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.