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

Abstract

Amelioration of immune overactivity during sepsis is key to restoring hemodynamics, microvascular blood flow, and tissue oxygenation, and in preventing multi-organ dysfunction syndrome. The systemic inflammatory response syndrome that results from sepsis ultimately leads to degradation of the endothelial glycocalyx and subsequently increased vascular leakage. Current fluid resuscitation techniques only transiently improve outcomes in sepsis, and can cause edema. Nitric oxide (NO) treatment for sepsis has shown promise in the past, but implementation is difficult due to the challenges associated with delivery and the transient nature of NO. To address this, we tested the anti-inflammatory efficacy of sustained delivery of exogenous NO using i.v. infused NO releasing nanoparticles (NO-np). The impact of NO-np on microhemodynamics and immune response in a lipopolysaccharide (LPS) induced endotoxemia mouse model was evaluated. NO-np treatment significantly attenuated the pro-inflammatory response by promoting M2 macrophage repolarization, which reduced the presence of pro-inflammatory cytokines in the serum and slowed vascular extravasation. Combined, this resulted in significantly improved microvascular blood flow and 72-h survival of animals treated with NO-np. The results from this study suggest that sustained supplementation of endogenous NO ameliorates and may prevent the morbidities of acute systemic inflammatory conditions. Given that endothelial dysfunction is a common denominator in many acute inflammatory conditions, it is likely that NO enhancement strategies may be useful for the treatment of sepsis and other acute inflammatory insults that trigger severe systemic pro-inflammatory responses and often result in a cytokine storm, as seen in COVID-19.

A new perspective on NO pathway in sepsis and ADMA lowering as a potential therapeutic approach

“…Rather, eNOS derived NO was protective in sepsis [71,72]. Similarly, direct administration of sustained release NO-donor improved microvascular flow, capillary transit and 72-h survival of mice after LPS-induced endotoxemia [64]. Likewise, in salmonella typhimurium induced sepsis in iNOS-deficient mice showed aggravated hepatic and cardiovascular dysfunction and increased the risk of mortality as compared to the wild-type mice.…”

“…However, the potential efficacy of arginine or NO supplementation during sepsis and in critically ill patients remains to be confirmed using optimum drug-able approaches. More recently, sustained delivery of exogenous NO using NO-releasing nanoparticles was shown to improve microvascular flow and capillary transit, reduce inflammation, and significantly improve 72-h survival of mice after LPSinduced endotoxemia [64]. Although these studies provide encouraging preclinical and early clinical evidence for a beneficial response to improving NO bioavailability, there remain significant challenges to the development of these molecules as therapeutics [65].…”

Utility of NO and H2S donating platforms in managing COVID-19: Rationale and promise

“…The same results were found in macrophages stimulated by either lipopolysaccharide (LPS) and IFN-γ or IL-4 – eNOS-derived NO limited M1 activation and stimulation repolarization to M2, and the NO donor DETA-NO did the same [ 210 ]. Likewise, in LPS-induced endotoxemia in mice, treatment with NO-releasing nanoparticles increased M2 expression while reducing M1, with corresponding reductions in pro-inflammatory and increased anti-inflammatory cytokines; overall, 3-day survival was significantly improved in NO-treated mice compared to controls [ 211 ].…”

Boosting nitric oxide in stress and respiratory infection: Potential relevance for asthma and COVID-19

“… Alvarez et al, 2020 , Douglas et al, 2000 , Hasratian et al, , Johnston et al, 2006 , Kacmarek et al, 1996 , Lei et al, 2020 , Network, 2018 , Parikh et al, 2020 , Wells and Holian, 2007 , Williams et al, 2020 .…”