H₂S donor molecules against cold ischemia-reperfusion injury in preclinical models of solid organ transplantation

Cold ischemia-reperfusion injury (IRI) is an inevitable and unresolved problem that poses a great challenge in solid organ transplantation (SOT). It represents a major factor that increases acute tubular necrosis, decreases graft survival, and delays graft function. This complicates graft quality, post-transplant patient care and organ transplantation outcomes, and therefore undermines the success of SOT. Herein, we review recent advances in research regarding novel pharmacological strategies involving the use of different donor molecules of hydrogen sulfide (H₂S), the third established member of the gasotransmitter family, against cold IRI in different experimental models of SOT (kidney, heart, lung, liver, pancreas and intestine). Additionally, we discuss the molecular mechanisms underlying the effects of these H₂S donor molecules in SOT, and suggestions for clinical translation. Our reviewed findings showed that storage of donor organs in H₂S-supplemented preservation solution or administration of H₂S to organ donor prior to organ procurement and to recipient at the start and during reperfusion is a novel, simple and cost-effective pharmacological approach to minimize cold IRI, limit post-transplant complications and improve transplantation outcomes. In conclusion, experimental evidence demonstrate that H₂S donors can significantly mitigate cold IRI during SOT through inhibition of a complex cascade of interconnected cellular and molecular events involving microcirculatory disturbance and microvascular dysfunction, mitochondrial injury, inflammatory responses, cell damage and cell death, and other damaging molecular pathways while promoting protective pathways. Translating these promising findings from bench to bedside will lay the foundation for the use of H₂S donor molecules in clinical SOT in the future.