RRC ID 70898
Author Di Pietro C, Öz HH, Zhang PX, Cheng EC, Martis V, Bonfield TL, Kelley TJ, Jubin R, Abuchowski A, Krause DS, Egan ME, Murray TS, Bruscia EM.
Title Recruitment of monocytes primed to express heme oxygenase-1 ameliorates pathological lung inflammation in cystic fibrosis.
Journal Exp Mol Med
Abstract Overwhelming neutrophilic inflammation is a leading cause of lung damage in many pulmonary diseases, including cystic fibrosis (CF). The heme oxygenase-1 (HO-1)/carbon monoxide (CO) pathway mediates the resolution of inflammation and is defective in CF-affected macrophages (MΦs). Here, we provide evidence that systemic administration of PP-007, a CO releasing/O2 transfer agent, induces the expression of HO-1 in a myeloid differentiation factor 88 (MyD88) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)-dependent manner. It also rescues the reduced HO-1 levels in CF-affected cells induced in response to lipopolysaccharides (LPS) or Pseudomonas aeruginosa (PA). Treatment of CF and muco-obstructive lung disease mouse models with a single clinically relevant dose of PP-007 leads to effective resolution of lung neutrophilia and to decreased levels of proinflammatory cytokines in response to LPS. Using HO-1 conditional knockout mice, we show that the beneficial effect of PP-007 is due to the priming of circulating monocytes trafficking to the lungs in response to infection to express high levels of HO-1. Finally, we show that PP-007 does not compromise the clearance of PA in the setting of chronic airway infection. Overall, we reveal the mechanism of action of PP-007 responsible for the immunomodulatory function observed in clinical trials for a wide range of diseases and demonstrate the potential use of PP-007 in controlling neutrophilic pulmonary inflammation by promoting the expression of HO-1 in monocytes/macrophages.
Volume 54(5)
Pages 639-652
Published 2022-5-1
DOI 10.1038/s12276-022-00770-8
PII 10.1038/s12276-022-00770-8
PMID 35581352
PMC PMC9166813
MeSH Animals Cystic Fibrosis* / complications Cystic Fibrosis* / metabolism Cystic Fibrosis* / pathology Heme Oxygenase-1 Inflammation / metabolism Lipopolysaccharides / metabolism Lung / pathology Mice Monocytes / metabolism Phosphatidylinositol 3-Kinases / metabolism Pneumonia* / pathology
IF 5.418
Mice RBRC03163