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Reactive species of oxygen and nitrogen have been collectively implicated in pulmonary oxygen toxicity, but the contributions of specific molecules are unknown. Therefore, we assessed the roles of several reactive species, particularly nitric oxide, in pulmonary injury by exposing wild-type mice and seven groups of genetically altered mice to >98% 02 at 1, 3, or 4 atmospheres absolute. Genetically altered animals included knockouts lacking either neuronal nitric oxide synthase ([nNOS.sup.-/-]), endothelial nitric oxide synthase ([eNOS.sup.-/-] ), inducible nitric oxide synthase ([iNOS.sup.-/-]), extracellular superoxide dismutase (SOD3 /-), or glutathione peroxidase 1 ([GPxl.sup.-/-]), as well as two transgenic variants (S1179A and S1179D) having altered eNOS activities. We confirmed our earlier finding that normobaric hyperoxia (NB[O.sub.2]) and hyperbaric hyperoxia (HB[O.sub.2]) result in at least two distinct but overlapping patterns of pulmonary injury. Our new findings are that the role of nitric oxide in the pulmonary pathophysiology of hyperoxia depends both on the specific NOS isozyme that is its source and on the level of hyperoxia. Thus, iNOS predominates in the etiology of lung injury in NB[O.sub.2], and SOD3 provides an important defense. But in HB[O.sub.2], nNOS is a major contributor to pulmonary injury, whereas eNOS is protective. In addition, we demonstrated that nitric oxide derived from nNOS is involved in a neurogenic mechanism of HB[O.sub.2]-induced lung injury that is linked to central nervous system oxygen toxicity through adrenergic/cholinergic pathways. normobaric oxygen toxicity; hyperbaric oxygen toxicity; superoxide dismutase; glutathione peroxidase 1 ; neurogenic pulmonary oxygen toxicity

Pulmonary manifestations of oxygen toxicity were studied and quantified in rats breathing >98% [O.sub.2] at 1, 1.5, 2, 2.5, and 3 ATA to test our hypothesis that different patterns of pulmonary injury would emerge, reflecting a role for central nervous system (CNS) excitation by hyperbaric oxygen. At 1.5 atmosphere absolute (ATA) and below, the well-recognized pattern of diffuse pulmonary damage developed slowly with an extensive inflammatory response and destruction of the alveolar-capillary barrier leading to edema, impaired gas exchange, respiratory failure, and death; the severity of these effects increased with time over the 56-h period of observation. At higher inspired [O.sub.2] pressures, 2-3 ATA, pulmonary injury was greatly accelerated but less inflammatory in character, and events in the brain were a prelude to a distinct lung pathology. The CNS-mediated component of this lung injury could be attenuated by selective inhibition of neuronal nitric oxide synthase (nNOS) or by unilateral transection of the vagus nerve. We propose that extrapulmonary, neurogenic events predominate in the pathogenesis of acute pulmonary oxygen toxicity in hyperbaric oxygenation, as nNOS activity drives lung injury by modulating the output of central autonomic pathways. central nervous system oxygen toxicity; hyperbaric oxygen doi:10.1152/ajplung.00450.2006

Breathing hyperbaric oxygen (HBO₂), particularly at pressures above 3 atmospheres absolute, can cause acute pulmonary injury that is more severe if signs of central nervous system toxicity occur. This is consistent with the activation of an autonomic link between the brain and the lung, leading to acute pulmonary oxygen toxicity. This pulmonary damage is characterized by leakage of fluid, protein, and red blood cells into the alveoli, compatible with hydrostatic injury due to pulmonary hypertension, left atrial hypertension, or both. Until now, however, central hemodynamic parameters and autonomic activity have not been studied concurrently in HBO₂, so any hypothetical connections between the two have remained untested. Therefore, we performed experiments using rats in which cerebral blood flow, electroencephalographic activity, cardiopulmonary hemodynamics, and autonomic traffic were measured in HBO₂ at 5 and 6 atmospheres absolute. In some animals, autonomic pathways were disrupted pharmacologically or surgically. Our findings indicate that pulmonary damage in HBO₂ is caused by an abrupt and significant increase in pulmonary vascular pressure, sufficient to produce barotrauma in capillaries. Specifically, extreme HBO₂ exposures produce massive sympathetic outflow from the central nervous system that depresses left ventricular function, resulting in acute left atrial and pulmonary hypertension. We attribute these effects on the heart and on the pulmonary vasculature to HBO₂-mediated central sympathetic excitation and catecholamine release that disturbs the normal equilibrium between excitatory and inhibitory activity in the autonomic nervous system.