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Article: Characteristics and Determinants of Pulmonary Long COVID.

Patton, Michael John / Benson, Donald / Robison, Sarah W / Dhaval, Raval / Locy, Morgan L / Patel, Kinner / Grumley, Scott / Levitan, Emily B / Morris, Peter / Might, Matthew / Gaggar, Amit / Erdmann, Nathaniel

medRxiv : the preprint server for health sciences

2024

Abstract: Rationale: Persistent cough and dyspnea are prominent features of post-acute sequelae of SARS-CoV-2 (termed 'Long COVID'); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined.: Objectives!# ...

Abstract	Rationale: Persistent cough and dyspnea are prominent features of post-acute sequelae of SARS-CoV-2 (termed 'Long COVID'); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined. Objectives: Using longitudinal pulmonary function testing (PFTs) and CT imaging, this study aimed to identify the characteristics and determinants of pulmonary Long COVID. Methods: The University of Alabama at Birmingham Pulmonary Long COVID cohort was utilized to characterize lung defects in patients with persistent pulmonary symptoms after resolution primary COVID infection. Longitudinal PFTs including total lung capacity (TLC) and diffusion limitation of carbon monoxide (DLCO) were used to evaluate restriction and diffusion impairment over time in this cohort. Analysis of chest CT imaging was used to phenotype the pulmonary Long COVID pathology. Risk factors linked to development of pulmonary Long COVID were estimated using univariate and multivariate logistic regression models. Measurements and main results: Longitudinal evaluation 929 patients with post-COVID pulmonary symptoms revealed diffusion impairment (DLCO ≤80%) and restriction (TLC ≤80%) in 51% of the cohort (n=479). In multivariable logistic regression analysis (adjusted odds ratio; aOR, 95% confidence interval [CI]), invasive mechanical ventilation during primary infection conferred the greatest increased odds of developing pulmonary Long COVID with diffusion impaired restriction (aOR=10.9 [4.09-28.6]). Finally, a sub-analysis of CT imaging identified evidence of fibrosis in this population. Conclusions: Persistent diffusion impaired restriction was identified as a key feature of pulmonary Long COVID. Subsequent clinical trials should leverage combined symptomatic and quantitative PFT measurements for more targeted enrollment of pulmonary Long COVID patients.
Language	English
Publishing date	2024-02-14
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.13.24302781
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Article ; Online: Characteristics and Determinants of Pulmonary Long COVID.

Patton, Michael John / Benson, Donald / Robison, Sarah W / Raval, Dhaval / Locy, Morgan L / Patel, Kinner / Grumley, Scott / Levitan, Emily B / Morris, Peter / Might, Matthew / Gaggar, Amit / Erdmann, Nathaniel

JCI insight

2024

Abstract: BACKGROUNDPersistent cough and dyspnea are prominent features of post-acute sequelae of SARS-CoV-2 (also termed 'Long COVID'); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined. Using ... ...

Abstract	BACKGROUNDPersistent cough and dyspnea are prominent features of post-acute sequelae of SARS-CoV-2 (also termed 'Long COVID'); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined. Using longitudinal pulmonary function testing (PFTs) and CT imaging, this study aimed to identify the characteristics and determinants of pulmonary Long COVID.METHODSThis single-center retrospective study included 1,097 patients with clinically defined Long COVID characterized by persistent pulmonary symptoms (dyspnea, cough, and chest discomfort) lasting for ≥1 month after resolution of primary COVID infection.RESULTSAfter exclusion, a total of 929 patients with post-COVID pulmonary symptoms and PFTs were stratified diffusion impairment and restriction as measured by percent predicted diffusion capacity for carbon monoxide (DLCO) and total lung capacity (TLC). Dyspnea was the predominant symptom in the cohort (78%) and had similar prevalence regardless of degree of diffusion impairment or restriction. Longitudinal evaluation revealed diffusion impairment (DLCO ≤80%) and pulmonary restriction (TLC ≤80%) in 51% of the cohort overall (n=479). In multivariable logistic regression analysis (adjusted odds ratio; aOR, 95% confidence interval [CI]), invasive mechanical ventilation during primary infection conferred the greatest increased odds of developing pulmonary Long COVID with diffusion impairment and restriction (aOR=10.9 [4.09-28.6]). Finally, a sub-analysis of CT imaging identified radiographic evidence of fibrosis in this patient population.CONCLUSIONSLongitudinal PFT measurements in patients with prolonged pulmonary symptoms after SARS-CoV-2 infection revealed persistent diffusion impaired restriction as a key feature of pulmonary Long COVID. These results emphasize the importance of incorporating PFTs into routine clinical practice for evaluation of patients with prolonged pulmonary symptoms after resolution of SARS-CoV-2. Subsequent clinical trials should leverage combined symptomatic and quantitative PFT measurements for more targeted enrollment of pulmonary Long COVID patients.FUNDINGThis work was supported by the National Institute of Allergy and Infectious Diseases (AI156898, K08AI129705), the National Heart, Lung, and Blood Institute (HL153113, OTA21-015E, HL149944), and the COVID-19 Urgent Research Response Fund established by the Hugh Kaul Precision Medicine Network at the University of Alabama at Birmingham.
Language	English
Publishing date	2024-04-23
Publishing country	United States
Document type	Journal Article
ISSN	2379-3708
ISSN (online)	2379-3708
DOI	10.1172/jci.insight.177518
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Article ; Online: Characteristics and Determinants of Pulmonary Long COVID

Patton, Michael John / Benson, Donald / Robison, Sarah W. / Dhaval, Raval / Locy, Morgan L. / Patel, Kinner / Grumley, Scott / Levitan, Emily B. / Morris, Peter / Might, Matthew / Gaggar, Amit / Erdmann, Nathaniel

medRxiv

Abstract: RATIONALE: Persistent cough and dyspnea are prominent features of post-acute sequelae of SARS-CoV-2 (termed 9Long COVID9); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined. OBJECTIVES: ... ...

Abstract	RATIONALE: Persistent cough and dyspnea are prominent features of post-acute sequelae of SARS-CoV-2 (termed 9Long COVID9); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined. OBJECTIVES: Using longitudinal pulmonary function testing (PFTs) and CT imaging, this study aimed to identify the characteristics and determinants of pulmonary Long COVID. METHODS: The University of Alabama at Birmingham Pulmonary Long COVID cohort was utilized to characterize lung defects in patients with persistent pulmonary symptoms after resolution primary COVID infection. Longitudinal PFTs including total lung capacity (TLC) and diffusion limitation of carbon monoxide (DLCO) were used to evaluate restriction and diffusion impairment over time in this cohort. Analysis of chest CT imaging was used to phenotype the pulmonary Long COVID pathology. Risk factors linked to development of pulmonary Long COVID were estimated using univariate and multivariate logistic regression models. MEASUREMENTS AND MAIN RESULTS: Longitudinal evaluation 929 patients with post-COVID pulmonary symptoms revealed diffusion impairment (DLCO ≤80%) and restriction (TLC ≤80%) in 51% of the cohort (n=479). In multivariable logistic regression analysis (adjusted odds ratio; aOR, 95% confidence interval [CI]), invasive mechanical ventilation during primary infection conferred the greatest increased odds of developing pulmonary Long COVID with diffusion impaired restriction (aOR=10.9 [4.09-28.6]). Finally, a sub-analysis of CT imaging identified evidence of fibrosis in this population. CONCLUSIONS: Persistent diffusion impaired restriction was identified as a key feature of pulmonary Long COVID. Subsequent clinical trials should leverage combined symptomatic and quantitative PFT measurements for more targeted enrollment of pulmonary Long COVID patients.
Keywords	covid19
Language	English
Publishing date	2024-02-14
Publisher	Cold Spring Harbor Laboratory Press
Document type	Article ; Online
DOI	10.1101/2024.02.13.24302781
Database	COVID19

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Article ; Online: The thioredoxin reductase inhibitor auranofin induces heme oxygenase-1 in lung epithelial cells via Nrf2-dependent mechanisms.

Dunigan, Katelyn / Li, Qian / Li, Rui / Locy, Morgan L / Wall, Stephanie / Tipple, Trent E

American journal of physiology. Lung cellular and molecular physiology

2018 Volume 315, Issue 4, Page(s) L545–L552

Abstract: Thioredoxin reductase-1 (TXNRD1) inhibition effectively activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) responses and attenuates lung injury in acute respiratory distress syndrome (ARDS) and bronchopulmonary dysplasia (BPD) models. Upon ... ...

Abstract	Thioredoxin reductase-1 (TXNRD1) inhibition effectively activates nuclear factor (erythroid-derived 2)-like 2 (Nrf2) responses and attenuates lung injury in acute respiratory distress syndrome (ARDS) and bronchopulmonary dysplasia (BPD) models. Upon TXNRD1 inhibition, heme oxygenase-1 (HO-1) is disproportionally increased compared with Nrf2 target NADPH quinone oxidoreductase-1 (Nqo1). HO-1 has been investigated as a potential therapeutic target in both ARDS and BPD. TXNRD1 is predominantly expressed in airway epithelial cells; however, the mechanism of HO-1 induction by TXNRD1 inhibitors is unknown. We tested the hypothesis that TXNRD1 inhibition induces HO-1 via Nrf2-dependent mechanisms. Wild-type (WT), Nrf2
MeSH term(s)	Animals ; Antirheumatic Agents/pharmacology ; Auranofin/pharmacology ; Cells, Cultured ; Epithelial Cells/drug effects ; Epithelial Cells/enzymology ; Gene Expression Regulation, Enzymologic/drug effects ; Heme Oxygenase-1/genetics ; Heme Oxygenase-1/metabolism ; Lung/drug effects ; Lung/enzymology ; Membrane Proteins/genetics ; Membrane Proteins/metabolism ; Mice ; Mice, Inbred C3H ; Mice, Knockout ; NF-E2-Related Factor 2/physiology ; Thioredoxin Reductase 1/antagonists & inhibitors ; Thioredoxin Reductase 1/physiology
Chemical Substances	Antirheumatic Agents ; Membrane Proteins ; NF-E2-Related Factor 2 ; Nfe2l2 protein, mouse ; Auranofin (3H04W2810V) ; Heme Oxygenase-1 (EC 1.14.14.18) ; Hmox1 protein, mouse (EC 1.14.14.18) ; Thioredoxin Reductase 1 (EC 1.8.1.9) ; Txnrd1 protein, mouse (EC 1.8.1.9)
Language	English
Publishing date	2018-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	1013184-x
ISSN	1522-1504 ; 1040-0605
ISSN (online)	1522-1504
ISSN	1040-0605
DOI	10.1152/ajplung.00214.2018
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Article ; Online: Targeted Therapy for Idiopathic Pulmonary Fibrosis: Where To Now?

Rangarajan, Sunad / Locy, Morgan L / Luckhardt, Tracy R / Thannickal, Victor J

Drugs

2016 Volume 76, Issue 3, Page(s) 291–300

Abstract: Idiopathic pulmonary fibrosis (IPF) is an aging-associated, recalcitrant lung disease with historically limited therapeutic options. The recent approval of two drugs, pirfenidone and nintedanib, by the US Food and Drug Administration in 2014 has heralded ...

Abstract	Idiopathic pulmonary fibrosis (IPF) is an aging-associated, recalcitrant lung disease with historically limited therapeutic options. The recent approval of two drugs, pirfenidone and nintedanib, by the US Food and Drug Administration in 2014 has heralded a new era in its management. Both drugs have demonstrated efficacy in phase III clinical trials by retarding the rate of progression of IPF; neither drug appears to be able to completely arrest disease progression. Advances in the understanding of IPF pathobiology have led to an unprecedented expansion in the number of potential therapeutic targets. Drugs targeting several of these are under investigation in various stages of clinical development. Here, we provide a brief overview of the drugs that are currently approved and others in phase II clinical trials. Future therapeutic opportunities that target novel pathways, including some that are associated with the biology of aging, are examined. A multi-targeted approach, potentially with combination therapies, and identification of individual patients (or subsets of patients) who may respond more favourably to specific agents are likely to be more effective.
MeSH term(s)	Aging/drug effects ; Aging/metabolism ; Aging/pathology ; Clinical Trials, Phase II as Topic ; Drug Approval ; Humans ; Idiopathic Pulmonary Fibrosis/drug therapy ; Idiopathic Pulmonary Fibrosis/metabolism ; Idiopathic Pulmonary Fibrosis/pathology ; Indoles/administration & dosage ; Indoles/adverse effects ; Indoles/pharmacokinetics ; Indoles/therapeutic use ; Molecular Targeted Therapy ; Pyridones/administration & dosage ; Pyridones/adverse effects ; Pyridones/pharmacokinetics ; Pyridones/therapeutic use
Chemical Substances	Indoles ; Pyridones ; pirfenidone (D7NLD2JX7U) ; nintedanib (G6HRD2P839)
Language	English
Publishing date	2016-01-04
Publishing country	New Zealand
Document type	Journal Article ; Review
ZDB-ID	120316-2
ISSN	1179-1950 ; 0012-6667
ISSN (online)	1179-1950
ISSN	0012-6667
DOI	10.1007/s40265-015-0523-6
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Article ; Online: Mitochondrial uncoupling protein-2 reprograms metabolism to induce oxidative stress and myofibroblast senescence in age-associated lung fibrosis.

Rangarajan, Sunad / Locy, Morgan L / Chanda, Diptiman / Kurundkar, Ashish / Kurundkar, Deepali / Larson-Casey, Jennifer L / Londono, Pilar / Bagchi, Rushita A / Deskin, Brian / Elajaili, Hanan / Nozik, Eva S / Deshane, Jessy S / Zmijewski, Jaroslaw W / Eickelberg, Oliver / Thannickal, Victor J

Aging cell

2022 Volume 21, Issue 9, Page(s) e13674

Abstract: Mitochondrial dysfunction has been associated with age-related diseases, including idiopathic pulmonary fibrosis (IPF). We provide evidence that implicates chronic elevation of the mitochondrial anion carrier protein, uncoupling protein-2 (UCP2), in ... ...

Abstract	Mitochondrial dysfunction has been associated with age-related diseases, including idiopathic pulmonary fibrosis (IPF). We provide evidence that implicates chronic elevation of the mitochondrial anion carrier protein, uncoupling protein-2 (UCP2), in increased generation of reactive oxygen species, altered redox state and cellular bioenergetics, impaired fatty acid oxidation, and induction of myofibroblast senescence. This pro-oxidant senescence reprogramming occurs in concert with conventional actions of UCP2 as an uncoupler of oxidative phosphorylation with dissipation of the mitochondrial membrane potential. UCP2 is highly expressed in human IPF lung myofibroblasts and in aged fibroblasts. In an aging murine model of lung fibrosis, the in vivo silencing of UCP2 induces fibrosis regression. These studies indicate a pro-fibrotic function of UCP2 in chronic lung disease and support its therapeutic targeting in age-related diseases associated with impaired tissue regeneration and organ fibrosis.
MeSH term(s)	Aged ; Animals ; Fibroblasts/metabolism ; Fibrosis ; Humans ; Idiopathic Pulmonary Fibrosis/metabolism ; Lung/metabolism ; Mice ; Myofibroblasts/metabolism ; Oxidative Stress ; Reactive Oxygen Species/metabolism ; Uncoupling Protein 2/genetics ; Uncoupling Protein 2/metabolism
Chemical Substances	Reactive Oxygen Species ; UCP2 protein, human ; Ucp2 protein, mouse ; Uncoupling Protein 2
Language	English
Publishing date	2022-08-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2113083-8
ISSN	1474-9726 ; 1474-9718
ISSN (online)	1474-9726
ISSN	1474-9718
DOI	10.1111/acel.13674
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Article ; Online: Reversing Mechanoinductive DSP Expression by CRISPR/dCas9-mediated Epigenome Editing.

Qu, Jing / Zhu, Lanyan / Zhou, Zijing / Chen, Ping / Liu, Shuyan / Locy, Morgan L / Thannickal, Victor J / Zhou, Yong

American journal of respiratory and critical care medicine

2018 Volume 198, Issue 5, Page(s) 599–609

Abstract: Rationale: DSP (desmoplakin), the most abundant component of desmosomes, which maintain the mechanical integrity of epithelium, is a genome-wide association study-identified genetic risk locus in human idiopathic pulmonary fibrosis (IPF). Subjects with ... ...

Abstract	Rationale: DSP (desmoplakin), the most abundant component of desmosomes, which maintain the mechanical integrity of epithelium, is a genome-wide association study-identified genetic risk locus in human idiopathic pulmonary fibrosis (IPF). Subjects with IPF express a significantly higher level of DSP than control subjects. Objectives: Determine potential mechanisms by which DSP is regulated in lung fibrosis. Methods: Matrigel-coated soft and stiff polyacrylamide gels were made to simulate the stiffness of normal and fibrotic lungs. Quantitative chromatin immunoprecipitation and electrophoretic mobility shift assay were used to evaluate transcription factor binding to the DSP promoter. Targeted DNA methylation was achieved by CRISPR (clustered regularly interspaced short palindromic repeats)/dCas9 (deactivated CRISPR-associated protein-9 nuclease)-mediated Dnmt3A (DNA methyltransferase 3A) expression under the guidance of sequence-specific single guide RNAs. Measurements and main results: Stiff matrix promotes DSP gene expression in both human and rodent lung epithelial cells as compared with soft matrix. A conserved region in the proximal DSP promoter is hypermethylated under soft matrix conditions and becomes hypomethylated/demethylated under stiff matrix conditions. Demethylation of this conserved DSP promoter region is associated with transactivation of transcription factor EGR1 (early growth response protein 1), resulting in EGR1-dependent DSP overexpression. Targeted DNA methylation by CRISPR/dCas9/Dnmt3A-mediated epigenome editing blocks EGR1 binding to the DSP promoter and inhibits stiff matrix-induced DSP overexpression. Conclusions: DSP is a matrix stiffness-regulated mechanosensitive gene. CRISPR/dCas9-Dnmt3A-mediated epigenome editing reverses DSP overexpression by reestablishment of the epigenetic control of DSP under the mechanically homeostatic environment. It provides a useful tool for investigations of the functional role of DSP in the pathogenesis of lung fibrosis.
MeSH term(s)	Animals ; Clustered Regularly Interspaced Short Palindromic Repeats ; DNA Methylation/genetics ; DNA Methyltransferase 3A ; Desmoplakins/genetics ; Disease Models, Animal ; Epigenomics/methods ; Gene Editing/methods ; Genome-Wide Association Study/methods ; Humans ; Idiopathic Pulmonary Fibrosis/genetics ; Mice ; Mice, Inbred C57BL ; Rats
Chemical Substances	DNMT3A protein, human ; Desmoplakins ; Dnmt3a protein, mouse ; DNA Methyltransferase 3A (EC 2.1.1.37)
Language	English
Publishing date	2018-06-23
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1180953-x
ISSN	1535-4970 ; 0003-0805 ; 1073-449X
ISSN (online)	1535-4970
ISSN	0003-0805 ; 1073-449X
DOI	10.1164/rccm.201711-2242OC
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Article ; Online: Oxidative cross-linking of fibronectin confers protease resistance and inhibits cellular migration.

Locy, Morgan L / Rangarajan, Sunad / Yang, Sufen / Johnson, Mark R / Bernard, Karen / Kurundkar, Ashish / Bone, Nathaniel B / Zmijewski, Jaroslaw W / Byun, Jaeman / Pennathur, Subramaniam / Zhou, Yong / Thannickal, Victor J

Science signaling

2020 Volume 13, Issue 644

Abstract: The oxidation of tyrosine residues to ... ...

Abstract	The oxidation of tyrosine residues to generate
MeSH term(s)	A549 Cells ; Animals ; Cell Line ; Cell Movement/physiology ; Cells, Cultured ; Cross-Linking Reagents/chemistry ; Extracellular Matrix/metabolism ; Female ; Fibronectins/chemistry ; Fibronectins/metabolism ; Humans ; Mice, Inbred C57BL ; Mice, Knockout ; Myofibroblasts/cytology ; Myofibroblasts/metabolism ; Neutrophils/cytology ; Neutrophils/metabolism ; Oxidation-Reduction ; Oxidative Stress/physiology ; Peptide Hydrolases/metabolism ; Peroxidase/genetics ; Peroxidase/metabolism ; Transforming Growth Factor beta1/metabolism ; Tyrosine/analogs & derivatives ; Tyrosine/chemistry ; Tyrosine/metabolism
Chemical Substances	Cross-Linking Reagents ; Fibronectins ; Transforming Growth Factor beta1 ; Tyrosine (42HK56048U) ; dityrosine (CJ9XG8HS20) ; Peroxidase (EC 1.11.1.7) ; Peptide Hydrolases (EC 3.4.-)
Language	English
Publishing date	2020-08-11
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.aau2803
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Article ; Online: Glutathione reductase deficiency alters lung development and hyperoxic responses in neonatal mice.

Robbins, Mary E / Cho, Hye-Youn / Hansen, Jason M / Luchsinger, Joseph R / Locy, Morgan L / Velten, Markus / Kleeberger, Steven R / Rogers, Lynette K / Tipple, Trent E

Redox biology

2020 Volume 38, Page(s) 101797

Abstract: Cellular antioxidants protect against hyperoxic lung injury. The role of the glutathione (GSH) system in lung development and bronchopulmonary dysplasia (BPD) pathogenesis has not been systematically investigated. The current study utilized GSH reductase- ...

Abstract	Cellular antioxidants protect against hyperoxic lung injury. The role of the glutathione (GSH) system in lung development and bronchopulmonary dysplasia (BPD) pathogenesis has not been systematically investigated. The current study utilized GSH reductase-deficient (Gsr-KO) neonatal mice to test the hypothesis that early disruption of the GSH system negatively impacts lung development and hyperoxic responses. Lungs from wild-type (Gsr-WT) and Gsr-KO mice were analyzed for histopathology, developmental markers, redox indices, and transcriptome profiling at different developmental stages following exposure to room air or hyperoxia (85% O
MeSH term(s)	Animals ; Animals, Newborn ; Glutathione ; Glutathione Reductase/genetics ; Hyperoxia/genetics ; Lung ; Mice ; Oxidoreductases
Chemical Substances	Oxidoreductases (EC 1.-) ; Glutathione Reductase (EC 1.8.1.7) ; Glutathione (GAN16C9B8O)
Language	English
Publishing date	2020-11-13
Publishing country	Netherlands
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2701011-9
ISSN	2213-2317 ; 2213-2317
ISSN (online)	2213-2317
ISSN	2213-2317
DOI	10.1016/j.redox.2020.101797
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Article ; Online: The thioredoxin reductase-1 inhibitor aurothioglucose attenuates lung injury and improves survival in a murine model of acute respiratory distress syndrome.

Britt, Rodney D / Velten, Markus / Locy, Morgan L / Rogers, Lynette K / Tipple, Trent E

Antioxidants & redox signaling

2014 Volume 20, Issue 17, Page(s) 2681–2691

Abstract: Aims: Inflammation and oxygen toxicity increase free radical production and contribute to the development of acute respiratory distress syndrome (ARDS), which is a significant cause of morbidity and mortality in intensive care patients. We have ... ...

Abstract	Aims: Inflammation and oxygen toxicity increase free radical production and contribute to the development of acute respiratory distress syndrome (ARDS), which is a significant cause of morbidity and mortality in intensive care patients. We have previously reported increased glutathione (GSH) levels in lung epithelial cells in vitro and attenuated adult murine hyperoxic lung injury in vivo after pharmacological thioredoxin reductase-1 (TrxR1) inhibition. Using a murine ARDS model, we tested the hypothesis that aurothioglucose (ATG) treatment increases pulmonary GSH levels, attenuates lung injury, and decreases mortality in a GSH-dependent manner. Results: Adult mice received a single intratracheal dose of 0.375 μg/g lipopolysaccharide (LPS) 12 h before a single intraperitoneal injection of 25 mg/kg ATG. Control mice received intratracheal and/or intraperitoneal saline. Mice were then exposed to room air or hyperoxia (>95% O2). Lung injury was assessed by bronchoalveolar lavage protein concentrations. Expression of glutamate-cysteine ligase modifier subunit (GCLM), GSH, cytokines, and chemokines was determined. Exposure to LPS/hyperoxia induced inflammation and lung injury. ATG treatment significantly attenuated lung injury, increased lung GCLM expression and GSH levels, and decreased mortality. GSH depletion completely prevented the protective effects of ATG in LPS/hyperoxia-exposed mice. Innovation: ATG treatment significantly attenuates lung injury and enhances survival in a clinically relevant murine model of ARDS. The protective effects of ATG are GSH dependent. Conclusion: Augmentation of GSH systems by TrxR1 inhibition could represent a promising therapeutic approach to attenuate oxidant-mediated lung injury and improve patient outcomes.
MeSH term(s)	Animals ; Aurothioglucose/administration & dosage ; Disease Models, Animal ; Free Radicals/toxicity ; Glutathione/metabolism ; Humans ; Hyperoxia/metabolism ; Hyperoxia/pathology ; Inflammation/chemically induced ; Inflammation/drug therapy ; Inflammation/metabolism ; Lung/drug effects ; Lung/pathology ; Lung Injury/chemically induced ; Lung Injury/drug therapy ; Lung Injury/metabolism ; Mice ; Oxygen/toxicity ; Respiratory Distress Syndrome/drug therapy ; Respiratory Distress Syndrome/etiology ; Respiratory Distress Syndrome/metabolism ; Respiratory Distress Syndrome/pathology ; Thioredoxin Reductase 1/antagonists & inhibitors ; Thioredoxin Reductase 1/metabolism
Chemical Substances	Free Radicals ; Aurothioglucose (2P2V9Q0E78) ; TXNRD1 protein, human (EC 1.8.1.9) ; Thioredoxin Reductase 1 (EC 1.8.1.9) ; Glutathione (GAN16C9B8O) ; Oxygen (S88TT14065)
Language	English
Publishing date	2014-02-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1483836-9
ISSN	1557-7716 ; 1523-0864
ISSN (online)	1557-7716
ISSN	1523-0864
DOI	10.1089/ars.2013.5332
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