Type 2 deiodinase and host responses of sepsis and acute lung injury
Open accessAbstract
The role of thyroid hormone metabolism in clinical outcomes of the critically ill remains unclear. Using preclinical models of acute lung injury (ALI), we assessed the gene and protein expression of type 2 deiodinase (DIO2), a key driver for synthesis of biologically active triiodothyronine, and addressed potential association of DIO2 genetic variants with ALI in a multiethnic cohort. DIO2 gene and protein expression levels in murine lung were validated by microarrays and immunoblotting. Lung injury was assessed by levels of bronchoalveolar lavage protein and leukocytes. Single-nucleotide polymorphisms were genotyped and ALI susceptibility association assessed. Significant increases in both DIO2 gene and D2 protein expression were observed in lung tissues from murine ALI models (LPS- and ventilator-induced lung injury), with expression directly increasing with the extent of lung injury. Mice with reduced levels of DIO2 expression (by silencing RNA) demonstrated reduced thyroxine levels in plasma and increased lung injury (increased bronchoalveolar lavage protein and leukocytes), suggesting a protective role for DIO2 in ALI. The G (Ala) allele of the Thr92Ala coding single-nucleotide polymorphism (rs225014) was protective in severe sepsis and severe sepsis-associated ALI after adjustments for age, sex, and genetic ancestry in a logistic regression model in European Americans. Our studies indicate that DIO2 is a novel ALI candidate gene, the nonsynonymous Thr92Ala coding variant of which confers ALI protection. Increased DIO2 expression may dampen the ALI inflammatory response, thereby strengthening the premise that thyroid hormone metabolism is intimately linked to the integrated response to inflammatory injury in critically ill patients.
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The Thr92Ala polymorphism has been shown to be beneficial in the general population: heterozygosity reduces acute lung injury in sepsis by 35% and reduces mortality from COVID-19 by 50%.
“This polymorphism has been shown to be beneficial in the general population (heterozygosity reduces acute lung injury in sepsis by 35% and reduces mortality from COVID-19 by 50%) (39, 40).”
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- Authors
- Ma, S.-F., Xie, L., Pino-Yanes, M., Sammani, S., Wade, M. S., Letsiou, E., Siegler, J., Wang, T., Infusino, G., Kittles, R. A., Flores, C., Zhou, T., Prabhakar, B. S., Moreno-Vinasco, L., Villar, J., Jacobson, J. R., Dudek, S. M., & Garcia, J. G. N.
- Affiliations
- University of Chicago (US)
- University of Illinois Chicago (US)
- Instituto de Salud Carlos III (ES)
- Institute for Personalized Respiratory Medicine, Section of Pulmonary, Critical Care Sleep and Allergy, University of Illinois at Chicago, Chicago, Illinois
- Centro de Investigacion Biomedica en Red Enfermedades Respiratorias, Instituto de Salud Carlos III, Madrid, Spain
- Corresponding author
- Garcia, Joe G. N.
- ORCID
- Venue
- American Journal of Respiratory Cell and Molecular Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2011-12-01
- Volume
- 45
- Issue
- 6
- Pages
- 1203-1211
- ISSN
- 1044-1549 (ISSN-L)
- 1535-4989
- PMC
- PMC3262665
- OpenAlex
- W1963631663
- Cited by
- 60
- References
- 64
- Citations by year
- 2026: 2 · 2025: 2 · 2023: 3 · 2022: 4 · 2021: 4 · 2020: 3 · 2019: 5 · 2018: 6 · 2017: 1 · 2016: 5 · 2015: 7 · 2014: 9 · 2013: 3 · 2012: 5
- FWCI
- 4.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- American Journal of Respiratory Cell and Molecular Biology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (EMER07/001)
- Instituto de Salud Carlos III
- National Heart, Lung, and Blood Institute (HL58094)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Respiratory Support and Mechanisms
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Thyroid Disorders and Treatments
- Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
- Keywords
- type 2 deiodinase, DIO2, acute lung injury, sepsis, thyroid hormone metabolism, triiodothyronine, genetic susceptibility, ventilator-induced lung injury, lipopolysaccharide-induced lung injury, bronchoalveolar lavage protein, leukocytes, inflammation, critically ill patients, thyroxine
- MeSH terms
- Iodothyronine Deiodinase Type II, Age Factors, Alleles, Animals, Disease Models, Animal, Humans, Iodide Peroxidase, Lung, Sex Factors, Thyroid Hormones, Cohort Studies, Gene Expression Regulation, Enzymologic, Critical Illness, Sepsis, Polymorphism, Single Nucleotide, Mice, Acute Lung Injury
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