Peroxynitrite decomposition catalyst reduces vasopressin requirement in ovine MRSA sepsis

Abstract

Background Sepsis is one of the most frequent causes of death in the intensive care unit. Host vascular hypo-responsiveness to vasopressors during septic shock is one of the challenging problems. This study tested the hypothesis that adjunct therapy with peroxynitrite decomposition catalyst (WW-85) would reduce arginine vasopressin (AVP) requirements during sepsis resuscitation, using ovine sepsis model. Methods Thirteen adult female Merino sheep, previously instrumented with multiple vascular catheters, were subjected to “two-hit” (cotton smoke inhalation and intrapulmonary instillation of live methicillin-resistant Staphylococcus aureus; 3.5 × 1011 colony-forming units) injury. Post injury, animals were awakened and randomly allocated to the following groups: (1) AVP: injured, fluid resuscitated, and titrated with AVP, n = 6 or (2) WW-85 + AVP: injured, fluid resuscitated, treated with WW-85, and titrated with AVP, n = 7. One-hour post injury, a bolus intravenous injection of WW-85 (0.1 mg/kg) was followed by a 23-h continuous infusion (0.02 mg/kg/h). Titration of AVP started at a dose of 0.01 unit/min, when mean arterial pressure (MAP) decreased by 10 mmHg from baseline, despite aggressive fluid resuscitation, and the rate was further adjusted to maintain MAP. After the injury, all animals were placed on a mechanical ventilator and monitored in the conscious state for 24 h. Results The injury induced severe hypotension refractory to aggressive fluid resuscitation. High doses of AVP were required to partially attenuate the sepsis-induced hypotension. However, the cumulative AVP requirement was significantly reduced by adjunct treatment with WW-85 at 17–24 h after the injury (p < 0.05). Total AVP dose and the highest AVP rate were significantly lower in the WW-85 + AVP group compared to the AVP group (p = 0.02 and 0.04, respectively). Treatment with WW-85 had no adverse effects. In addition, the in vitro effects of AVP on isolated artery diameter changes were abolished with peroxynitrite co-incubation. Conclusions The modulation of reactive nitrogen species, such as peroxynitrite, may be considered as a novel adjunct treatment option for septic shock associated with vascular hypo-responsiveness to vasopressors.

Macrophage-produced peroxynitrite induces antibiotic tolerance and supersedes intrinsic mechanisms of persister formation

“…Scavenging peroxynitrite exogenously or repairing peroxynitrite-mediated damage have been shown to improve disease outcome in a variety of diseases, including ischemic stroke and septic shock (44)(45)(46). There are both direct and indirect methods for resolving peroxynitrite-mediated damage.…”

“…Metallic porphyrins, like FeTPPS and WW-85, facilitate decomposition of peroxynitrite by catalyzing the isomerization of peroxynitrite into nitrate (44,46,49). WW-85 has been shown to diminish the need for arginine vasopression treatment during methicillin-resistant S. aureus (MRSA) septic shock, improving disease outcome (46). Historically, mechanisms underlying antibiotic tolerant and persister cell formation have been studied under in vitro conditions using pure bacterial cultures.…”

“…Thiols, like glutathione and bacillithiol, directly scavenge peroxynitrite via reduction reaction, whereas ascorbic and uric acid indirectly resolve damage by inhibiting tyrosine nitration (47, 48). Metallic porphyrins, like FeTPPS and WW-85, facilitate decomposition of peroxynitrite by catalyzing the isomerization of peroxynitrite into nitrate (44, 46, 49). WW-85 has been shown to diminish the need for arginine vasopression treatment during methicillin-resistant S. aureus (MRSA) septic shock, improving disease outcome (46).…”

The Chemistry of Reactive Oxygen Species (ROS) Revisited: Outlining Their Role in Biological Macromolecules (DNA, Lipids and Proteins) and Induced Pathologies

“…The hydroxyl radical • OH ( Figure 3 A–C), the most powerful ROS oxidant, is formed during the Haber–Weiss reaction [ 8 ], by the Fenton reaction [ 9 ] or by decomposition of peroxynitrite [ 10 ], and has a very short half-life (10 −9 s) and high reactivity.…”

An electrophysiological evaluation method for the ovine facial nerve

“…Sheep, in which the current CMAP measurement method was established, have been widely used as a translational animal model in studies of intensive care [ 15 ] and wound healing [ 16 ]. The advantages of using sheep as an experimental model include (a) their anatomical and pathophysiological similarities to humans, and (b) their calm nature compared to other large animals commonly used as experimental models, such as pigs, enabling easier postoperative wound management.…”