Nitric Oxide and Superoxide Play a Role

Nitric oxide (NO) is formed from three known isoforms of nitric oxide synthase (NOS). Endothelial NOS (eNOS) is constitutively expressed in endothelial cells and produces basic amounts of NO, which regulates microcirculation by dilating vascular smooth muscle cells and preventing platelet aggregation. NO also prevents neutrophil and macrophage activation and inhibits cytokine production. Neuronal NOS (nNOS) is another constitutive NOS in brain and nerve endings and is also reported to be present in neu-trophils. We have determined that the administration of an inhibitor of nNOS would reduce the acute lung injury noted with ALI induced both by a combination of pneumonia and smoke inhalation. Similar beneficial effect was observed in ALI induced and by 40 percent burns combined with smoke inhalation. There is also an inducible NOS (iNOS) in macrophages, monocytes, lung epithelial cells, and so on. iNOS is expressed as a result of cytokine or endotoxin stimulation. New evidence also suggests that iNOS may be induced directly or indirectly by poly(ADP-ribose) polymerase (PARP). This latter enzyme is formed as a result of oxidative damage to DNA. PARP is present after injury. When iNOS is induced during acute lung injury, enormous amounts of NO are formed. This NO has been shown to form reactive nitrogen species (RNS) that result in leakage of the pulmonary microcirculation, since activated neutro-phils release reactive oxygen species that can also combine with NO to contribute to the microvascular injury.

Normally the microcirculation to nonventilated lung is vasoconstricted, a process called hypoxic pulmonary vasoconstriction (HPV). Excess NO formed in acute lung injury abolishes HPV consequently; some of the blood going through the lung is not oxygenated. Thus with acute lung injury arterial blood is poorly saturated with oxygen. Administration of NOS inhibitors has been shown to restore HPV and arterial oxygen saturation.

RNS, especially peroxynitrite, injures DNA and induces single-strand breaks. As a consequence, PARP is activated. The activation of PARP has been shown in various ALI

models. PARP inhibition has been shown to reduce pulmonary transvascular fluid flux and bronchial blood flow after injury by bacteria or burn/smoke [2]. PARP has been shown to play a role in activation of nuclear regulatory factors, NOS, and IL-8. A multicenter clinical trial using PARP inhibitors in ALI began in early 2004.

Essentials of Human Physiology

Essentials of Human Physiology

This ebook provides an introductory explanation of the workings of the human body, with an effort to draw connections between the body systems and explain their interdependencies. A framework for the book is homeostasis and how the body maintains balance within each system. This is intended as a first introduction to physiology for a college-level course.

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