An oral carbon monoxide-releasing molecule protects against acute hyperhemolysis 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 hyperhemolysis 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 multiorgan failure. Here, we developed in vitro and in vivo animal models to mimic endothelial damage during the early phase of hyperhemolysis 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 upregulation of relevant proinflammatory and proadhesion markers controlled by the NF-κB enhancer of activated B cells, 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-κB proinflammatory and Nrf2 antioxidant pathways. Our data demonstrate the efficacy of CORM-401 as a novel therapeutic agent to counteract hemolysate-induced organ damage during hyperhemolysis in SCD. This approach might be considered as possible preventive treatment in high-risk situations such as patients with SCD with history of DHTR.
Keyphrases
- oxidative stress
- sickle cell disease
- nuclear factor
- diabetic rats
- drug induced
- liver failure
- poor prognosis
- end stage renal disease
- signaling pathway
- toll like receptor
- endothelial cells
- respiratory failure
- single cell
- newly diagnosed
- chronic kidney disease
- ejection fraction
- binding protein
- cell proliferation
- prognostic factors
- long non coding rna
- immune response
- type diabetes
- high glucose
- pi k akt
- data analysis
- high fat diet induced
- hepatitis b virus
- transcription factor
- intensive care unit
- stem cells
- adipose tissue
- mesenchymal stem cells
- bone marrow
- patient reported outcomes
- acute kidney injury
- endovascular treatment