Role of type 2 deiodinase in response to acute lung injury (ALI) in mice

Abstract

Thyroid hormone (TH) metabolism, mediated by deiodinase types 1, 2, and 3 (D1, D2, and D3) is profoundly affected by acute illness. We examined the role of TH metabolism during ventilator-induced lung injury (VILI) in mice. Mice exposed to VILI recapitulated the serum TH findings of acute illness, namely a decrease in 3,5,3′-triiodothyronine (T 3 ) and thyroid-stimulating hormone and an increase in reverse T 3 . Both D2 immunoreactivity and D2 enzymatic activity were increased significantly. D1 and D3 activity did not change. Using D2 knockout (D2KO) mice, we determined whether the increase in D2 was an adaptive response. Although similar changes in serum TH levels were observed in D2KO and WT mice, D2KO mice exhibited greater susceptibility to VILI than WT mice, as evidenced by poorer alveoli integrity and quantified by lung chemokine and cytokine mRNA induction. These data suggest that an increase in lung D2 is protective against VILI. Similar findings of increased inflammatory markers were found in hypothyroid WT mice exposed to VILI compared with euthyroid mice, indicating that the lungs were functionally hypothyroid. Treatment of D2KO mice with T 3 reversed many of the lung chemokine and cytokine profiles seen in response to VILI, demonstrating a role for T 3 in the treatment of lung injury. We conclude that TH metabolism in the lung is linked to the response to inflammatory injury and speculate that D2 exerts its protective effect by making more TH available to the injured lung tissue.nonthyroidal illness | euthyroid sick | reverse triiodothyronine | bronchial alveolar lavage | sepsis T hyroid hormone [TH, here denoting the active hormone 3,5,3′-triiodothyronine (T 3 ) and its precursor thyroxine (T 4 )] is necessary for the normal development and function of virtually every vertebrate tissue. Although the thyroid gland is predominantly responsible for the production and release of T 4 , the cellular bioavailability of the active T 3 depends on TH-specific transporters and tissue TH metabolism. Metabolism of TH is regulated by three iodothyronine deiodinases. Both type 1 (D1) and type 2 (D2) deiodinases serve to generate bioactive T 3 by outer-ring deiodination of T 4 . D2 has a major role in the intracellular generation of the active TH in mouse; the role of the D1, with its broad substrate specificity and ability to carry out both outer-and inner-ring deiodination, is less well understood. In contrast, type 3 iodothyronine deiodinase (D3) inactivates TH by inner-ring deiodination of T 4 to reverse T 3 (3′,5,3-triiodothyronine; rT 3 ) and T 3 to 3,3′-diiodothyronine (T 2 ), both biologically inactive compounds (1).Studies have elucidated the dynamic effects of TH action on brain, bone, liver (2-5), and maturation of the fetal lung (6, 7), but little is known regarding the role of TH in adult lung physiology. Until now, evidence suggesting that TH influences adult lung physiology has been indirect and based on the presence of TH receptors (8), deiodinases (9-12), and measured TH concentrations (10,13,14) i...

The molecular basis of the non-thyroidal illness syndrome

“…( Barca-Mayo et al 2011, Ma et al 2011. VILI leads to local increases of TNFa, IL6 and IL1b, again suggesting the involvement of cytokines in the upregulation of Dio2 (Barca-Mayo et al 2011) via NF-kB activation (Lentsch et al 1998, Leeper-Woodford & Detmer 1999.…”

Establishment of an Effective Radioiodide Thyroid Ablation Protocol in Mice

“…Since then, numerous protocols for radioiodide ablation of the mouse thyroid gland have been published with broad variation of the thyroid-lethal dose of 131 I administered to mice ranging from 28 to 1,000 µCi (1-37 MBq) in the presence or absence of stimulation of thyroidal iodide uptake by treatment with a low-iodine diet (LID) for 1-4 weeks or exogenous thyroid-stimulating hormone (TSH) application prior to the administration of radioiodide [3,4,5,6,7,8,9,10,11,12]. …”

Methylation differences and expression profiles of the caprine DIO3 gene

“…The iodothyronine deiodinases, comprising types 1, 2, and 3 (D1, D2, and D3), have key roles to play in the activation and inactivation of thyroid hormones, injury response, tissue repair, energy homeostasis, and hypothalamic function (Barca-Mayo et al, 2011;Fonseca et al, 2014). D3 has an inactivating role in converting T4 into T3 and T3 into diiodothyronine (T2) by removing iodine moieties from T4 and T3 inner rings, respectively (Bianco et al, 2002).…”