Recruitment of monocytes primed to express heme oxygenase-1 ameliorates pathological lung inflammation in cystic fibrosis

Author:

Di Pietro Caterina,Öz Hasan H.,Zhang Ping-xia,Cheng Ee-chun,Martis Valentino,Bonfield Tracey L.,Kelley Thomas J.,Jubin Ronald,Abuchowski Abraham,Krause Diane S.,Egan Marie E.,Murray Thomas S.,Bruscia Emanuela M.

Abstract

AbstractOverwhelming 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.

Funder

Cystic Fibrosis Foundation

U.S. Department of Health & Human Services | NIH | National Heart, Lung, and Blood Institute

NIDDK Yale Cooperative Hematology Specialized Core Center

Publisher

Springer Science and Business Media LLC

Subject

Clinical Biochemistry,Molecular Biology,Molecular Medicine,Biochemistry

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