| 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
|
| Resource |
| Mice |
RBRC03163 |
