Type 2 Deiodinase and Host Responses of Sepsis and Acute Lung Injury

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. 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.Keywords: acute respiratory distress syndrome; hypothyroidism; mechanical ventilation; sepsis Acute lung injury (ALI) is one of the major causes of acute respiratory failure that usually develops in response to major insults, such as sepsis, trauma, pneumonia, and multiple transfusions (1). Although mechanical ventilation (MV) is indispensable for the survival of patients with ALI (2), clinical trials have shown that improperly delivered MV causes or worsens lung injury, a syndrome known as ventilator-induced lung injury (VILI). ALI and VILI are characterized by augmented capillary leakage, acute inflammation, and increases in inflammatory cytokine expression (3, 4). Microarray analyses have identified a number of ALI-associated candidate genes correlated with the outcome of both ALI and VILI (5-8). Case-control association studies further support that genetic variants in these genes contribute to susceptibility and survival of sepsis and ALI (8-12). Despite these increasing insights into ALI/VILI pathobiology, ALI continues to carry an unacceptably high mortality (.30%), and the basis for the increased ALI morbidity/mortality remains poorly understood.Clinicians have had a long-standing interest in the enigmatic role of thyroid hormones (THs) in critically ill patients (13) who e...

The molecular basis of the non-thyroidal illness syndrome

“…During LPS induced lung injury (caused by intranasal LPS administration) and ventilator-induced lung injury (VILI) in mice, the expression of D2 in the lung is increased (Ma et al 2011). In addition, D2 protein expression is increased in human microvascular endothelial cells that are subjected to cyclic stretch (Ma et al 2011).…”

“…During LPS induced lung injury (caused by intranasal LPS administration) and ventilator-induced lung injury (VILI) in mice, the expression of D2 in the lung is increased (Ma et al 2011). In addition, D2 protein expression is increased in human microvascular endothelial cells that are subjected to cyclic stretch (Ma et al 2011). The increase in D2 expression and the subsequent rise in local T 3 concentrations might be an adaptive and protective mechanisms of the lung to prevent lung damage during inflammation, since knocking down D2 in vivo aggravates lung injury after VILI (B) During inflammation, competition for co-factors by cytokine induced pathways such as activator protein-1 (AP-1) and/or nuclear factor-kappa B (NF-kB) leads to less TR mediated transcription of the Dio1 gene.…”

“…( 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.…”

GENETICS IN ENDOCRINOLOGY: Genetic variation in deiodinases: a systematic review of potential clinical effects in humans

“…Furthermore, a significant positive relationship between D2 expression and extent of lung injury was found (75). The interaction between thyroid hormone metabolism and inflammatory response is complex and far from elucidated.…”

Sp1‐Mediated Nonmuscle Myosin Light Chain Kinase Expression and Enhanced Activity in Vascular Endothelial Growth Factor–Induced Vascular Permeability

“…In addition to these epidemiologic studies, race and sex differences in ARDS deaths in the United States over the past several decades have clearly demonstrated an increase in incidence and mortality due to sepsis and acute lung injury in African Americans and Latinos compared with non-Latino whites, 3,4 highlighting the contribution of genetic components in disease susceptibility and severity. [5][6][7][8][9][10][11][12] Increased lung vascular permeability is a major pathobiologic feature of ARDS and drives morbidity and mortality. At a mechanistic level, increased gaps between lung endothelium are directly related to the extent of lung fluid imbalance and lung edema.…”