Reducing Ischemia/Reperfusion Injury by the Targeted Delivery of Nitric Oxide from Magnetic-Field-Induced Localization of S-Nitrosothiol-Coated Paramagnetic Nanoparticles

Abstract

Nitric oxide (NO) is an important factor during an ischemia/reperfusion (I/R) injury. Protective actions of NO during I/R are attributed to antioxidant and anti-inflammatory effects, as well as cell-signaling-based inhibition of nuclear proteins. The therapeutic potential of supplemented NO during I/R is nonetheless uncertain, since peroxynitrite formed from NO near superoxide can be potentially harmful due to NF-κB up-regulation and direct cytotoxicity. This study investigates new technology to provide the magnet-assisted delivery of therapeutic levels of localized NO to targeted I/R tissues using biocompatible gadolinium-oxide-based paramagnetic nanoparticles coated with S-nitrosothiols (SNO-PMNPs). Hamsters fitted with a window chamber were subjected to ischemia by application of a tourniquet at the periphery of the window chamber for 1 h. The SNO-PMNPs were intravenously infused (10 mg/kg) during the reperfusion phase, during which time a localized external magnetic field was either applied or not applied to the I/R area. The microvascular hemodynamics, functional capillary density (FCD), rolling and adherent leukocytes, reactive oxygen and nitrogen species, and tissue viability were assessed using intravital microscopy. Control animals did not receive SNO-PMNPs. Treatment with SNO-PMNPs plus a magnet but not without a magnet increased reflow, decreased leukocytes rolling and sticking in postcapillary venules, limited cell death, and restored the FCD. The absence of the magnet resulted in systemic changes in heart rate and mean arterial blood pressure, consistent with the systemic delivery of NO by the SNO-PMNP. These results indicate that the localized delivery of NO during reperfusion counters the deleterious consequences of peroxynitrite and other reactive species generated upon reperfusion as reflected in localized increases in blood flow and tissue viability, all with minimal systemic effects. This technology can provide the basis for a timely treatment of a localized ischemia-associated disease to prevent injury in different tissues and organs.

Harnessing nitric oxide for preventing, limiting and treating the severe pulmonary consequences of COVID-19

“…This mechanism of action suggests an additional effect of preserving host ACE2 levels that may better regulate RAS and promote endogenous NO production as described above. NO releasing nanoparticles (NO-nps) demonstrate potential in limiting inflammatory cascades and ischemia reperfusion injury [ 50 , 51 ]. We propose that delivering modest, persistent amounts of iNO or RSNO at the early stages of COVID-19 infection might limit the progression toward ARDS and fulminant systemic failure, particularly in vulnerable patients who may have decreased levels of endogenous NO due to increased age or comorbid conditions.…”

Control of systemic inflammation through early nitric oxide supplementation with nitric oxide releasing nanoparticles

“…The results of this study have implications for other acute systemic inflammatory conditions such as hemorrhagic shock due to the proinflammatory triggers associated with both ischemia-reperfusion and hypoxia-reoxgenation injuries. Indeed we have recently shown that exogenously delivered NO targeted to the site of an induced ischemic insult prevented the usual inflammatory consequences [ 38 ]. The observed array of clinical manifestations associated with Corona Virus Disease 2019 (COVID-19) that correspond to many of the anticipated consequences of systemic endothelial dysfunction due to a cytokine storm is relevant when discussing exogenous NO treatments during LPS-induced endotoxemia [ 39 ].…”

Role of Nitric Oxide and Protein S-Nitrosylation in Ischemia-Reperfusion Injury

“…Moreover, recent advances have been made in nanotherapy, which enable a targeted delivery of NO to ischemia reperfusion-injured tissues. It was also demonstrated that S-nitrosothiol coated paramagnetic nanoparticles (SNO-PMNPs) improved reflow and functional capillary density while preventing cell death in the presence of a magnet in animal IRI setting, indicating a potential usage of magnetic-field-induced delivery of NO to treat localized ischemic diseases [ 87 ].…”