The role of NMDA glutamate receptors in lung injury caused by chronic long-term intermittent hypobaric hypoxia

Chronic intermittent hypoxia (CIH), a component of sleep apnea-hypopnea syndrome, is suggested to cause damage to lung tissue, and the role of glutamate is not well studied. We used a chronic long-term intermittent hypobaric hypoxia (CLTIHH) model of rats to find out if such procedure causes lung injury and the potential effect of N-methyl-D-aspartate receptors (NMDARs) by using receptor antagonist MK-801 (dizocilpine). Thirty-two rats were placed into four groups; a control and three CLTIHH groups where rats were placed into a low-pressure chamber set to 430 mmHg for 5 h/day, 5 days/week, for 5 weeks. Only one group received MK-801 (0.3 mg/kg, ip) daily. We evaluated tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-10, and nuclear factor (NF)-kB for the inflammatory process, superoxide dismutase (SOD), malondialdehyde (MDA), catalase (CAT), glutathione peroxidase (GPX), total antioxidant status (TAS), and total oxidant status (TOS) for oxidative stress, and caspase-9 levels. Blood plasma, bronchoalveolar fluid (BALF), and lung tissue extracts were evaluated. Both oxidant and inflammatory parameters were significantly increased in all the mediums of the CLTIHH groups except the group that received MK-801. Significant evidence was collected on MK-801 alleviating the effect of CLTIHH. Histological evaluations revealed lung damage and fibrotic changes in the CLTIHH groups. It was first shown that the CLTIHH procedure caused chronic lung injury, and that inflammation and oxidant stress were influential in the formation of lung injury. Secondly, NMDAR antagonist MK-801 effectively inhibited the development of lung injury and fibrosis.

[1]  P. Siques,et al.  Long-term chronic intermittent hypoxia: a particular form of chronic high-altitude pulmonary hypertension , 2020, Pulmonary circulation.

[2]  E. Gozal,et al.  Metallothionein induction attenuates the progression of lung injury in mice exposed to long-term intermittent hypoxia , 2019, Inflammation Research.

[3]  O. Sonmez,et al.  Protective Effect of Thymosin β4 against Abdominal Aortic Ischemia–Reperfusion-Induced Acute Lung Injury in Rats , 2019, Medicina.

[4]  Yu Cao,et al.  Tempol relieves lung injury in a rat model of chronic intermittent hypoxia via suppression of inflammation and oxidative stress , 2018, Iranian journal of basic medical sciences.

[5]  Liming Cai,et al.  Sinomenine Attenuates Chronic Intermittent Hypoxia-Induced Lung Injury by Inhibiting Inflammation and Oxidative Stress , 2018, Medical science monitor : international medical journal of experimental and clinical research.

[6]  Yi Zhang,et al.  Chronic intermittent hypobaric hypoxia attenuates monocrotaline-induced pulmonary arterial hypertension via modulating inflammation and suppressing NF-κB/p38 pathway , 2018, Iranian journal of basic medical sciences.

[7]  X. He,et al.  Intermittent hypoxia simulating obstructive sleep apnea causes pulmonary inflammation and activates the Nrf2/HO-1 pathway , 2017, Experimental and therapeutic medicine.

[8]  Y. Li,et al.  Angiotensin-(1–7) inhibits inflammation and oxidative stress to relieve lung injury induced by chronic intermittent hypoxia in rats , 2016, Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologicas.

[9]  Jie Du,et al.  Glutamate in peripheral organs: Biology and pharmacology. , 2016, European journal of pharmacology.

[10]  Min Zhang,et al.  [The pulmonary injury in rats caused by chronic intermittent hypoxia and the intervention effect of Edaravone]. , 2015, Lin chuang er bi yan hou tou jing wai ke za zhi = Journal of clinical otorhinolaryngology, head, and neck surgery.

[11]  Wei Liu,et al.  NMDA Receptor Antagonist Attenuates Bleomycin-Induced Acute Lung Injury , 2015, PloS one.

[12]  H. Uzun,et al.  Fluoxetine ameliorates imbalance of redox homeostasis and inflammation in an acute kidney injury model , 2014, Journal of Physiology and Biochemistry.

[13]  Jianbo Sun,et al.  1,8-Cineol Attenuates LPS-Induced Acute Pulmonary Inflammation in Mice , 2014, Inflammation.

[14]  J. Palermo-neto,et al.  Effects of MK-801 and amphetamine treatments on allergic lung inflammatory response in mice. , 2013, International immunopharmacology.

[15]  Y. Karter,et al.  The Effect of Chronic Long-Term Intermittent Hypobaric Hypoxia on Bone Mineral Density in Rats: Role of Nitric Oxide , 2013, Biological Trace Element Research.

[16]  I. Yoshino,et al.  Aberrant methylation of N-methyl-D-aspartate receptor type 2B (NMDAR2B) in non-small cell carcinoma , 2011, BMC Cancer.

[17]  Y. Michotte,et al.  Loss of System xc− Does Not Induce Oxidative Stress But Decreases Extracellular Glutamate in Hippocampus and Influences Spatial Working Memory and Limbic Seizure Susceptibility , 2011, The Journal of Neuroscience.

[18]  R. Roesler,et al.  N-methyl-D-aspartate glutamate receptor blockade attenuates lung injury associated with experimental sepsis. , 2010, Chest.

[19]  S. Lam,et al.  The xc− cystine/glutamate antiporter as a potential therapeutic target for small-cell lung cancer: use of sulfasalazine , 2009, Cancer Chemotherapy and Pharmacology.

[20]  Lian Li,et al.  Glutamate mediates hyperoxia-induced newborn rat lung injury through N-methyl-D-aspartate receptors. , 2009, American journal of respiratory cell and molecular biology.

[21]  T. Wynn,et al.  Pulmonary fibrosis: pathogenesis, etiology and regulation , 2009, Mucosal Immunology.

[22]  Michael L. Smith,et al.  Intermittent Hypoxia: Cause of or Therapy for Systemic Hypertension? , 2008, Experimental biology and medicine.

[23]  E. Riley,et al.  IL-10: The Master Regulator of Immunity to Infection , 2008, The Journal of Immunology.

[24]  H. Bolte,et al.  Standardized quantification of pulmonary fibrosis in histological samples. , 2008, BioTechniques.

[25]  Ibrahim Guner,et al.  Respiratory alterations due to chronic long-term intermittent hypobaric hypoxia in rabbits: importance of peripheral chemoreceptors. , 2007, Archives of medical research.

[26]  I. Adcock,et al.  Oxidative stress and redox regulation of lung inflammation in COPD , 2006, European Respiratory Journal.

[27]  K. Dickman,et al.  Ionotropic glutamate receptors in lungs and airways: molecular basis for glutamate toxicity. , 2004, American journal of respiratory cell and molecular biology.

[28]  J. Weiss,et al.  Ca2+-Permeable AMPA/Kainate and NMDA Channels: High Rate of Ca2+ Influx Underlies Potent Induction of Injury , 1996, The Journal of Neuroscience.

[29]  A. Chaouat,et al.  Pulmonary hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences. , 1996, The European respiratory journal.

[30]  M. Beal.  Mechanisms of excitotoxicity in neurologic diseases , 1992, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  Min Zhang,et al.  [Protective Effect of Angiotensin Converting Enzyme 2 (ACE2) Against Chronic Intermittent Hypoxia-induced Pulmonary Oxidative Stress Injury in Rats]. , 2016, Sichuan da xue xue bao. Yi xue ban = Journal of Sichuan University. Medical science edition.

[32]  H. Uzun,et al.  The effects of acute intermittent hypoxia on cardiovascular parameters in normotensive and chronic hypobaric hypoxia-induced hypertensive rabbits. , 2014, General physiology and biophysics.

[33]  Semra Ozdemir,et al.  The effects of chronic long-term intermittent hypobaric hypoxia on blood rheology parameters. , 2011, General physiology and biophysics.

[34]  W. Seeger,et al.  Serum levels of vascular endothelial growth factor are elevated in patients with obstructive sleep apnea and severe nighttime hypoxia. , 2002, American journal of respiratory and critical care medicine.

[35]  T. Serebrovskaya.  Intermittent hypoxia research in the former soviet union and the commonwealth of independent States: history and review of the concept and selected applications. , 2002, High altitude medicine & biology.

[36]  K. Prowse,et al.  Sleep apnoea. , 1988, British journal of diseases of the chest.

[37]  Judith A. Neubauer.  highlighted topics Physiological and Genomic Consequences of Intermittent Hypoxia Invited Review: Physiological and pathophysiological responses to intermittent hypoxia , 2022 .

[38]  P. Kovacic,et al.  review Oxidative Medicine and Cellular Longevity 3:1, 13-22; January/February 2010; © 2010 Landes Bioscience REVIEW Clinical physiology and mechanism of dizocilpine (MK-801) Electron transfer, radicals, redox metabolites and bioactivity , 2022 .