Beneficial pulmonary effects of a metalloporphyrinic peroxynitrite decomposition catalyst in burn and smoke inhalation injury

Abstract

During acute lung injury, nitric oxide (NO) exerts cytotoxic effects by reacting with superoxide radicals, yielding the reactive nitrogen species peroxynitrite (ONOO(-)). ONOO(-) exerts cytotoxic effects, among others, by nitrating/nitrosating proteins and lipids, by activating the nuclear repair enzyme poly(ADP-ribose) polymerase and inducing VEGF. Here we tested the effect of the ONOO(-) decomposition catalyst INO-4885 on the development of lung injury in chronically instrumented sheep with combined burn and smoke inhalation injury. The animals were randomized to a sham-injured group (n = 7), an injured control group [48 breaths of cotton smoke, 3rd-degree burn of 40% total body surface area (n = 7)], or an injured group treated with INO-4885 (n = 6). All sheep were mechanically ventilated and fluid-resuscitated according to the Parkland formula. The injury-related increases in the abundance of 3-nitrotyrosine, a marker of protein nitration by ONOO(-), were prevented by INO-4885, providing evidence for the neutralization of ONOO(-) action by the compound. Burn and smoke injury induced a significant drop in arterial Po(2)-to-inspired O(2) fraction ratio and significant increases in pulmonary shunt fraction, lung lymph flow, lung wet-to-dry weight ratio, and ventilatory pressures; all these changes were significantly attenuated by INO-4885 treatment. In addition, the increases in IL-8, VEGF, and poly(ADP-ribose) in lung tissue were significantly attenuated by the ONOO(-) decomposition catalyst. In conclusion, the current study suggests that ONOO(-) plays a crucial role in the pathogenesis of pulmonary microvascular hyperpermeability and pulmonary dysfunction following burn and smoke inhalation injury in sheep. Administration of an ONOO(-) decomposition catalyst may represent a potential treatment option for this injury.

Arginase Inhibition Prevents Inflammation and Remodeling in a Guinea Pig Model of Chronic Obstructive Pulmonary Disease

“…In addition, increased arginase activity causes uncoupling of iNOS and subsequent production of the proinflammatory oxidant species peroxynitrite (Maarsingh et al, 2008a), which induces IL-8 expression in various cell types (Zouki et al, 2001;Sarir et al, 2010). Accordingly, breakdown of peroxynitrite reduces smoke-induced IL-8 levels in sheep lung (Lange et al, 2011).…”

SOD Therapeutics: Latest Insights into Their Structure-Activity Relationships and Impact on the Cellular Redox-Based Signaling Pathways

“…With E 1/2 of + 228 mV versus NHE (* + 300 mV vs. NHE for SOD enzyme), MnTE-2-PyP 5 + reduces and oxidizes O 2 $ -with nearly identical rate constants as does the SOD (31,32). Such a design later led to imidazolyl analog, MnTDE-2-ImP 5 + (26-28, 131, 211, 225, 239), and to a series of Fe porphyrins (FePs) (30,146,172,173,193,207,214,215,244,259,273) (see also under Drug Design section). Further, the increased bioavailability and reduced toxicity was achieved through modifications of the substituents in ortho positions (216,274).…”

“…Recently, we synthesized a series of ortho and meta Fe complexes to understand the intriguing differential in vivo behavior of Fe and MnPs (273). FePs have also been often used in cellular and animal models of oxidative stress (146,172,173,193,207,214,215,244,259 …”

Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction

“…The divergent effects of cGMP on the endothelial barrier may contribute to the failure of inhalative NO therapy to improve outcome of ARDS patients and might be governed by subcellular gradients of cGMP and its molecular targets (2,129). During ALI, NO reacts with superoxide radicals, yielding the reactive nitrogen species ONOO Ϫ , which leads to endothelial barrier hyperpermeability, protein nitration, poly(ADPribose) polymerase activation, and vascular endothelial growth factor (VEGF) activation (223), and the use of a metalloporphyrinic peroxynitrite decomposition catalyst has recently been shown to be effective in preventing cytotoxic effects in burn and smoke inhalation injury-induced ALI (132).…”

“…A likely underlying reason is the heterogeneity of the disease, which might be associated with a direct insult by, e.g., infection, aspiration, or injurious ventilation, or an indirect one during situations of severe systemic inflammation, or, frequently, a combination thereof. Efforts to define endogenous pathways or molecules that protect from ALI have recently significantly contributed to our understanding of ALI pathophysiology (5,36,51,81,95,99,132,150,176,189,226,245,254,256,261). Imai et al (106) were the first to suggest that the signals impacting on the balance between angiotensin converting enzymes (ACE) 1 and 2 modulate the degree of inflammatory lung injury after sepsis, and ACE I/D polymorphism was recently associated with mortality risk of ALI/ ARDS in patients (152).…”