Thyroid Hormone Supplementation in Sepsis: An Experimental Study

Inan, Murat; Koyuncu, Ayhan; Aydın, Cengiz; Turan, Mustafa; Gökgöz, Şehsuvar; Şen, Metin

doi:10.1007/s005950300004

Cited by 29 publications

(21 citation statements)

References 46 publications

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“…Consistently, airspace T 3 rapidly stimulates the clearance of alveolar fluid in rat lungs with and without lung injury (61) by regulating Na-K-ATPase activity (62). Decreased serum TH levels have been associated with worsening pulmonary function in lung injury or during sepsis (63); in agreement with these observations, administration of TH to patients with respiratory distress syndrome and sepsis improves lung compliance (64). In agreement with these studies, we demonstrated that hypothyroidism worsens lung damage after VILI.…”

Section: Discussionmentioning

confidence: 79%

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

Barca-Mayo

Liao

DiCosmo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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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...

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Section: Discussionmentioning

confidence: 79%

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

Barca-Mayo

Liao

DiCosmo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition, hypothyroidism appears to aggravate the clinical setting of lung injury, and TH deprivation impedes alveolar fluid clearance, resulting in persistent hypoxia, reduced antioxidant profiles, and worsening lung function (18). In contrast, administration of TH to critically ill patients with ALI or sepsis improves lung mechanics (19).…”

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confidence: 99%

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

Fan

Xie

Pino-Yanes

et al. 2011

Am J Respir Cell Mol Biol

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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...

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“…Another experimental study in rats showed that thyroid hormone supplementation during sepsis can increase survival (33). A particular beneficial effect of thyroid hormone administration in rats with experimentally induced sepsis has been documented on lung mechanics and histology, which was mainly attributed to enhanced synthesis of surfactant (34,35).…”

Section: Discussionmentioning

confidence: 99%

Association between thyroid function tests at baseline and the outcome of patients with sepsis or septic shock: a systematic review

Angelousi

Karageorgopoulos

Kapaskelis

et al. 2011

European Journal of Endocrinology

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Introduction: The severity of critical illness is associated with various patterns of thyroid hormone abnormalities. We sought to evaluate whether the outcome of patients with, specifically, sepsis or septic shock is associated with the thyroid function tests evaluated at diagnosis or admission in the intensive care unit (ICU). Methods: We performed a systematic review of relevant studies by searching PubMed. Results: We included nine studies that all had a prospective cohort design. Seven involved children or neonates, and two involved adults. Mortality was the outcome evaluated in eight studies, while the length of ICU stay was evaluated in the remaining study. In univariate analysis, six of the nine included studies showed that either, free or total, triiodothyronine or thyroxine was lower in the group of patients with sepsis or septic shock who had unfavorable outcome than in those who had favorable outcome. Two other studies showed higher TSH values in the group of patients with unfavorable outcome. No significant relevant findings were observed in the remaining study. Regarding the correlation of sepsis prognostic scoring systems with thyroid function tests, the three studies that provided specific relevant data showed variable findings. Discussion: Most of the relevant studies identified favor the concept that decreased thyroid function at baseline might be associated with a worse outcome of patients with sepsis or septic shock. Although these findings are not consistent, the role of thyroid function in affecting or merely predicting the outcome of sepsis or septic shock merits further investigation.

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Thyroid Hormone Supplementation in Sepsis: An Experimental Study

Abstract: Thyroid hormone supplementation in septic rats had a beneficial effect on the sepsis criteria and also resulted in a lower rate of mortality.

Cited by 29 publications

References 46 publications

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

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

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

Association between thyroid function tests at baseline and the outcome of patients with sepsis or septic shock: a systematic review

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