Thyroid Hormone and Tissue Repair: New Tricks for an Old Hormone?

Although the role of thyroid hormone during embryonic development has long been recognized, its role later in adult life remains largely unknown. However, several lines of evidence show that thyroid hormone is crucial to the response to stress and to poststress recovery and repair. Along this line, TH administration in almost every tissue resulted in tissue repair after various injuries including ischemia, chemical insults, induction of inflammation, or exposure to radiation. This novel action may be of therapeutic relevance, and thyroid hormone may constitute a paradigm for pharmacologic-induced tissue repair/regeneration.


Introduction
Although the role of thyroid hormone (TH) during development has long been recognized, its role later in adult life remains largely unknown [1]. A growing body of evidence reveals that thyroid hormone may be a major player for the response to stress and its presence crucial to poststress adaptation and recovery. Thus, thyroid hormone is now thought to have a reparative action later in adult life, and this has been recently documented in several studies; see Table 1.

Adaptation to Environmental Stress and Species Evolution: The Critical Role of Thyroid Hormone
The most important challenge that living organisms faced during species evolution was the ability to adapt to the transition from the aquatic environment, a condition of low oxygen, to the ground, an oxygen-rich state. This required a gene programming that would enable organ protection and remodeling during this transition. Interestingly, studies on amphibians revealed that thyroid-hormone-regulated gene programming is critical for the metamorphosis of tadpoles into juvenile frogs [2]. Several studies have shown that the morphological and functional changes of metamorphosis are the result of alterations in the transcription of specific sets of genes induced by TH and TH alterations can lead to developmental failures [3][4][5][6].

Thyroid Hormone and Stress Response: An Evolutionary Conserved Mechanism
The potential role of thyroid hormone in stress response has been, until now, underestimated. However, thyroid hormone signaling is altered during various stressful stimuli and thyroid hormone is crucial to poststress recovery and injury repair [7][8][9]. Interestingly, the importance of thyroid hormone for stress response has been documented in several species ranging from fish to humans [10]. Thus, exposure of air-breathing perch to water-born kerosene resulted in low T3 and unfavorable metabolic changes, while the administration of TH reversed this response [11]. Along this line, cold stunning Kemp's ridley sea turtles had undetectable levels of thyroid hormone, and recovery was observed only in those who recovered thyroid hormone levels in blood [12]. Interestingly, a similar response is also observed in humans. In fact, after an index event, such as myocardial infarction, T3 levels significantly drop and lower levels of T3 are associated with high mortality [13,14]. Furthermore, T3 levels are strongly correlated to early and late recovery of cardiac function, with T3 levels at 6 months to be an independent predictor of the recovery of the myocardium [15]. In fact, patients who spontaneously recover T3 levels in plasma after myocardial infarction are those with markedly improved cardiac functional recovery [15]. These observations provide clear evidence that thyroid-hormone-regulated mechanisms may be evolutionary conserved and are crucial to the response to stress and poststress recovery and tissue repair [11]. Along this line, several studies have demonstrated the reparative action of thyroid hormone. We have recently shown that T3 at a dose which had no effect on noninjured myocardium significantly limited apoptosis in the ischemic myocardium and improved postischemic function in an isolated rat heart model of ischemia-reperfusion. This effect was due to the suppression of the ischemia-reperfusion-induced activation of the proapoptotic p38 MAPK [16,17] as shown in, Figure 1

Thyroid Hormone:
The ''Black Box of Repair?'' Accumulating experimental evidence shows that thyroid hormone may play a critical role in the repair after injury in almost every tissue and organ as shown in Table 1. This probably implies that organisms may have a common mechanism of repair which may be regulated by thyroid hormone and has been established during evolution. Thus, thyroid hormone was shown to control DNA repair after irradiation-induced damage in mouse intestine [38]. A single dose of T3 in rats significantly diminished hepatocellular injury induced by ischemia-reperfusion (I/R) when given 48 h before the I/R protocol. This effect was mediated by a T3 transient oxidative stress, and thus, it was abrogated by the administration of antioxidant N-acetyl-cysteine [23]. Thyroxine was cytoprotective in toxic and ischemic injury in kidney [24,26]. Thus, T3 administration 24 h prior to renal ischemia could precondition against ischemia-reperfusion (I/R) injury. This was evident by a marked decrease in I/Rinduced proteinuria. T3 treatment also improved lipid peroxidation biomarkers and increased antioxidant enzymes [24]. In another study, T4 administration immediately or 24 h after ischemia resulted in higher Inulin clearance and preserved cellular integrity [26]. In accordance with these observations in animal models, T4 was shown to be cytoprotective, in a cellular model of reoxygenation injury in isolated proximal tubule cells [25]. Such evidence may provide an explanation to the clinical observation that low T3 has been associated with increased mortality in hemodialyzed patients [39]. T3 treatment prevented streptozocin-induced toxic injury in pancreatic cells. This effect was associated with an increased activation of the prosurvival Akt signaling [27]. Similarly, T3 was shown to improve function and survival of rat pancreatic islets in in vitro cell cultures [40]. Moreover, T3 was found to preserve ovarian granulose cells exposed to paclitaxel. In fact, T3 significantly reduced the paclitaxel-induced cell injury via downregulation of caspase3 and Bax and upregulation of Bcl2 [28]. T3 pretreatment in rats instilled with an isosmolar 5% albumin solution resulted in the upregulation of alveolar epithelial fluid clearance [41]. T3 was also shown not only to stimulate alveolar fluid clearance in normal but also in hypoxia-injured lungs [29]. The administration of T3 attenuated neointimal formation after balloon injury of carotid artery [35]. Thyroid hormone enhanced transected axonal regeneration and muscle reinnervation following rat sciatic nerve injury [22] and improved recovery of sensory function [21]. Similarly, thyroid hormone was shown to be essential for muscle regeneration after injury [33,34]. Thyroid hormone promoted the survival of injured neurons [18] and enhanced remyelination in demyelinating inflammatory disease [20]. Thyroid hormone has also been shown to accelerate wound healing in mice and guinea pigs [36,37].

Conclusions
Thyroid hormone appears to be a common player for the organ development and response to stress. Thyroid hormone was crucial for species evolution, and thyroid-hormoneregulated mechanisms have been evolutionary conserved and play an important role early during development. However, recent research has revealed that thyroid hormone has a reparative role later in adult life. This novel action may be of therapeutic relevance, and thyroid hormone may constitute a paradigm for pharmacologic induced tissue repair/regeneration.