Aerosolized Thyroid Hormone Prevents Radiation Induced Lung Fibrosis
source:ELK Biotechnologydate:2021-09-16views:153


Literature reading

  On September15, 2020, Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, published A paper named “Aerosolized Thyroid Hormone Prevents Radiation Induced Lung Fibrosis” on Frontiers in Oncology.

  In this paper, the ELK Biotechnology ELISA kits was used,Product information is as follows:

ELK1204   General T4(Thyroxine) ELISA Kit

ELK1339   General T3(Triiodothyronine) ELISA Kit

ELK2284   Mouse TSH(Thyroid Stimulating Hormone) ELISA Kit



   Radiotherapy is widely used in tumor treatment. More than 50 percent of malignant cancer patients require radiation therapy for both curative and palliative purposes . However, the application of radiotherapy is limited by the radiation-induced lung injury (RILI), which is a common complication after radiotherapy of thoracic malignant tumors. RILI often causes early radiation pneumonitis and late-onset radiation induced lung fibrosis (RILF) usually occurs in 1 year after radiotherapy . The incidence of symptomatic RILF in patients receiving thoracic radiotherapy is about 5–24%, and higher in patients with subclinical damage . Because effective treatments are lacking, RILF has an adverse impact on the quality of life of suffering patients, causing cough, shortness of breath, fever, progressive respiratory dysfunction, or even death . Currently, corticosteroids are commonly used in the clinic for radiation induced lung injury. Several prevention strategies have shown certain promising effects in murine models of RILF, including treatments with amifostine, ACE inhibitors, angiotensin II receptor inhibitors, pentoxifylline as well as with inhibitors of PDGF, VEGF, FGF, TGF-β1, and Cox-2, but firm clinical evidence is lacking .


   Thyroid hormone is one of the most important hormones that regulate energy metabolism. The levels of active triiodothyronine and its precursor thyroxine (T4) are mainly regulated by DIO2 in cells and tissues . There is growing evidence of the correlation between thyroid function and fibrosis disease in patients. Grazinao found that patients with idiopathic retroperitoneal fibrosis (IRF) had a higher risk of hypothyroidism than controls (OR = 3.56, 95%CI 1.48–8.59, and P = 0.004). Nearly a quarter of IRF patients received L-thyroxine at the end of the follow-up (median, 45 month), but only 3% of controls needed treatment in the same period. The incidence of hypothyroidism in idiopathic pulmonary fibrosis (IPF) was 16.8%, compared with 7.1% in control group; multivariate analysis showed that hypothyroidism was an independent predictor of death risk in IPF patients . Clinical data from a large sample showed that hypothyroidism significantly correlated with non-alcoholic fatty liver fibrosis (OR = 2.23, 95%CI 1.18–4.23, and P = 0.014) . Hypothyroidism also plays an important role in myocardial fibrosis and diabetic nephropathy .Materials and Methods related to the product


Serum TH Assay

   Total serum TH in NPC patients, including thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) were measured in the Laboratory Department of our hospital by using the electrochemiluminescence immunoassay. The normal values for TSH, fT3, and fT4 were considered to be 0.35–4.94 μIU/mL, 1.71–3.71 pg/mL, and 0.7–1.48 ng/dL, respectively. The presence of abnormally elevated TSH in the serum was defined as hypothyroidism, with or without decreases in fT4.

   Serum samples were prepared from mouse blood collected from eyelids using BD vacutainers on the days of micro-CT chest scans. In the remaining mice, serum was obtained at week 25 after RT using the same method. Total serum T3, T4, and TSH levels were measured using a T3 (ELK1339, ELK Biotechnology, Wuhan, China), T4 (ELK1204, ELK Biotechnology), and TSH (ELK2284, ELK Biotechnology) ELISA kits, following the manufacturers’ protocols.



   Radiation induced lung fibrosis is a common complication in the management of radiotherapy and it seriously affects patients’ quality of life. To date, however, there is still no viable therapeutic strategy for RILF, and its mechanism remains unclear. With the growing incidence and mortality rate of lung cancer worldwide , therapies that prevent RILF represent an unmet clinical need. In the current study, we have demonstrated a therapeutic effect of aerosolized T3 treatment in a rodent experiment model during the post RT phase. Secondly, we showed that the antifibrotic effect of T3 does not require increased serum levels of T3, T4, or TSH, suggesting that aerosolized delivery may be effective without side effects of iatrogenically elevated thyroid hormones. Thirdly, we found that hypothyroidism increases the risk of RILF in NPC patients; moreover, M2-like macrophages were associated with RILF. Considering these results, we suggest the delivery of aerosolized T3 as a new potential treatment strategy for RILF attenuation.


   Thyroid hormone regulates diverse biological processes, from growth to metabolism, and is critically important for nearly all tissues . Both T4 and T3 can be deiodinated either into the active form by DIO1 and DIO2 or into the inactive form — by DIO3 . DIO2 plays a major role in the synthesis of biologically active TH. Increased expression of DIO2 in tissues may reflect either a lack of TH or the need for increased metabolism. Previous studies have shown that hypothyroidism is associated with poor prognosis in many critical diseases, including heart failure , non-alcoholic fatty liver disease , chronic kidney disease, and lung disease . Hypothyroid mice suffered more severe lung injury than those with normal serum TH levels in a mouse model of ventilator-induced lung injury, and administration of T3 reduced chemokine and cytokine levels in Dio2 knockout mice (16).

   Our results showed that the relationship between both the expression of DIO2 protein as well as TH levels and RILF was consistent with the above results, indicating that there is a correlation between RILF and TH. It is common to find pulmonary shadows in follow-up CT image examinations in some NPC patients due to upper lungs being exposed to the radiation field, which could also be classified as RILI. According to two population-based studies, the incidence of radiation-induced hypothyroidism varied from 27 to 70% in patients that received a dose of 7.5–40 Gy . The incidence of hypothyroidism induced by radiation was 38.75% during the follow-up in our study. All patients observed in this cohort had subclinical hypothyroidism. The reasons for this finding likely include insufficient follow-up duration in a small sample and wide use of IMRT in our hospital . Bhandare’s study reported that the median latency of clinical hypothyroidism was 4.8 years. RILF occurred in 18 (22.0%) of 82 patients from our cohort during a median follow-up of 25.5 months (range 2–79 months). The proportion of RILF in subjects with hypothyroidism was obviously higher than that in subjects with normal thyroid function, and hypothyroidism was significantly associated with RILF in multivariate logistic regression analysis model. This finding may help understanding the mechanisms of RILF occurrence.


   The pathological mechanism of hypothyroidism leading to RILF remains unclear. One possible link may lie in thyroid transcription factor-1 (TTF-1). It plays an important role in the differentiation and formation of both thyroid and lung. Increased expression of TTF-1 was found in some thyroiditis patients . In the lung, TTF-1 regulates the differentiation of alveolar epithelial cells and the expression of alveolar surfactant protein, which is very important to maintain alveolar ventilation function and repair lung injury . Another possible link maybe related to the biological functions of thyroid hormone, which is not only an important in regulating human endocrine metabolism, but also affects mitochondrial function and transformation. Mitochondrial damage contributes to the development of RILF.

   Treatment with TH, an old but probably underused drug, may be utilized in cases with pathologies other than thyroid dysfunction. Some synthetic TH mimetics have shown encouraging results in the experimental treatment of obesity, dyslipidemia, and liver cancer . T3 also could alleviate the pulmonary fibrosis in TGF transgenic mice, but the mechanism is not fully explained . Recent studies showed that TH attenuated skin and pulmonary fibrosis induced by bleomycin and liver fibrosis caused by carbon tetrachloride in mouse models. These actions may be explained by TH effects on mitochondrial biogenesis and inhibition of TGF-β1-dependent transcription . TGF-β1 plays a critical role in profibrotic signals: about 80% of the proteins encoded by genes dysregulated in pulmonary tissues from IPF patients have been reported to be associated with TGF-β1 signaling pathway . RILF is similar to other forms of lung fibrosis, especially IPF. Aerosolized TH treatment significantly reduced expression of profibrotic growth proteins, including collagen I, PAI-1 and TGF-β1, whereas no such down-regulation was observed in the RT + PDN group in our study. We concluded that PDN did not inhibit the elevation of TGF-β1 and thus had no anti-fibrotic effect previously suggested by Arata et al..

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