論文 - 詳細
| RRC ID | 70898 |
|---|---|
| 著者 | 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. |
| タイトル | Recruitment of monocytes primed to express heme oxygenase-1 ameliorates pathological lung inflammation in cystic fibrosis. |
| ジャーナル | 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. |
| 巻・号 | 54(5) |
| ページ | 639-652 |
| 公開日 | 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 |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 10 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 実験動物マウス | RBRC03163 |