H. I. Berisha

NMDA receptor activation: critical role in oxidant tissue injury.

The excitatory amino acid glutamate serves important neurologic functions, but overactivation of its N-methyl-D-aspartate (NMDA) receptor is toxic to neurons (excitotoxicity). We report that NMDA receptor blocker MK-801 (dizocilpine maleate) attenuated oxidant injury induced by paraquat or by xanthine oxidase. We conclude that excitotoxicity may be a key factor in oxidant tissue injury.

N-methyl-d-aspartate receptors outside the central nervous system: Activation causes acute lung injury that is mediated by nitric oxide synthesis and prevented by vasoactive intestinal peptide

N-methyl-D-aspartate receptors, found throughout the mammalian brain, are a component of the major excitatory transmitter system. Strong evidence exists that N-methyl-D-aspartate receptors, by promoting excessive entry of Ca2+ into neurons, play a role in neuronal damage that follows head injury, strokes, and epileptic seizures, and is associated with degenerative diseases such as Alzheimers disease. Huntingtons disease, Parkinsons disease, and amyotrophic lateral sclerosis. We have investigated whether N-methyl-D-aspartate receptors exist in peripheral neurons, and, if so, whether their activation may result in tissue injury. We report that N-methyl-D-aspartate receptors exist in the lung, that their activation triggers acute injury, and that, as in toxicity to central neurons, this injury is associated with stimulation of nitric oxide synthesis, and can be attenuated by inhibition of this synthesis. Finally, vasoactive intestinal peptide, which protects the lung and heart against oxidant injury and promotes neuronal survival and differentiation also prevented N-methyl-D-aspartate lung injury, apparently by inhibiting a key neurotoxic action of nitric oxide, but not its production. The findings suggest that N-methyl-D-aspartate receptors exist in the peripheral nervous system and that activation of these receptors, resulting in damage to peripheral neurons, may be a novel mechanism of lung and other organ injury.

Glutamate toxicity in the lung and neuronal cells: prevention or attenuation by VIP and PACAP.

Abstract: VIP, which has been demonstrated to reduce or prevent oxidant injury in the lungs and other organs, is shown here to protect against excitotoxic injury of the lung and excitotoxic death of cortical neuronal cells in primary culture. Glutamate killing of neuron‐like PC‐12 cells, attributable to oxidant stress rather that to excitotoxicity, is also reduced or prevented by VIP and by the closely related peptide PACAP. The exact mechanisms of this protection remain to be determined, but appear to include antioxidant and anti‐apoptotic actions, and suppression of glutamate‐induced upregulation of its own receptor. Both VIP and PACAP offer the promise of novel and nontoxic means of defending against NMDA and glutamate toxicity.

Attenuation of oxidant-induced lung injury by the synthetic matrix metalloproteinase inhibitor BB-3103.

Acute, diffuse lung injury often complicates sepsis, gastric acid aspiration, extensive trauma, and other conditions. The lung endothelial and epithelial cells are the early targets of this injury leading to increased pulmonary vascular permeability and pulmonary edema. Clinically, this condition is characterized by catastrophic respiratory failure, known as the a dult r espiratory d istress s yndrome (ARDS). Despite advances in our understanding of the pathogenesis of this type of lung injury and in the management of patients with this disorder, the outcome remains grave. There is an urgent need for an effective treatment. Recently matrix metalloproteinases (MMPs), especially gelatinases, have been implicated in the pathogenesis of acute lung injury. Gelatinase A and B and their activated forms are increased in the bronchoalveolar lavage fluid (BAL) of both animal models of acute lung injury and patients with ARDS. 1–4 In this study we sought to investigate the protective effect of an MMP inhibitor in an experimental model of acute lung injury caused by oxygen free radicals. We examined the MMP inhibitor BB-3103, a soluble, low-molecular-weight broad spectrum inhibitor obtained from British Biotechnology Ltd., Oxford, England.

Nitric oxide mediates oxidant tissue injury caused by paraquat and xanthine oxidase.

Abstract In both paraquat and X/XO models of lung injury, the injury, previously attributed to the generation of reactive oxygen species, was related to the induction of NO. synthesis, and was totally preventable by inhibition of this synthesis. The results support the view that the NO. radical itself is an essential intermediary in the pathogenesis of at least some forms of oxidant tissue damage. Another form of oxidant injury, caused by prolonged perfusion of the lung ex vivo, is not mediated by NO. however.

17β-estradiol protects the lung against acute injury: possible mediation by vasoactive intestinal polypeptide.

Beyond their classical role as a class of female sex hormones, estrogens (e.g. 17β-estradiol) exert important biological actions, both protective and undesirable. We have investigated the ability of estradiol to protect the lung in three models of acute injury induced by 1) oxidant stress due to the herbicide paraquat; 2) excitotoxicity, caused by glutamate agonist N-methyl-d-aspartate; and 3) acute alveolar anoxia. We also assessed the role of estrogen receptors (ER) ERα and ERβ and the neuropeptide vasoactive intestinal peptide (VIP) in mediating this protection. Isolated guinea pig or rat lungs were perfused in situ at constant flow and mechanically ventilated. The onset and severity of lung injury were monitored by increases in pulmonary arterial and airway pressures, wet/dry lung weight ratio, and bronchoalveolar lavage fluid protein content. Estradiol was infused into the pulmonary circulation, beginning 10 min before induction of injury and continued for 60-90 min. Lung injury was marked by significant increases in the above measurements, with paraquat producing the most severe, and excitotoxicity the least severe, injury. Estradiol significantly attenuated the injury in each model. Both ER were constitutively expressed and immunohistochemically demonstrable in normal lung, and their selective agonists reduced anoxic injury, the only model in which they were tested. As it protected against injury, estradiol rapidly and significantly stimulated VIP mRNA expression in rat lung. Estradiol attenuated acute lung injury in three experimental models while stimulating VIP gene expression, a known mechanism of lung protection. The up-regulated VIP expression could have partially mediated the protection by estrogen.

Enhancement of systemic and pulmonary vasoconstriction by beta-amyloid peptides and its suppression by vasoactive intestinal peptide.

(1) A beta peptides potentiate vasoconstriction, caused by norepinephrine, and possibly other endogenous vasoconstrictors. If this potentiation occurs in the cerebral circulation, close to sites of A beta deposition in AD brains, the enhanced vasoconstriction could result in neuronal ischemia and death. (2) By neutralizing this deleterious effect of A beta, and through other neuroprotective mechanisms, VIP may provide an important defense against neuronal loss in AD.

VIP Enhances and Nitric Oxide Synthase Inhibitor Reduces Survival of Rat Lungs Perfused ex Vivo

Abstract VIP delayed the onset of edematous lung injury in isolated perfused rat lungs by 64%, and was more effective than PGI2 in prolonging lung survival ex vivo. While PGI2 increased survival by 37 min versus Krebs/BSA only, VIP increased it by 2 h and 17 min. On the other hand, inhibition of NO. synthase, which protected the lung against oxidant injury caused by paraquat or X/XO,3 actually hastened the onset of injury caused by prolonged perfusion ex vivo, suggesting opposite roles for NO. in different forms of oxidant injury.