Inhibition of neuronal nitric oxide synthase in ovine model of acute lung injury
ABSTRACT 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.
- Critical care medicine 02/2009; 37(1):361-3. DOI:10.1097/CCM.0b013e31818bd862 · 6.15 Impact Factor
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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.Critical care (London, England) 08/2009; 13(4):218. DOI:10.1186/cc7706
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ABSTRACT: Pulmonary injury from smoke inhalation is common in burn victims, significantly contributing to the morbidity and mortality of fire-related injuries. The impacts of improvement in other aspects of burn care have not been mirrored in treatment of smoke inhalation. Smoke is heterogeneous and unique to each fire; it comprises particulates, respiratory irritants and systemic toxins as well as heat, all contributing to the pathological insult. Thermal injury below the vocal cords is rare because of effective heat dissipation in the upper airway. Particulate matter is the chief contributor to the pathophysiology of smoke inhalation injury, which has been extensively described. Of paramount importance is the cascade of inflammatory mediators following interaction of irritant substances with lung parenchyma, leading to pulmonary oedema, cast formation, airway obstruction, loss of hypoxic pulmonary vasoconstriction and ventilation/perfusion mismatch. Current treatment is based on supportive care, with airway management, mechanical ventilation, humidification and aggressive airway toilet the mainstays. Nebulisation of n2-agonists, heparin and N-acetylcysteine have a role in management, as does more specific treatment of carbon monoxide or cyanide intoxication. Many promising treatments are currently under investigation. The therapeutic strategy of decontaminating the lungs early after smoke exposure to prevent inhalation injury has received little attention and may be of significant value. This could potentially utilise amphoteric, hypertonic chelating agents developed for topical and ocular chemical exposures.Critical care and resuscitation: journal of the Australasian Academy of Critical Care Medicine 03/2010; 12(1):53-61. · 2.15 Impact Factor