Type 2 deiodinase and host responses of sepsis and acute lung injury

Shwu Fan Ma, Lishi Xie, Maria Pino-Yanes, Saad Sammani, Michael S. Wade, Eleftheria Letsiou, Jessica Siegler, Ting Wang, Giovanni Infusino, Rick A. Kittles, Carlos Flores, Tong Zhou, Bellur S. Prabhakar, Liliana Moreno-Vinasco, Jesus Villar, Jeffrey R. Jacobson, Steven M. Dudek, Joe G N Garcia

Research output: Contribution to journalArticle

42 Scopus citations

Abstract

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.DIO2geneandprotein 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 proteinandleukocytes), 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 non-synonymous Thr92Ala coding variant of which confers ALI protection. Increased DIO2 expression may dampen the ALI inflammatory response, thereby strengthening the premise that thyroid hormone metabolismis intimately linked to the integrated response to inflammatory injury in critically ill patients.

Original languageEnglish (US)
Pages (from-to)1203-1211
Number of pages9
JournalAmerican journal of respiratory cell and molecular biology
Volume45
Issue number6
DOIs
StatePublished - Dec 1 2011

Keywords

  • Acute respiratory distress syndrome
  • Hypothyroidism
  • Mechanical ventilation
  • Sepsis

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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    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. (2011). Type 2 deiodinase and host responses of sepsis and acute lung injury. American journal of respiratory cell and molecular biology, 45(6), 1203-1211. https://doi.org/10.1165/rcmb.2011-0179OC