Acute respiratory distress syndrome/acute lung injury is a serious complication of burn patients with concomitant smoke inhalation injury. Nitric oxide has been shown to play a major role in pulmonary dysfunction from thermal damage. In this study, we have tested the hypothesis that inhibition of neuronal nitric oxide synthase could ameliorate the severity of acute lung injury using our well-established ovine model of cutaneous burn and smoke inhalation.
Prospective, randomized, controlled, experimental animals study.
Investigational intensive care unit at university hospital.
Adult female sheep.
Female sheep (n = 16) were surgically prepared for the study. Seven days after surgery, all sheep were randomly allocated into three study groups: sham (noninjured, nontreated, n = 6); control (injured, treated with saline, n = 6); and neuronal nitric oxide synthase (injured, treated with specific neuronal nitric oxide synthase inhibitor, ZK 234238 (n = 4). Control and neuronal nitric oxide synthase groups were given a cutaneous burn (40% of total body surface, third degree) and insufflated with cotton smoke (48 breaths, <40 degrees C) under halothane anesthesia. Animals in sham group received fake injury also under halothane anesthesia. After injury or fake injury procedure, all sheep were placed on ventilators and resuscitated with lactated Ringer's solution. Neuronal nitric oxide synthase group was administered with continuous infusion of ZK 234238 started 1 hr postinjury with a dose of 100 microg/kg/hr. Sham and control groups received same amount of saline.
Cardiopulmonary hemodynamics monitored during the 24-hr experimental time period was stable in the sham group. Control sheep developed multiple signs of acute lung injury. This pathophysiology included decreased pulmonary gas exchange and lung compliance, increased pulmonary edema, and inflammatory indices, such as interleukin-8. Treatment of injured sheep with neuronal nitric oxide synthase inhibitor attenuated all the observed pulmonary pathophysiology.
The results provide definitive evidence that inhibition of neuronal nitric oxide synthase-derived excessive nitric oxide may be a novel and beneficial treatment strategy for pulmonary pathology in burn victims with smoke inhalation injury.
"Following baseline measurements (BL) in the healthy sheep, a tracheostomy was performed and a urinary bladder catheter was placed under deep anesthesia. Twelve animals were then subjected to 40% of total body surface area third degree flame burn and 4 × 12 breaths of cold cotton smoke under deep anesthesia using an established protocol [16,17]. The arterial carboxyhemoglobin level was determined immediately after smoke inhalation to quantify the degree of injury. "
[Show abstract][Hide abstract] ABSTRACT: Introduction
We hypothesized that maintaining physiological plasma levels of antithrombin attenuates myocardial dysfunction and inflammation as well as vascular leakage associated with burn and smoke inhalation injury. Therefore, the present prospective, randomized experiment was conducted using an established ovine model.
Following 40% of total body surface area, third degree flame burn and 4 × 12 breaths of cold cotton smoke, chronically instrumented sheep were randomly assigned to receive an intravenous infusion of 6 IU/kg/h recombinant human antithrombin (rhAT) or normal saline (control group; n = 6 each). In addition, six sheep were designated as sham animals (not injured, continuous infusion of vehicle). During the 48 h study period the animals were awake, mechanically ventilated and fluid resuscitated according to standard formulas.
Compared to the sham group, myocardial contractility was severely impaired in control animals, as suggested by lower stroke volume and left ventricular stroke work indexes. As a compensatory mechanism, heart rate increased, thereby increasing myocardial oxygen consumption. In parallel, myocardial inflammation was induced via nitric oxide production, neutrophil accumulation (myeloperoxidase activity) and activation of the p38-mitogen-activated protein kinase pathway resulting in cytokine release (tumor necrosis factor-alpha, interleukin-6) in control vs. sham animals. rhAT-treatment significantly attenuated these inflammatory changes leading to a myocardial contractility and myocardial oxygen consumption comparable to sham animals. In control animals, systemic fluid accumulation progressively increased over time resulting in a cumulative positive fluid balance of about 4,000 ml at the end of the study period. Contrarily, in rhAT-treated animals there was only an initial fluid accumulation until 24 h that was reversed back to the level of sham animals during the second day.
Based on these findings, the supplementation of rhAT may represent a valuable therapeutic approach for cardiovascular dysfunction and inflammation after burn and smoke inhalation injury.
"Investigators recently noticed that 7-nitroindazole (NI), an inhibitor of neuronal NOS (nNOS), attenuates ALI after smoke inhalation and burns  as well as after inhalation of smoke followed by instillation of live bacteria into the airways of sheep . Although nNOS is abundantly distributed in airway epithelial and neuronal tissues , it is still unsettled whether this isoform of NOS is involved in the pathogenesis of VILI after pneumonectomy, and whether NI might antagonize this particular subtype of lung injury. "
[Show abstract][Hide abstract] ABSTRACT: Mechanical ventilation with high tidal volumes may cause ventilator-induced lung injury (VILI) and enhanced generation of nitric oxide (NO). We demonstrated in sheep that pneumonectomy followed by injurious ventilation promotes pulmonary edema. We wished both to test the hypothesis that neuronal NOS (nNOS), which is distributed in airway epithelial and neuronal tissues, could be involved in the pathogenesis of VILI and we also aimed at investigating the influence of an inhibitor of nNOS on the course of VILI after pneumonectomy.
Anesthetized sheep underwent right pneumonectomy, mechanical ventilation with tidal volumes (VT) of 6 mL/kg and FiO2 0.5, and were subsequently randomized to a protectively ventilated group (PROTV; n = 8) keeping VT and FiO2 unchanged, respiratory rate (RR) 25 inflations/min and PEEP 4 cm H2O for the following 8 hrs; an injuriously ventilated group with VT of 12 mL/kg, zero end-expiratory pressure, and FiO2 and RR unchanged (INJV; n = 8) and a group, which additionally received the inhibitor of nNOS, 7-nitroindazole (NI) 1.0 mg/kg/h intravenously from 2 hours after the commencement of injurious ventilation (INJV + NI; n = 8). We assessed respiratory, hemodynamic and volumetric variables, including both the extravascular lung water index (EVLWI) and the pulmonary vascular permeability index (PVPI). We measured plasma nitrite/nitrate (NOx) levels and examined lung biopsies for lung injury score (LIS).
Both the injuriously ventilated groups demonstrated a 2-3-fold rise in EVLWI and PVPI, with no significant effects of NI. In the INJV group, gas exchange deteriorated in parallel with emerging respiratory acidosis, but administration of NI antagonized the derangement of oxygenation and the respiratory acidosis significantly. NOx displayed no significant changes and NI exerted no significant effect on LIS in the INJV group.
Inhibition of nNOS improved gas exchange, but did not reduce lung water extravasation following injurious ventilation after pneumonectomy in sheep.
"As in other fields, different isoforms are involved and play different roles. In a sheep model of combined burn injury and Pseudomonas pneumonia in which selective iNOS inhibition had previously been shown to improve gas exchange, a new study showed that selective nNOS inhibition improved pulmonary gas exchange, lung compliance, and lung edema . nNOS inhibition also decreased nitrotyrosine in lung tissue, a marker of peroxynitrite formation, and, interestingly, diminished levels of iNOS protein in the lung . "
[Show abstract][Hide abstract] ABSTRACT: Nitric oxide (NO) is a unique and nearly ubiquitous molecule that is widely utilized as a signaling molecule in cells throughout the body. NO is highly diffusible, labile, and multiply reactive, suiting it well for its role as an important regulator of a number of diverse biologic processes, including vascular tone and permeability, platelet adhesion, neurotransmission, and mitochondrial respiration. NO can protect cells against antioxidant injury, can inhibit leukocyte adhesion, and can participate in antimicrobial defense, but can also have deleterious effects, including inhibition of enzyme function, promotion of DNA damage, and activation of inflammatory processes. This molecule's chemistry dictates its biologic activity, which can be both direct and indirect. In addition, NO has bimodal effects in a number of cells, maintaining homeostasis at low doses, and participating in pathophysiology in others. Perturbation of NO regulation is involved in the most important and prevalent disease processes in critical care units, including sepsis, acute lung injury, and multiple organ failure. Given that NO is ubiquitous, highly diffusible, and promiscuously reactive, its regulation is complex. The NO concentration, kinetics, and localization, both inside and outside the cell, are clearly crucial factors. In the present update we review a selection of studies that have yielded important information on these complex but important issues. Interpretation of these and other studies aimed at elucidating physiologic and pathophysiologic roles of NO must take this complexity into account. A full review of the role of NO in these diseases is beyond the scope of the current manuscript; the present article will focus on recent advances in understanding the complex role of NO in health and disease.
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