An Oral Carbon Monoxide-Releasing Molecule Protects against Acute Hyper-hemolysis in Sickle Cell Disease.
Kim Anh NguyenAlessandro MatteRoberta ForestiEnrica FedertiLaurent KigerCécile LefebvreHakim HociniYanis PelinskiHiroaki KitagishiLaura BencheikhFrançoise PirenneLucia De FranceschiRoberto MotterliniPablo BartolucciPublished in: Blood (2024)
Acute hyper-hemolysis is a severe life-threatening complication in patients with sickle cell disease (SCD) that may occur during delayed hemolytic transfusion reaction (DHTR), or vaso-occlusive crises associated with multi-organ failure. Here, we developed in vitro and in vivo animal models to mimic endothelial damage during the early phase of hyper-hemolysis in SCD. We then used the carbon monoxide (CO)-releasing molecule CORM-401 and examined its effects against endothelial activation, damage, and inflammation inflicted by hemolysates containing red blood cell membrane-derived particles. The in vitro results revealed that CORM-401: 1) prevented the up-regulation of relevant pro-inflammatory, and pro-adhesion controlled by the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), and 2) abolished the expression of the nuclear factor erythroid-2-related factor 2 (Nrf2) that regulates the inducible antioxidant cell machinery. We also show in SCD mice that CORM-401 protects against hemolysate-induced acute damage of target organs such as the lung, liver, and kidney through modulation of NF-kB pro-inflammatory and Nrf2 antioxidant pathways. Our data demonstrate the efficacy of CORM-401 as a novel therapeutic agent to counteract hemolysate-induced organ damage during hyper-hemolysis in SCD. This approach might be considered as possible preventive treatment in high-risk situations such as SCD patients with history of DHTR.
Keyphrases
- nuclear factor
- oxidative stress
- sickle cell disease
- toll like receptor
- diabetic rats
- drug induced
- liver failure
- red blood cell
- single cell
- respiratory failure
- end stage renal disease
- newly diagnosed
- endothelial cells
- anti inflammatory
- poor prognosis
- ejection fraction
- binding protein
- chronic kidney disease
- stem cells
- inflammatory response
- high glucose
- immune response
- cell therapy
- metabolic syndrome
- cell proliferation
- transcription factor
- aortic dissection
- insulin resistance
- mesenchymal stem cells
- escherichia coli
- extracorporeal membrane oxygenation
- adipose tissue
- pseudomonas aeruginosa
- mechanical ventilation
- signaling pathway
- high fat diet induced
- deep learning
- bone marrow
- stress induced
- replacement therapy