMed ID | 34318714 | Mgi Jnum | J:310432 |
| Mgi Id | MGI:6762490 | Doi | 10.1152/ajplung.00145.2021 |
| Citation | Rochford I, et al. (2021) Evidence for reprogramming of monocytes into reparative alveolar macrophages in vivo by targeting PDE4b. Am J Physiol Lung Cell Mol Physiol 321(4):L686-L702 |
| abstractText | Increased lung vascular permeability and neutrophilic inflammation are hallmarks of acute lung injury. Alveolar macrophages (AMvarphi), the predominant sentinel cell type in the airspace, die in massive numbers while fending off pathogens. Recent studies indicate that the AMvarphi pool is replenished by airspace-recruited monocytes, but the mechanisms instructing the conversion of recruited monocytes into reparative AMvarphi remain elusive. Cyclic AMP (cAMP) is a vascular barrier protective and immunosuppressive second messenger in the lung. Here, we subjected mice expressing GFP under the control of the Lysozyme-M promoter (LysM-GFP mice) to the LPS model of rapidly resolving lung injury to address the impact of mechanisms determining cAMP levels in AMvarphi and regulation of mobilization of the reparative AMvarphi-pool. RNA-seq analysis of flow-sorted Mvarphi identified phosphodiesterase 4b (PDE4b) as the top LPS-responsive cAMP-regulating gene. We observed that PDE4b expression markedly increased at the time of peak injury (4 h) and then decreased to below the basal level during the resolution phase (24 h). Activation of transcription factor NFATc2 was required for the transcription of PDE4b in Mvarphi. Inhibition of PDE4 activity at the time of peak injury, using intratracheal rolipram, increased cAMP levels, augmented the reparative AMvarphi pool, and resolved lung injury. This response was not seen following conditional depletion of monocytes, thus establishing airspace-recruited PDE4b-sensitive monocytes as the source of reparative AMvarphi. Interestingly, adoptive transfer of rolipram-educated AMvarphi into injured mice resolved lung edema. We propose suppression of PDE4b as an effective approach to promote reparative AMvarphi generation from monocytes for lung repair. |
