Sodium Nitrite Mitigates Ventilator-induced Lung Injury in Rats

Pickerodt, Philipp A.; Emery, Michael J.; Zarndt, Rachel; Martin, William J.; Francis, Roland C. E.; Boemke, Willehad; Swenson, Erik R.

doi:10.1097/aln.0b013e3182655f80

Cited by 22 publications

(18 citation statements)

References 52 publications

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“…In the current study, use of 10-fold higher or lower dose of nitrite resulted in a loss of protection. Similar "U"-shaped dependence for nitrite therapy has been observed previously for ischemia-reperfusion injury (7,27). That said, even at the highest dose tested here, nitrite did not increase Cl 2 toxicity (see Fig.…”

Section: Discussionsupporting

confidence: 61%

“…4) (11). Also, nitrite afforded protection against acute lung injury in a model of sublethal Cl 2 exposure, and similar results have been shown in a model of mechanical ventilatorinduced injury (27,28,36). This suggests that the therapeutic mechanisms of action of nitrite may target aspects of lung injury common to distinct initiators of acute lung injury.…”

Section: Discussionsupporting

confidence: 56%

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Nitrite therapy improves survival postexposure to chlorine gas

Honavar

Doran

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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Exposure to relatively high levels of chlorine (Cl2) gas can occur in mass-casualty scenarios associated with accidental or intentional release. Recent studies have shown a significant postexposure injury phase to the airways, pulmonary, and systemic vasculatures mediated in part by oxidative stress, inflammation, and dysfunction in endogenous nitric oxide homeostasis pathways. However, there is a need for therapeutics that are amenable to rapid and easy administration in the field and that display efficacy toward toxicity after chlorine exposure. In this study, we tested whether nitric oxide repletion using nitrite, by intramuscular injection after Cl2 exposure, could prevent Cl2 gas toxicity. C57bl/6 male mice were exposed to 600 parts per million Cl2 gas for 45 min, and 24-h survival was determined with or without postexposure intramuscular nitrite injection. A single injection of nitrite (10 mg/kg) administered either 30 or 60 min postexposure significantly improved 24-h survival (from ∼20% to 50%). Survival was associated with decreased neutrophil accumulation in the airways. Rendering mice neutropenic before Cl2 exposure improved survival and resulted in loss of nitrite-dependent survival protection. Interestingly, female mice were more sensitive to Cl2-induced toxicity compared with males and were also less responsive to postexposure nitrite therapy. These data provide evidence for efficacy and define therapeutic parameters for a single intramuscular injection of nitrite as a therapeutic after Cl2 gas exposure that is amenable to administration in mass-casualty scenarios.

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Section: Discussionsupporting

confidence: 61%

Section: Discussionsupporting

confidence: 56%

Nitrite therapy improves survival postexposure to chlorine gas

Honavar

Doran

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Moreover, nitrite therapy also protects against pulmonary and vascular smooth muscle remodeling after injury and improves lung function after transplantation (4,88,111,139). Additionally, nitrite therapy protects against ALI induced by mechanical ventilation and inhaled chemical toxicants, in the latter of which the risk of developing reactive airways is also reduced (40,96,101,132). Improvement in both inflammatory and permeability components of ALI has been documented, suggesting that nitrite therapy prevents early events in the disease.…”

Section: No and Nitrite Therapeutics For Airway And Pulmonary Vasculamentioning

confidence: 94%

Working with nitric oxide and hydrogen sulfide in biological systems

Yuan

Patel

Kevil

2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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(H 2S) are gasotransmitter molecules important in numerous physiological and pathological processes. Although these molecules were first known as environmental toxicants, it is now evident that that they are intricately involved in diverse cellular functions with impact on numerous physiological and pathogenic processes. NO and H 2S share some common characteristics but also have unique chemical properties that suggest potential complementary interactions between the two in affecting cellular biochemistry and metabolism. Central among these is the interactions between NO, H 2S, and thiols that constitute new ways to regulate protein function, signaling, and cellular responses. In this review, we discuss fundamental biochemical principals, molecular functions, measurement methods, and the pathophysiological relevance of NO and H 2S. thiol; oxidation; redox; pulmonary; cardiovascular HISTORICALLY CONSIDERED ONLY as industrial pollutants, nitric oxide (NO) and hydrogen sulfide (H 2 S) are now appreciated as two key physiologically produced signaling molecules that control multiple cellular functions. Appreciation that dysfunction in how these solvated gases affect these functions, through either deficient formation or downstream reactivity, has opened up new therapeutic avenues for a host of diseases in all major organ systems including the lung. Our understanding of NO homeostasis mechanisms are relatively advanced compared with H 2 S, primarily because of the latter's discovery as a biologically relevant entity being postdated by a decade or more compared with NO. Although they are chemically distinct, there are intriguing parallel mechanisms/concepts in NO and H 2 S biology that include overlapping functions, technical challenges in how each of these gases are measured in biological milieu, appreciation of the mechanisms and factors that modulate how metabolism of each of these is regulated, and therapeutic potential for either inhibiting or repleting NO or H 2 S. In this article, and within the framework outlined above, we provide a general overview of NO and H 2 S biology. Nitric Oxide Formation: Enzymatic and Nonenzymatic SourcesEnzymatic sources. Nitric oxide is synthesized by one of three different isoforms of nitric oxide synthase (NOS) that differ in enzymatic activity, in how they are regulated (transcriptional, translational, and posttranslational mechanisms), and in how they are expressed/compartmentalized in tissues as well as the subcellular level. These are called NOS I, II, and III, corresponding to the inducible (iNOS), neuronal (nNOS), and endothelial (eNOS) isoforms, typically with high, mid, and low activities, respectively. In the systemic and pulmonary vasculature, eNOS plays a key role in controlling blood flow and maintaining an antithrombotic and anti-inflammatory luminal surface. On the other hand, iNOS is induced by inflammatory stimuli in leukocytes, airway epithelial cells, and alveolar macrophages to mediate pathogen killing. However, production of NO at higher concentrations in ...

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“…Nitrite reductase activity has thus far been assigned to AO, sulfite oxidase and XOR with the majority of reports focused on the later (Li et al 2009;Millar et al 1998;Millar 2004;Wang et al 2014;Li et al 2001Li et al , 2005Li et al , 2008. Evidence for XO-catalyzed • NO formation has originated from basic biochemical studies with purified enzyme preparations as well as in vivo models of ischemia/reperfusion where salutary outcomes attributable to NO 2 − administration were abrogated by concomitant XOR inhibition (Alef et al 2011;Samal et al 2012;Pickerodt et al 2012;Sugimoto et al 2012;Zuckerbraun et al 2010;Baker et al 2007;Tripatara et al 2007;Webb et al 2004;Lu et al 2005). In the aggregate, these studies reveal a novel function for XOR as a source of salutary • NO; yet, they identify a significant dilemma as they were conducted using models similar to or the same as those that have previously revealed XOR inhibition, in the absence of NO 2 − treatment, to be of benefit.…”

Section: Xor As a Source Of Nitric Oxidementioning

confidence: 95%

Dispelling dogma and misconceptions regarding the most pharmacologically targetable source of reactive species in inflammatory disease, xanthine oxidoreductase

Kelley

2015

Arch Toxicol

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Xanthine oxidoreductase (XOR), the molybdoflavin enzyme responsible for the terminal steps of purine degradation in humans, is also recognized as a significant source of reactive species contributory to inflammatory disease. In animal models and clinical studies, inhibition of XOR has resulted in diminution of symptoms and enhancement of function in a number of pathologies including heart failure, diabetes, sickle cell anemia, hypertension and ischemia-reperfusion injury. For decades, XOR involvement in pathologic processes has been established by salutary outcomes attained from treatment with the XOR inhibitor allopurinol. This has served to frame a working dogma that elevation of XOR-specific activity is associated with enhanced rates of reactive species generation that mediate negative outcomes. While adherence to this narrowly focused practice of designating elevated XOR activity to be "bad" has produced some benefit, it has also led to significant underdevelopment of the processes mediating XOR regulation, identification of alternative reactants and products as well as micro-environmental factors that alter enzymatic activity. This is exemplified by recent reports: (1) identifying XOR as a nitrite reductase and thus a source of beneficial nitric oxide ((•)NO) under in vivo conditions similar to those where XOR inhibition has been assumed an optimal treatment choice, (2) describing XOR-derived uric acid (UA) as a critical pro-inflammatory mediator in vascular and metabolic disease and (3) ascribing an antioxidant/protective role for XOR-derived UA. When taken together, these proposed and countervailing functions of XOR affirm the need for a more comprehensive evaluation of product formation as well as the factors that govern product identity. As such, this review will critically evaluate XOR-catalyzed oxidant, (•)NO and UA formation as well as identify factors that mediate their production, inhibition and the resultant impact on inflammatory disease.

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Sodium Nitrite Mitigates Ventilator-induced Lung Injury in Rats

Cited by 22 publications

References 52 publications

Nitrite therapy improves survival postexposure to chlorine gas

Nitrite therapy improves survival postexposure to chlorine gas

Working with nitric oxide and hydrogen sulfide in biological systems

Dispelling dogma and misconceptions regarding the most pharmacologically targetable source of reactive species in inflammatory disease, xanthine oxidoreductase

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