Thyroid hormone: a resurgent treatment for an emergent concern

Abstract

The story of thyroid hormone in human physiology is one of mixed emotions. Studying past literature on its use leads one to believe that it serves only a few functions in a handful of diseases. In reality, the pathophysiological role of thyroid hormone is an uncharted expanse. Over the past few decades, research on thyroid hormone has been understandably monopolized by studies of hypo- and hyperthyroidism and cancers. However, in our focused pursuit, we have neglected to observe its role in systems that are not so easily relatable. Recent evidence in lung disease suggests that the thyroid hormone is capable of preserving mitochondria in an indirect manner. This is an exciting revelation given the profound implications of mitochondrial dysfunction in several lung diseases. When paired with known links between thyroid hormone and fibrotic pathways, thyroid hormone-based therapies become more enticing for research. In this article, we inspect the sudden awareness surrounding thyroid hormone and discuss why it is of paramount importance that further studies scrutinize the potential of thyroid hormone, and/or thyromimetics, as therapies for lung diseases.

INTRODUCTION

Lung diseases impact countless lives globally with each passing day. Chronic obstructive pulmonary disease (COPD) holds steady as the third most common cause of death, while asthma significantly dampens the quality of life for more than 22 million people in the United States alone (23, 62). Yet another lung disease, idiopathic pulmonary fibrosis (IPF), affects more than 120,000 individuals in the United States and has an average survival time of 3 yr (53). Researchers are in a grueling race against growing incidence and mortality rates, determined to find a cure for these deleterious diseases. Despite considerable efforts, there remains a paucity of treatment options, and of those few, many are crippling financially and/or do little more than alleviate symptoms. In the scientific community, we face the challenge of understanding these diseases so that we may develop more effective therapies. In the pursuit of these goals, we must sometimes turn to the past.

The application of thyroid hormone (TH) is an old, but possibly underutilized, avenue. Studies have keenly evaluated the thyroid and its diseases as a potential target and concern in medical illnesses spanning from obesity and cardiac diseases to renal disease and liver fibrosis (5, 9, 13, 16, 24, 25, 31, 36). Even still, with the obvious exception of hypo- and hyperthyroidism, the pathological role of TH is largely unexplored. The controversy surrounding the use of TH may be the underlying cause of this gap. It has a wide spectrum of effects and impacts diseases in very distinct ways; for instance, increased TH and TH receptors have been linked to the exacerbation of several cancers including those of the prostate, breast, and pancreas (37). Conversely, hypothyroidism has been associated with increased risk of hepatocellular carcinoma (22, 39). Even TH replacement therapy has its challenges. Studies have shown that a substantial percentage of patients do not benefit fully from certain TH replacement strategies and that combined therapies may be required for them to reach adequate euthyroidism (42, 63). Others have reported cardiac complications as a result of TH treatment at certain doses and are attempting to circumnavigate the issue by generating more specific TH-mimic compounds (thyromimetics) (7, 28, 58). These observations instill a sense of uncertainty regarding the thought-provoking therapeutic target. Perhaps it is for this reason that excitement for TH has been historically ambivalent.

To date, articles discussing the therapeutic potential of TH appear to represent less than one-third of literature published on TH. Nevertheless, following a brief decline in the late 1990s, TH has been quietly reemerging as a research topic. A broad search reveals that the number articles discussing its therapeutic use has been climbing steadily in recent years. Fascinatingly, the research on TH is still dominated by studies on hyper- and hypothyroidism, with an occasional modicum of studies on the overlap between the thyroid and certain cancers. Despite noteworthy evidence that the thyroid can be an important regulator of several physiological systems, research seems to have overlooked TH treatment in diseases not overtly dealing with the thyroid. Indeed, this may be a calculated decision: one that assesses TH as a nonvaluable broad effector. Alternatively, it is possible that TH could be a very viable and potent therapy for more than just thyroid diseases and cancer. The lung, for example, is a prime candidate for the evaluation of TH-based therapies. In this article we will discuss in greater detail the plausibility of treating lung diseases with TH and examine the perspectives of aging and mitochondrial dysfunction, among others, to explain how this novel mechanism may impart beneficial effects on such deleterious diseases (Fig. 1).

Fig. 1.

Schematic overview of novel connections between thyroid hormone and pulmonary disease. 1: Several forms of thyroid hormone (TH) can be derived from tyrosine and with the action of the enzyme iodothyronine deiodinase 2 (DIO2). In this article, we discuss thyroxine (T₄) and 3,5,3′-triiodothyronine (T₃). 2: Lung damage can be caused by several mechanisms, including through natural aging and exposure to reactive oxygen species (ROS). As a result of various types of insult, cells such as alveolar epithelial cells can be damaged. Likewise, mitochondria can lose prominent regulatory functions, such as mitophagy, via loss or downregulation of key proteins like PTEN-induced putative kinase 1 (Pink1). 3: Ultimately, damage within mitochondria and cells can accumulate to cause or exacerbate pulmonary diseases, including pulmonary fibrosis and chronic obstructive pulmonary disease (COPD). Notably, there can be many other factors and mechanisms involved that are not displayed in this figure. Recent evidence has suggested that T₃, and other forms of TH, may prevent cell damage and preserve mitochondrial network stability, thus carrying the potential to treat lung diseases.

TH AND THE LUNG

TH is known to regulate several processes from growth to metabolism (8, 20, 21, 40, 66). As suggested earlier, variances in TH can have an astounding range of effects on human physiology, including the dichotomy of weight loss and energy expenditure during hyperthyroidism and weight gain and decreased energetics during hypothyroidism (40). It is also known that TH is involved in regulation during conditions of cellular stress (oxidative, ultraviolet, starvation, etc.) and is readily activated from its prohormone form thyroxine (T₄) to active TH (T₃) via the iodothyronine deiodinase 2 (DIO2) enzyme (64). The serum T₃/T₄ ratio is often used as a measure to inform of thyroid health and sometimes disease status, but both T₃ and T₄, as well as the receptor for TH, have been targeted as potential therapeutics.

Although TH-based therapies may be beneficial for diseases across several organs, examining TH in lung diseases has been of rising interest due to compelling anatomical knowledge linking the thyroid and lung. Even during the embryonic stages, the two distinct organs derive from the same origin: Nkx2.1 cells in the endoderm (11, 61). This common beginning is significant because TTF-1, a protein encoded by Nkx2.1, is implicated in alveolar epithelial cell (AEC) differentiation as well as surfactant production and serves as a reliable immunohistochemistry marker for metastases in lung adenocarcinoma patients (11, 35).

Moving past germline associations, a prominent AEC-based connection was found in the form of the two antiarrhythmic drugs: amiodarone and its derivative dronedarone. Studies reported that both drugs promote the apoptosis of AECs, which can lead to interstitial lung disease and pulmonary fibrosis (PF) (33, 51). Building on this, other studies found that these two drugs have no significant effect on the hearts of thyroxine-treated rats but can induce dyslipidemia and thyroid dysfunction in vivo (27, 44). In an entirely different topic of research, one study revealed that administration of T₄ increases preservation of organs from intensive care unit brain-dead patients (41). Whether this is through averting vascular collapse, preserving the TH axis, or promoting AEC structural and functional stability remains unclear (41). These insights suggest that not only are the status of the thyroid and the lung interwoven but also that a TH-lung axis may be targeted by pharmacokinetic compounds.

Returning to broader relationships, patients with hypothyroidism have an increased prevalence of respiratory symptoms such as shortness of breath, cough, and sputum production (10). A 2015 retrospective case-control study suggested that hypothyroidism is a common occurrence in patients with IPF and may even be used as an indicator for mortality (43). Another study identified that both DIO2 and TH are elevated in the lungs of IPF subjects (67). Based on this information, it was suggested that the elevation of DIO2 is an attempt to bolster the production of TH, and thus one study examined this relationship.

DIO2-knockout mice displayed significantly higher hydroxyproline levels, and T₃ introduced to mice via aerosolization with either bleomycin- or transforming growth factor-β (TGF-β)-induced fibrosis demonstrated a significant decrease in hydroxyproline levels and fibrotic remodeling (67). Promisingly, aerosolized delivery of T₃ resulted in a significantly higher survival rate (8 times higher) in bleomycin-treated mice vs. those administered either pirfenidone or nintedanib, two Food and Drug Administration-approved IPF medications (47, 67). The evidence provided by this study strongly suggests a high therapeutic potential for TH in lung diseases: a potential worth investigating. If we give credence to this suggestion, the question that remains is how TH remediates damage in a pathological mechanism such as PF.

AGING LUNG AND THYROID

Research has established that with age comes an increased susceptibility to pernicious agents. The lung is no exception. A number of prominent studies have validated that AECs of aging lungs have a greater vulnerability to the dysregulation of their vital processes, such as in mitochondrial metabolism, and thus can be prone to complex diseases such as IPF (38, 68). Studies have identified IPF as an age-associated lung disease, perhaps in part due to accumulated failures in damage-control and reparative processes such as mitophagy (14, 57).

This then is an interesting opportunity for a connection. One study examined the relationship between chronic obstructive pulmonary disease (COPD) and nonthyroid illness syndrome, finding that THs are significantly altered in COPD patients, yet it is unclear whether these alterations should be treated (29). Fascinatingly, increasing age was found to correlate with decreased serum T₃ levels and increased T₄ levels in stable COPD patients (29). It is plausible that these alterations of TH in aged individuals contribute to a range of events experienced in lung diseases and may even serve as reliable indicators for disease status (59). A notable study suggested that nonthyroid illness syndrome could be a significant predictor of lung cancer prognosis (65). Further examination of these relationships could lead to the development of new prognostic methods based on TH, but additional testing is required to determine their efficacy in a clinical setting.

MITOCHONDRIAL DYSFUNCTION

While aging is a well-studied and ever-present angle on the pathology of lung diseases, there are other perspectives that have shown promise for therapeutic targeting. It has long since been known that one of the most prominent methods of cellular preservation is the ability to mark and destroy damaged material, especially in disease conditions (45). Studies have suggested that TH is a stimulator of autophagy and that autophagy is inhibited in IPF (2, 32, 45). In recent years, the discussion on mitochondrial autophagy, or mitophagy, has been growing (57, 69). It is a highly regulated process that is capable of maintaining mitochondrial networks during elevated levels of stress (45). Failure of this process, and others that regulate mitochondrial stability, is an apparent recurring theme in many pathologies. Interestingly, during the determination of whether T₄ administration affected rat lung development, one study found that mitochondria were pronounced (24). An aforementioned study noted this connection and found that administration of TH inhibits PF through interaction with mitochondria (67).

Although a captivating topic, the connection between mitochondrial dysfunction and lung disease is not surprising. There is no shortage of recent studies demonstrating the importance of mitochondria in lung diseases. Several articles report mitochondrial dysfunction playing a role in the complication and development of lung problems such as asthma, COPD, lung injury, and neonatal lung diseases (14, 57, 67). Particularly, mitochondrial dysfunction is an emerging concern in PF, a disease characterized by progressive lung remodeling and distinct phenotypic alterations in fibroblasts and AECs (38, 49). Continual epithelial cell injury results in irreversible fibrosis of the lung, which is commonly observed in IPF (49). Specifically, within the damaged alveolar type II cells of IPF patients, it has been shown that mitochondrial dysfunction is widespread (12). Control mechanisms that regulate network stability, such as mitophagy, can be easily disrupted, and catastrophic changes in mitochondria have been found to exacerbate fibrosis (12, 45, 67, 69).

A PLAUSIBLE MITOCHONDRIAL MECHANISM

It is believed that PTEN-induced putative kinase 1 (PINK1) is one of the critical determinants in the preservation of mitochondria, a protein also shown to have decreased expression in the lung tissues of IPF patients (3, 12, 67). By administration of T₃ to bleomycin-treated mice, one study found that T₃ treatment prevents significant damage of mitochondrial cristae and ameliorates mitochondrial membrane potential and oxygen consumption rates within alveolar type II cells (67). Assessment of isolated human small AECs treated with both bleomycin and T₃, revealed significantly restored PINK1 levels and autophagic flux (67). When Pink1 was knocked out in mice, aerosolized T₃ did not ameliorate fibrosis; instead, hydroxyproline levels were increased (67). This evidence highly suggests that TH is an effective means of preserving mitochondria during disease conditions and that this preservation is dependent on interactions involving PINK1. Based on these observations, it is possible that not only could mitochondrial dysfunction be an excellent therapeutic target for the amelioration of lung diseases, administration of TH may be an effective means of facilitating this therapy.

INTERACTION BETWEEN THE THYROID AND OTHER ORGANS

Beyond the lung, it is important to acknowledge the research that has been conducted on the cytoprotective effects of TH in other organs. There have been several notable studies that have explored the potential of TH in other diseases such as those in the kidney, heart, and liver.

Renal

A study on the status of kidney function in patients with either hypo- or hyperthyroidism, found that treatment of the former improved renal function, while therapy for hyperthyroidism had the opposite effect (16). A similar study evaluated glomerular filtration rate in 309 patients with hypothyroidis and reported that the patients who received TH treatment displayed significant decreases in glomerular filtration rate decline and overall, better preservation of renal function (54). Another study has also shown that TH can impact renal blood flow, glomerular filtration rate, and renal tubular physiology (5).

Cardiac

The connection between the thyroid and the heart is one of the longest standing research topics pertaining to TH. A large number of studies have demonstrated that changes in thyroid status can impact the function of the endothelium and lead to changes in hemodynamics and that treatments that help manage thyroid disease may also have a beneficial effect on cardiovascular risk factors (15, 26, 48). Interestingly, some studies suggest that the relationship is bidirectional, wherein cardiovascular disease can also upset thyroid balance and perhaps cascade into pronounced health issues (26). Despite the vast wealth of knowledge on the cross talk between the two organs, it remains a burgeoning field with some controversy regarding the safety of using TH approaches for treatment (7, 19, 28, 37).

Liver Inflammation/Fibrosis

As described earlier, studies have thoroughly investigated how TH can regulate lipid metabolism, and as such determined that TH plays a crucial role in the functioning of the liver (25). The interaction between TH and TRβ2 within the liver promotes the expression of genes that can either increase or decrease lipolysis and thus impact the regulation of lipid and carbohydrate metabolism (25, 34). Of particular interest in relation to TH is nonalcoholic fatty liver disease (NAFLD). Studies have suggested that TH may serve as an indicator for NAFLD severity and that the ratios of free T₃ and T₄ can divulge useful information about liver diseases (25, 34). One study demonstrated that nutritional coadministration of T₃ and a choline-methionine-deficient diet was sufficient to reverse liver steatosis and decrease lipid peroxidation (46). A thorough examination of thyroid receptor agonists directed to the liver, an alternative approach to direct T₃ administration, demonstrated less nonhepatic tissue disruption while maintaining a notable reduction of triglycerides and cholesterol (19).

NAFLD carries the potential to develop into the more severe nonalcoholic steatohepatitis (NASH) and advanced fibrosis. A recent study found that NASH was associated with low thyroid function (30). This is of substantial interest due to the known progression of NAFLD to NASH and ultimately cirrhosis. It is possible that the TH axis, due to its profound involvement in the liver metabolism and fibrotic processes, may not only be useful for the prevention of NAFLD development and thus its more severe counterparts, but may also be useful in the mediation of fibrotic processes. One study demonstrated that TH was capable of attenuating both liver and skin fibrosis in mice via disruption of the TGF-β/SMAD pathway (2). TGF-β is a prominent cytokine with wide-spanning functionality, especially in the case of fibrotic diseases and cancers. It is known that TGF-β promotes collagen deposition as well as the differentiation of fibroblasts into myofibroblasts (2). Therefore, based on connections in our studies of other organs, we may glean useful information regarding TH and apply it the study of similar mechanisms in the lung.

THERAPEUTIC POTENTIAL

As mentioned, TH is relatively unstudied in relation to lung diseases. However, mitochondrial dysfunction is not new to the field of pulmonology. Given the suggested connection between mitochondrial dysfunction and TH, we can safely posit that TH is worthy of examination in lung diseases, including those beyond PF. Specifically, mitochondrial dysfunction has been documented in both COPD and asthma. In asthma, oxidative stress and reactive oxygen species (ROS) are known to be a significant factor, and ROS have been shown to disrupt mitochondrial integrity (1, 23). The same relationship can be seen in COPD, where ROS decrease mitochondrial membrane potential and disrupt oxidative metabolism (62). Since TH has been shown to preserve mitochondria during bleomycin insult, it is very likely that TH may be capable of mitigating the mitochondrial damage caused by ROS during disease conditions (67).

Another study evaluated the efficacy of TH administration in the amelioration of ventilator-induced lung injury (VILI) in mice. In agreement with similar research in other lung injury models, it was determined that DIO2 knockout mice displayed greater levels of inflammation following VILI, with notably higher chemokine and cytokine levels (4). Treatment of the VILI mice with TH resulted in a significant decrease in proinflammatory cytokine levels and an interesting increase in Hsp1 (4). Taken together, these data provide evidence that TH administration may alleviate inflammation of the lung during injurious conditions and that this protection may extend to other lung diseases by means of reducing inflammation. However, identifying the axis to target is only half of the battle. One of the most challenging aspects of therapy is choosing the proper means of administration.

One of the most promising TH-based treatment avenues is the use of thyroid-mimetic agents. In some cases, such as cardiovascular diseases, the potential application of TH is limited due to unwanted side-effects at high doses, including tachycardia, arrhythmia, and heart failure (4a, 7, 28, 56). To combat this issue, mimetic compounds have been developed to pinpoint the beneficial effects of TH and avoid the instigation of unwanted complications. The majority of studies have employed these thyroid mimetics for the goal of curing hypercholesterolemia due to their strong effects on the metabolism of cholesterol and fat, but others have specifically explored the application of thyromimetics in diabetes and obesity (6, 7, 50, 52, 55, 60).

The use of thyromimetics continues to be a topic of growing interest but has yet to spark widespread interest in the lung. It is well established that these mimetics impact various metabolic mechanisms and, as described above, many chronic lung diseases display disruption of cellular metabolism. It is therefore possible that these mimetics may be employed to selectively remediate cellular metabolism that has been derailed by lung disease. Sobetirome is one such thyromimetic that may possess a potential for treating lung diseases.

As budding evidence of this supposition, an aforementioned study assessed the efficacy of administering sobetirome to bleomycin-treated mice (6). After it was determined that TH receptors were essential for T₃-administration-mediated repair, the study demonstrated that sobetirome alleviated fibrosis (6). Both Masson’s trichome staining and hydroxyproline assays revealed a significant resolution of PF (9). These findings further solidify the assertion that T₃ and, more specifically, thyromimetics like sobetirome are a possible new avenue to treat lung diseases, including PF. Although these results are promising, research should proceed with caution as always. It has been acknowledged that thyroid mimetics can carry the potential for undesirable effects. Particularly, eprotirome, which is similar to sobetirome, was flagged for negative effects on the cartilage of canines (18).

Altogether, the role of TH in pulmonary pathologies is an exciting new avenue for research, albeit one that should be approached with careful consideration. Recent evidence has provided a few fascinating links between TH and familiar mechanisms of pulmonary disease, including mitochondrial dysfunction, fibrotic change, AEC damage, and aging (Fig. 1). Future research should seek to elucidate the targeting potential of these mechanism and the capability of thyromimetics in the treatment of lung diseases.

CONCLUSIONS

It is intriguing that something as simple as a hormone could be a practical answer to the remediation of some of the most challenging diseases known to the human species. Over the past several decades, the history of TH has been speckled with controversy and unanswered questions. Its administration and inhibition have a delicate and vast range of effects on the human physiology, and although it is likely not a miracle treatment, it carries the strong possibility of being an effective therapy for a number of diseases that are in dire need of new approaches. Recent evidence that TH administration can protect mitochondrial function during PF not only managed to support the nascent importance of mitochondrial dysfunction, it also provided the field with a path not yet mapped (67). Needless to say, TH has regained some attention as a feasible therapeutic agent for lung diseases. It is not clear where this trail will lead; however, it is certainly welcome news in the fight for those who suffer these serious diseases every day.

GRANTS

N. Kolliputi was funded by National Heart, Lung, and Blood Institute Grant R01-HL-105932 and the Joy McCann Culverhouse Endowment to the Division of Allergy and Immunology.

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

M.T.B. prepared figures; M.T.B. drafted manuscript; M.T.B., M.D.A., and R.F.L. edited and revised manuscript; R.F.L. and N.K. approved final version of manuscript.