{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T02:27:35Z","timestamp":1760149655598,"version":"build-2065373602"},"reference-count":50,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T00:00:00Z","timestamp":1692748800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Defense Health Program","award":["F1604"],"award-info":[{"award-number":["F1604"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Our aim was to identify proteins that reflect an acute systemic response to prolonged hyperbaric stress and discover potential biomarker pathways for pulmonary O2 toxicity. The study was a double-blind, randomized, crossover design in trained male Navy diver subjects. Each subject completed two dry resting hyperbaric chamber dives separated by a minimum of one week. One dive exposed the subject to 6.5 h of 100% oxygen (O2) at 2ATA. The alternate dive exposed the subjects to an enhanced air nitrox mixture (EAN) containing 30.6% O2 at the same depth for the same duration. Venous blood samples collected before (PRE) and after (POST) each dive were prepared and submitted to LC-MS\/MS analysis (2 h runs). A total of 346 total proteins were detected and analyzed. A total of 12 proteins were significantly increased at EANPOST (vs. EANPRE), including proteins in hemostasis and immune signaling and activation. Significantly increased proteins at O2PRE (vs. O2POST) included neural cell adhesion molecule 1, glycoprotein Ib, catalase, hemoglobin subunit beta, fibulin-like proteins, and complement proteins. EANPOST and O2POST differed in biomarkers related to coagulation, immune signaling and activation, and metabolism. Of particular interest is (EANPOST vs. O2POST), which is protective against oxidative stress.<\/jats:p>","DOI":"10.3390\/metabo13090970","type":"journal-article","created":{"date-parts":[[2023,8,23]],"date-time":"2023-08-23T08:20:30Z","timestamp":1692778830000},"page":"970","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plasma Proteomics-Based Discovery of Mechanistic Biomarkers of Hyperbaric Stress and Pulmonary Oxygen Toxicity"],"prefix":"10.3390","volume":"13","author":[{"given":"Kyle J.","family":"Mahoney","sequence":"first","affiliation":[{"name":"Department of Kinesiology, University of Connecticut, Storrs, CT 06269, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6055-8220","authenticated-orcid":false,"given":"Jacob S.","family":"Bowie","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, University of Connecticut, Storrs, CT 06269, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Austin E.","family":"Ford","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, University of Connecticut, Storrs, CT 06269, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Neranjan","family":"Perera","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, University of Connecticut, Storrs, CT 06269, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2972-8738","authenticated-orcid":false,"given":"Yasuki","family":"Sekiguchi","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, University of Connecticut, Storrs, CT 06269, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6251-3774","authenticated-orcid":false,"given":"David M.","family":"Fothergill","sequence":"additional","affiliation":[{"name":"Naval Submarine Medical Research Laboratory, Groton, CT 06349, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Elaine C.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Kinesiology, University of Connecticut, Storrs, CT 06269, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2023,8,23]]},"reference":[{"unstructured":"Moon, R. (2019). Undersea and Hyperbaric Medicine Society, Hyperbaric Oxygen Therapy Indiciations, Best Publishing. [14th ed.].","key":"ref_1"},{"doi-asserted-by":"crossref","unstructured":"Yuan, Y., Zhou, Y., Li, Y., Hill, C., Ewing, R.M., Jones, M.G., Davies, D.E., Jiang, Z., and Wang, Y. (2020). Deconvolution of RNA-Seq Analysis of Hyperbaric Oxygen-Treated Mice Lungs Reveals Mesenchymal Cell Subtype Changes. Int. J. Mol. Sci., 21.","key":"ref_2","DOI":"10.3390\/ijms21041371"},{"key":"ref_3","first-page":"759","article-title":"RNA sequencing analysis reveals new findings of hyperbaric oxygen treatment on rats with acute carbon monoxide poisoning","volume":"43","author":"Wang","year":"2016","journal-title":"Undersea Hyperb. Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"8743","DOI":"10.4081\/idr.2020.8743","article-title":"Hyperbaric hyperoxia exposure in suppressing human immunodeficiency virus replication: An experimental in vitro in peripheral mononuclear blood cells culture","volume":"12","author":"Budiarti","year":"2020","journal-title":"Infect. Dis. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1152\/japplphysiol.00434.2001","article-title":"Modeling pulmonary and CNS O(2) toxicity and estimation of parameters for humans","volume":"92","author":"Arieli","year":"2002","journal-title":"J. Appl. Physiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5383","DOI":"10.1021\/ac025747h","article-title":"Empirical statistical model to estimate the accuracy of peptide identifications made by MS\/MS and database search","volume":"74","author":"Keller","year":"2002","journal-title":"Anal. Chem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1265","DOI":"10.1002\/pmic.200900437","article-title":"Scaffold: A bioinformatic tool for validating MS\/MS-based proteomic studies","volume":"10","author":"Searle","year":"2010","journal-title":"Proteomics"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1021\/pr070540w","article-title":"Improving sensitivity by probabilistically combining results from multiple MS\/MS search methodologies","volume":"7","author":"Searle","year":"2008","journal-title":"J. Proteome Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"713","DOI":"10.1042\/BJ20111166","article-title":"Selective reduction of hydroperoxyeicosatetraenoic acids to their hydroxy derivatives by apolipoprotein D: Implications for lipid antioxidant activity and Alzheimer\u2019s disease","volume":"442","author":"Bhatia","year":"2012","journal-title":"Biochem. J."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1111\/j.1474-9726.2008.00395.x","article-title":"Apolipoprotein D is involved in the mechanisms regulating protection from oxidative stress","volume":"7","author":"Ganfornina","year":"2008","journal-title":"Aging Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"17023","DOI":"10.1073\/pnas.1315986110","article-title":"Identification of apolipoprotein D as a cardioprotective gene using a mouse model of lethal atherosclerotic coronary artery disease","volume":"110","author":"Tsukamoto","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","first-page":"260482","article-title":"Consequences of hyperoxia and the toxicity of oxygen in the lung","volume":"2011","author":"Mach","year":"2011","journal-title":"Nurs. Res. Pract."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"601","DOI":"10.3892\/mmr.2021.12239","article-title":"Pulmonary coagulation and fibrinolysis abnormalities that favor fibrin deposition in the lungs of mouse antibody-mediated transfusion-related acute lung injury","volume":"24","author":"Yu","year":"2021","journal-title":"Mol. Med. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"571","DOI":"10.1111\/jth.14685","article-title":"Effects of nebulized antithrombin and heparin on inflammatory and coagulation alterations in an acute lung injury model in rats","volume":"18","author":"Tantinya","year":"2020","journal-title":"J. Thromb. Haemost."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"L967","DOI":"10.1152\/ajplung.90349.2008","article-title":"The fibrinolytic system and the regulation of lung epithelial cell proteolysis, signaling, and cellular viability","volume":"295","author":"Shetty","year":"2008","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"S213","DOI":"10.1097\/01.CCM.0000057846.21303.AB","article-title":"Coagulation, fibrinolysis, and fibrin deposition in acute lung injury","volume":"31","author":"Idell","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"L463","DOI":"10.1152\/ajplung.00099.2011","article-title":"Regulation of alveolar epithelial cell apoptosis and pulmonary fibrosis by coordinate expression of components of the fibrinolytic system","volume":"302","author":"Bhandary","year":"2012","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1007\/BF00422896","article-title":"Blood biochemical factors in humans resistant and susceptible to formation of venous gas emboli during decompression","volume":"55","author":"Jauchem","year":"1986","journal-title":"Eur. J. Appl. Physiol. Occup. Physiol."},{"key":"ref_19","first-page":"31","article-title":"Complement system response to decompression","volume":"23","author":"Pekna","year":"1996","journal-title":"Undersea Hyperb. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1152\/jappl.1987.62.3.1160","article-title":"Relation between complement activation and susceptibility to decompression sickness","volume":"62","author":"Ward","year":"1987","journal-title":"J. Appl. Physiol."},{"key":"ref_21","first-page":"51","article-title":"Complement activation involvement in decompression sickness of rabbits","volume":"17","author":"Ward","year":"1990","journal-title":"Undersea Biomed. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1152\/japplphysiol.00811.2010","article-title":"Microparticles initiate decompression-induced neutrophil activation and subsequent vascular injuries","volume":"110","author":"Thom","year":"2011","journal-title":"J. Appl. Physiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"839632","DOI":"10.3389\/fimmu.2022.839632","article-title":"Venous Air Embolism Activates Complement C3 Without Corresponding C5 Activation and Trigger Thromboinflammation in Pigs","volume":"13","author":"Storm","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"144874","DOI":"10.1016\/j.gene.2020.144874","article-title":"Apolipoprotein D","volume":"756","author":"Rassart","year":"2020","journal-title":"Gene"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.3390\/antiox12051027","article-title":"Apolipoprotein D in Oxidative Stress and Inflammation","volume":"12","author":"Desmarais","year":"2023","journal-title":"Antioxidants"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"037105","DOI":"10.1088\/1752-7163\/acd715","article-title":"Exhaled breath condensate profiles of U.S. Navy divers following prolonged hyperbaric oxygen (HBO) and nitrogen-oxygen (Nitrox) chamber exposures","volume":"17","author":"Fothergill","year":"2023","journal-title":"J. Breath Res."},{"unstructured":"Fothergill, D.M., and Ross, W. (2018, January 23\u201329). Impulse oscillometry and spirometry indices of pulmonary function in a diver with severe symptoms of pulmonary oxygen toxicity, TRICON2018. Proceedings of the Second Tricontinental Conference on Diving and Hyperbaric Medicine, Durban, South Africa.","key":"ref_27"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"L229","DOI":"10.1152\/ajplung.00450.2006","article-title":"Similar but not the same: Normobaric and hyperbaric pulmonary oxygen toxicity, the role of nitric oxide","volume":"293","author":"Demchenko","year":"2007","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"L102","DOI":"10.1152\/ajplung.00178.2010","article-title":"Autonomic activation links CNS oxygen toxicity to acute cardiogenic pulmonary injury","volume":"300","author":"Demchenko","year":"2011","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1378\/chest.130.3.724","article-title":"Etiology and outcomes of pulmonary and extrapulmonary acute lung injury\/ARDS in a respiratory ICU in North India","volume":"130","author":"Agarwal","year":"2006","journal-title":"Chest"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e00282","DOI":"10.14814\/phy2.282","article-title":"Female rats are more susceptible to central nervous system oxygen toxicity than male rats","volume":"2","author":"Held","year":"2014","journal-title":"Physiol. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.taap.2013.06.007","article-title":"Sex-specific differences in hyperoxic lung injury in mice: Implications for acute and chronic lung disease in humans","volume":"272","author":"Lingappan","year":"2013","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1679","DOI":"10.1097\/00003246-200208000-00001","article-title":"Race and gender differences in acute respiratory distress syndrome deaths in the United States: An analysis of multiple-cause mortality data (1979\u20131996)","volume":"30","author":"Moss","year":"2002","journal-title":"Crit. Care Med."},{"key":"ref_34","first-page":"R475","article-title":"Castration prolongs tolerance of young male rats to pulmonary O2 toxicity","volume":"247","author":"Neriishi","year":"1984","journal-title":"Am. J. Physiol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1038\/s42255-022-00591-z","article-title":"Guidelines for measuring reactive oxygen species and oxidative damage in cells and in vivo","volume":"4","author":"Murphy","year":"2022","journal-title":"Nat. Metab."},{"doi-asserted-by":"crossref","unstructured":"Balestra, C., Arya, A.K., Leveque, C., Virgili, F., Germonpre, P., Lambrechts, K., Lafere, P., and Thom, S.R. (2022). Varying Oxygen Partial Pressure Elicits Blood-Borne Microparticles Expressing Different Cell-Specific Proteins-Toward a Targeted Use of Oxygen?. Int. J. Mol. Sci., 23.","key":"ref_36","DOI":"10.3390\/ijms23147888"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2220\/biomedres.42.1","article-title":"Mild hyperbaric oxygen exposure attenuates rarefaction of capillary vessels in streptozotocin-induced diabetic soleus muscle in rats","volume":"42","author":"Tanaka","year":"2021","journal-title":"Biomed. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1203\/00006450-199305000-00020","article-title":"Developmental differences in catalase activity and hypoxic-hyperoxic effects on fluid balance in isolated lamb lungs","volume":"33","author":"Bonuccelli","year":"1993","journal-title":"Pediatr. Res."},{"key":"ref_39","first-page":"259","article-title":"Hyperbaric oxygen pretreatment and preconditioning","volume":"41","author":"Camporesi","year":"2014","journal-title":"Undersea Hyperb. Med."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.brainres.2014.05.051","article-title":"A comparison of factors involved in the development of central nervous system and pulmonary oxygen toxicity in the rat","volume":"1574","author":"Eynan","year":"2014","journal-title":"Brain Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"21","DOI":"10.22462\/01.03.2020.3","article-title":"Hyperbaric oxygenation protects the kidney against ischemia-reperfusion injury","volume":"47","author":"Ivanov","year":"2020","journal-title":"Undersea Hyperb. Med."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"9","DOI":"10.4196\/kjpp.2023.27.1.9","article-title":"Hyperbaric oxygenation applied before or after mild or hard stress: Effects on the redox state in the muscle tissue","volume":"27","author":"Kormanovski","year":"2023","journal-title":"Korean J. Physiol. Pharmacol."},{"doi-asserted-by":"crossref","unstructured":"Peterson, A.L., Carr, J.F., Ji, X., Dennery, P.A., and Yao, H. (2020). Hyperoxic Exposure Caused Lung Lipid Compositional Changes in Neonatal Mice. Metabolites, 10.","key":"ref_43","DOI":"10.3390\/metabo10090340"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"318","DOI":"10.1002\/ppul.1950110408","article-title":"Prevention of chronic pulmonary oxygen toxicity in young rats with liposome-encapsulated catalase administered intratracheally","volume":"11","author":"Thibeault","year":"1991","journal-title":"Pediatr. Pulmonol."},{"doi-asserted-by":"crossref","unstructured":"Perroud, C., Porret, N., and Rovo, A. (2023). \u201cThe long journey of unexplained erythrocytosis\u201d. Erythrocytosis due to high oxygen affinity hemoglobinopathy\u2014Hemoglobin variant Little Rock (HBB:C.432C>A)\u2014A report of a Swiss Family and review of the literature. Acta Haematol., online ahead of print.","key":"ref_45","DOI":"10.1159\/000530240"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1186\/s40246-022-00395-y","article-title":"Human adaptation to high altitude: A review of convergence between genomic and proteomic signatures","volume":"16","author":"Sharma","year":"2022","journal-title":"Hum. Genom."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"394","DOI":"10.1007\/s10753-014-0043-7","article-title":"Early diagnosis of sepsis using serum hemoglobin subunit Beta","volume":"38","author":"Yoo","year":"2015","journal-title":"Inflammation"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"835","DOI":"10.1006\/bbrc.2000.2205","article-title":"Apolipoprotein E and apolipoprotein D expression in a murine model of singlet oxygen-induced cerebral stroke","volume":"268","author":"Trieu","year":"2000","journal-title":"Biochem. Biophys. Res. Commun."},{"doi-asserted-by":"crossref","unstructured":"Domoto, H., Iwaya, K., Ikomi, F., Matsuo, H., Tadano, Y., Fujii, S., Tachi, K., Itoh, Y., Sato, M., and Inoue, K. (2016). Up-Regulation of Antioxidant Proteins in the Plasma Proteome during Saturation Diving: Unique Coincidence under Hypobaric Hypoxia. PLoS ONE, 11.","key":"ref_49","DOI":"10.1371\/journal.pone.0163804"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1002\/prca.201600017","article-title":"Effect of simulated air dive and decompression sickness on the plasma proteome of rats","volume":"10","author":"Lautridou","year":"2016","journal-title":"Proteom. Clin. Appl."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/9\/970\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T20:40:07Z","timestamp":1760128807000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/13\/9\/970"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,8,23]]},"references-count":50,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2023,9]]}},"alternative-id":["metabo13090970"],"URL":"https:\/\/doi.org\/10.3390\/metabo13090970","relation":{},"ISSN":["2218-1989"],"issn-type":[{"type":"electronic","value":"2218-1989"}],"subject":[],"published":{"date-parts":[[2023,8,23]]}}}