Effects of Early Neuronal and Delayed Inducible Nitric Oxide Synthase Blockade on Cardiovascular, Renal, and Hepatic Function in Ovine Sepsis

Lange, Matthias; Hamahata, Atsumori; Traber, Daniel L.; Nakano, Yoshimitsu; Esechie, Aimalohi; Jonkam, Collette; Whorton, Elbert B.; Borzyskowski, Sanna von; Traber, Lillian D.; Enkhbaatar, Perenlei

doi:10.1097/aln.0b013e3181fc5588

Cited by 17 publications

(9 citation statements)

References 32 publications

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“…Thus, the results from the current experiment are not necessarily transmittable to acute lung injury from other etiologies. However, we chose this double-hit injury because it represents a frequent clinical setting in burn patients with smoke inhalation injury (2) and it provides the possibility of relating the current findings to several previous studies using the same animal model (7, 8, 10-13, 28). Moreover, we did not compare the contributions of the solitary injuries in the current experiment, but we have previously shown that the pulmonary response to the combination of both smoke inhalation and bacterial infection is different and more severe than with either injury alone (11).…”

Section: Discussionmentioning

confidence: 99%

Time Profile of Oxidative Stress and Neutrophil Activation in Ovine Acute Lung Injury and Sepsis

Lange¹,

Szabó²,

Traber³

et al. 2012

Shock

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The formation of oxidative stress in the lung and activation of neutrophils are major determinants in the development of respiratory failure following acute lung injury (ALI) and sepsis. However, the time changes of these pathogenic factors have not been sufficiently described. Twenty-four chronically instrumented sheep were subjected to cotton smoke inhalation injury and instillation of live Pseudomonas aeruginosa into both lungs. The sheep and were euthanized at 4, 8, 12, 18, and 24 hours postinjury. Additional sheep received sham injury and were euthanized after 24 hours. Pulmonary function was assessed by determination of oxygenation index and pulmonary shunt fraction. In addition, lung tissue was harvested at the respective time points for the measurement of malondialdehyde, interleukin-6 (IL-6), poly(ADP ribose) (PAR), myeloperoxidase, and alveolar polymorphonuclear neutrophil score. The injury induced severe respiratory failure which was associated with an early increase in lipid peroxidation and IL-6 expression. The injury further led to an increase in PAR activity that reached its peak at 12 hours postinjury and declined afterward. In addition, progressive increases in markers of neutrophil accumulation in the lung were observed. The peak of neutrophil accumulation in the lung was associated with a severe depletion of circulating neutrophils. The results from our model may enhance the understanding of the pathophysiological alterations following ALI and sepsis and thus be useful in exploring therapeutic interventions directed at modifying the expression or activation of inflammatory mediators.

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Section: Discussionmentioning

confidence: 99%

Time Profile of Oxidative Stress and Neutrophil Activation in Ovine Acute Lung Injury and Sepsis

Lange¹,

Szabó²,

Traber³

et al. 2012

Shock

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“…Sepsis-related increase in bilirubin level, international normalized ratio, and lipid peroxidation in liver tissue were significantly attenuated by the early neuronal NO synthase (nNOS) and delayed iNOS blockade. [8] Additionally, H 2 S contributes to microcirculatory dysfunction in the systemic as well as hepatic microcirculations due to a differential vasoactive function on presinusoidal and sinusoidal sites within the liver. [9]…”

Section: Pathophysiological Changes In Sepsis-associated Liver Dysfunmentioning

confidence: 99%

Advances in sepsis-associated liver dysfunction

2014

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Recent studies have revealed liver dysfunction as an early event in sepsis. Sepsis-associated liver dysfunction is mainly resulted from systemic or microcirculatory disturbances, spillovers of bacteria and endotoxin (lipopolysaccharide, LPS), and subsequent activation of inflammatory cytokines as well as mediators. Three main cell types of the liver which contribute to the hepatic response in sepsis are Kupffer cells (KCs), hepatocytes and liver sinusoidal endothelial cells (LSECs). In addition, activated neutrophils, which are also recruited to the liver and produce potentially destructive enzymes and oxygen-free radicals, may further enhance acute liver injury. The clinical manifestations of sepsis-associated liver dysfunction can roughly be divided into two categories: Hypoxic hepatitis and jaundice. The latter is much more frequent in the context of sepsis. Hepatic failure is traditionally considered as a late manifestation of sepsis-induced multiple organ dysfunction syndrome. To date, no specific therapeutics for sepsis-associated liver dysfunction are available. Treatment measure is mainly focused on eradication of the underlying infection and management for severe sepsis. A better understanding of the pathophysiology of liver response in sepsis may lead to further increase in survival rates.

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“…Thus, novel therapeutic strategies to interrupt this vicious circle of septic lung injury, pulmonary microvascular hyperpermeability, and ventilator-associated lung injury are of great clinical interest. In this regard, experimental inhibition of different isoforms of NO synthases delivered promising results [7, 13]. However, when considering specific treatment strategies, the identification of the time course of pathogenetic key factors of sepsis resulting from ALI and pneumonia appears to be crucial.…”

Section: Discussionmentioning

confidence: 99%

Pulmonary microvascular hyperpermeability and expression of vascular endothelial growth factor in smoke inhalation- and pneumonia-induced acute lung injury

Lange

Hamahata

Traber

et al. 2012

Burns

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Introduction: Acute lung injury (ALI) and sepsis are major contributors to the morbidity and mortality of critically ill patients. The current study was designed further evaluate the mechanism of pulmonary vascular hyperpermeability in sheep with these injuries. Methods: Sheep were randomized to a sham-injured control group (n=6) or ALI/Sepsis group (n=7). The sheep in the ALI/Sepsis group received inhalation injury followed by instillation of Pseudomonas aeruginosa into the lungs. These groups were monitored for 24 hours. Additional sheep (n=16) received the injury and lung tissue was harvested at different time points to measure lung wet/dry weight ratio, vascular endothelial growth factor (VEGF) mRNA and protein expression as well as 3-nitrotyrosine protein expression in lung homogenates. Results: The injury induced severe deterioration in pulmonary gas exchange, increases in lung lymph flow and protein content, and lung water content (p<0.015 each). These alterations were associated with elevated lung and plasma nitrite/nitrate concentrations, increased tracheal blood flow, and enhanced VEGF mRNA and protein expression in lung tissue as well as enhanced 3-nitrotyrosine protein expression (p<0.05 each). Conclusions: This study describes the time course of pulmonary microvascular hyperpermeability in a clinical relevant large animal model and may improve the experimental design of future studies.

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Effects of Early Neuronal and Delayed Inducible Nitric Oxide Synthase Blockade on Cardiovascular, Renal, and Hepatic Function in Ovine Sepsis

Abstract: The combination treatment shows potential benefit on sepsis-related arterial hypotension and surrogate parameters of organ dysfunctions in sheep. It may be crucial to identify the time course of expression and activation of different nitric oxide synthase isoforms in future investigations.

Cited by 17 publications

References 32 publications

Time Profile of Oxidative Stress and Neutrophil Activation in Ovine Acute Lung Injury and Sepsis

Time Profile of Oxidative Stress and Neutrophil Activation in Ovine Acute Lung Injury and Sepsis

Advances in sepsis-associated liver dysfunction

Pulmonary microvascular hyperpermeability and expression of vascular endothelial growth factor in smoke inhalation- and pneumonia-induced acute lung injury

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