dizocilpine-maleate and Hyperoxia

Previous studies have suggested that endogenous glutamate and its N-methyl-D-aspartate receptors (NMDARs) play important roles in hyperoxia-induced acute lung injury in newborn rats. We hypothesized that NMDAR activation also participates in the development of chronic lung injury after withdrawal of hyperoxic conditions.. In order to rule out the anti-inflammatory effects of NMDAR inhibitor on acute lung injury, the efficacy of MK-801 was evaluated in vivo using newborn Sprague-Dawley rats treated starting 4 days after cessation of hyperoxia exposure (on postnatal day 8). The role of NMDAR activation in hyperoxia-induced lung fibroblast proliferation and differentiation was examined in vitro using primary cells derived from the lungs of 8-day-old Sprague-Dawley rats exposed to hyperoxic conditions.. Hyperoxia for 3 days induced acute lung injury in newborn rats. The acute injury almost completely disappeared 4 days after cessation of hyperoxia exposure. However, pulmonary fibrosis, impaired alveolarization, and decreased pulmonary compliance were observed on postnatal days 15 and 22. MK-801 treatment during the recovery period was found to alleviate the chronic damage induced by hyperoxia. Four NMDAR 2 s were found to be upregulated in the lung fibroblasts of newborn rats exposed to hyperoxia. In addition, the proliferation and upregulation of alpha-smooth muscle actin and (pro) collagen I in lung fibroblasts were detected in hyperoxia-exposed rats. MK-801 inhibited these changes.. NMDAR activation mediated lung fibroblast proliferation and differentiation and played a role in the development of hyperoxia-induced chronic lung damage in newborn rats.

Topics: Actins; Animals; Animals, Newborn; Cell Differentiation; Cell Proliferation; Cells, Cultured; Collagen Type I; Disease Models, Animal; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Fibroblasts; Hyperoxia; Lung; Lung Injury; Procollagen; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Time Factors

Rats reared in hyperoxia exhibit a sustained (vs. biphasic) hypoxic ventilatory response (HVR) at an earlier age than untreated, Control rats. Given the similarity between the sustained HVR obtained after chronic exposure to developmental hyperoxia and the mature HVR, it was hypothesized that hyperoxia-induced plasticity and normal maturation share common mechanisms such as enhanced glutamate and nitric oxide signaling and diminished platelet-derived growth factor (PDGF) signaling. Rats reared in 21% O2 (Control) or 60% O2 (Hyperoxia) from birth until 4-5 days of age were studied after intraperitoneal injection of drugs targeting these pathways. Hyperoxia rats receiving saline showed a sustained HVR to 12% O2, but blockade of NMDA glutamate receptors (MK-801) restored the biphasic HVR typical of newborn rats. Blockade of PDGF-β receptors (imatinib) had no effect on the pattern of the HVR in Hyperoxia rats, although it attenuated ventilatory depression during the late phase of the HVR in Control rats. Neither nitric oxide synthase inhibitor used in this study (nNOS inhibitor I and l-NAME) altered the pattern of the HVR in Control or Hyperoxia rats. Drug-induced changes in the biphasic HVR were not correlated with changes in metabolic rate. Collectively, these results suggest that developmental hyperoxia hastens the transition from a biphasic to sustained HVR by upregulating glutamate-dependent mechanisms and downregulating PDGF-dependent mechanisms, similar to the changes underlying normal postnatal maturation of the biphasic HVR.

Topics: Analysis of Variance; Animals; Animals, Newborn; Benzamides; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Enzyme Inhibitors; Glutamic Acid; Hyperoxia; Hypoxia; Imatinib Mesylate; Neuroprotective Agents; NG-Nitroarginine Methyl Ester; Piperazines; Platelet-Derived Growth Factor; Pulmonary Ventilation; Pyrimidines; Rats; Rats, Sprague-Dawley

Our laboratory found that the N-methyl-D-aspartate receptor (NMDAR) antagonist, MK-801, was able to decrease hyperoxia-induced lung damage. To further search for direct evidence of glutamate and its NMDARs participating in hyperoxia-induced lung injury, the amount of glutamate in the bronchoalveolar lavage fluid and the expression of NMDAR 2D in lung tissue were tracked in newborn rats that were exposed to 95% oxygen for 1, 3, and 7 days. The protective effect of MK-801 was then observed at different hyperoxia exposure times. As demonstrated by RT-PCR, NMDAR 2D expression was much higher in hyperoxia exposure on the third and the seventh days than in the air control group. The levels of glutamate in the bronchoalveolar lavage fluid on the first and third days of hyperoxia exposure were significantly higher than in the air control group. MK-801 alleviated lung injury and inflammatory reaction induced by 95% O(2) for 3 and 7 days. These results indicate that large amounts of endogenous glutamate from the lungs were released, and its NMDAR were expressed strongly under conditions of high oxygen concentration. We conclude that the endogenous glutamate mediated newborn rat lung damage induced by hyperoxia through NMDARs.

Topics: Animals; Animals, Newborn; Bronchoalveolar Lavage Fluid; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Female; Glutamic Acid; Hyperoxia; Lung; Lung Injury; Organ Size; Pregnancy; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate

Glutamate (Glu) N-methyl-D-aspartate (NMDA) receptor is present in the lungs, and NMDA receptor antagonist MK-801 attenuates oxidant lung injury. We hypothesized that Glu excitotoxicity may participate in the pathogenesis of hyperoxia-induced lung injury. To determine possible pulmonary protective effects, we administered 0.05 ml/kg MK-801 or saline intraperitoneally daily to neonatal rats exposed to more than 95% oxygen in air. After 7 days, MK-801 decreased the hyperoxia-associated elevation of wet-to-dry lung weight, total leukocyte and neutrophil counts, total protein and lactate dehydroase in BAL fluid, total myeloperoxidase activity, and lung pathological injury. MK-801 inhibited hyperoxia-associated increments in reactive oxygen species production and NF-kappaB production. Hence, NMDA receptor antagonist MK-801 ameliorates hyperoxia-induced lung injury in neonatal rats, and is associated with decreased reactive oxygen species and NF-kappaB. We conclude that Glu may play an important role in hyperoxia-induced lung injury by activation of NMDA receptor.

Topics: Animals; Animals, Newborn; Biomarkers; Bronchoalveolar Lavage Fluid; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Hyperoxia; L-Lactate Dehydrogenase; Leukocyte Count; Lung; Models, Animal; Neoplasm Proteins; Neutrophils; NF-kappa B; Nucleocytoplasmic Transport Proteins; Organ Size; Peroxidase; Proteins; Rats; Rats, Sprague-Dawley; Reactive Oxygen Species; Receptors, N-Methyl-D-Aspartate