TRβ activation confers AT2-to-AT1 cell differen... - Thyroid UK

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TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA

helvella profile image
4 Replies

A big paper, covering a complex subjecy in great detail - especially the laboratory processes.

In summary:

Pulmonary fibrosis seems to occur because the lungs do not repair themselves. This seems to be in part because the body reduces T3 production when seriously ill.

But throwing T3 at the issue isn't the answer because that stimulates TRα receptors (which result in cell proliferation rather than maturation) and TRβ receptors.

Instead, use a substance (sobetirome) which affects only TRβ receptors (which are fundamental to this repair), rather than TRα receptors.

If this paper is verified, it might influence future treatment of multiple disorders. Indeed, could an imbalance between the stimulation of TRα versus TRβ receptors prove to be a key observation? After all, we see all too many who, despite seemingly adequate thyroid hormone levels (T4, T3 and the balance), appear to remain less than well. Years of excess or inadequate thyroid hormone could have resulted in accumulation of issues from inappropriate balance of stimulation.

Even if changes to treatment remain in the future, a step forward in understanding is some sort of progress.

TRβ activation confers AT2-to-AT1 cell differentiation and anti-fibrosis during lung repair via KLF2 and CEBPA

Xin Pan, Lan Wang, Juntang Yang, Yingge Li, Min Xu, Chenxi Liang, Lulu Liu, Zhongzheng Li, Cong Xia, Jiaojiao Pang, Mengyuan Wang, Meng Li, Saiya Guo, Peishuo Yan, Chen Ding, Ivan O. Rosas & Guoying Yu

Nature Communications volume 15, Article number: 8672 (2024)

Abstract

Aberrant repair underlies the pathogenesis of pulmonary fibrosis while effective strategies to convert fibrosis to normal regeneration are scarce. Here, we found that thyroid hormone is decreased in multiple models of lung injury but is essential for lung regeneration. Moreover, thyroid hormone receptor α (TRα) promotes cell proliferation, while TRβ fuels cell maturation in lung regeneration. Using a specific TRβ agonist, sobetirome, we demonstrate that the anti-fibrotic effects of thyroid hormone mainly rely on TRβ in mice. Cellularly, TRβ activation enhances alveolar type-2 (AT2) cell differentiation into AT1 cell and constrains AT2 cell hyperplasia. Molecularly, TRβ activation directly regulates the expression of KLF2 and CEBPA, both of which further synergistically drive the differentiation program of AT1 cells and benefit regeneration and anti-fibrosis. Our findings elucidate the modulation function of the TRβ-KLF2/CEBPA axis on AT2 cell fate and provide a potential treatment strategy to facilitate lung regeneration and anti-fibrosis.

Discussion (First paragraph only)

Multiple models exhibited a consistently low serum T3 level after lung injury. We found that the reduced synthesis and the conversion from T4 to T3 in peripheral tissue, but not the hypothalamus-pituitary, contributed to the low T3 in serum. Hypoxia and inflammation factors presumably mediated these systemic effects in the acute phase of lung injury. Most importantly, the local T3 in the lung is indispensable for lung regeneration in the PNX model. This exquisite and delicate regulation of T3 saved energy expenditure in the whole body while maintaining or enhancing the energy supply for local activation and repair processes, given that alveolar regeneration is an energetically costly process.

Open access here:

nature.com/articles/s41467-...

Sobetirome

Sobetirome (GC-1) is a thyromimetic drug that binds to the thyroid hormone receptor TRβ1 preferentially compared to TRα1. It has been investigated for the treatment of dyslipidemia, obesity, Pitt–Hopkins syndrome, cholestatic liver disease, multiple sclerosis, bleomycin-induced lung fibrosis, and COVID-19 caused ARDS. It was designated as an orphan drug by the FDA for the treatment of X-linked adrenoleukodystrophy.

en.wikipedia.org/wiki/Sobet...

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TSH110 profile image
TSH110

would this account for getting pneumonia when very young causing life long weakness to chest infections? Seems possible. I havent read it all yet. Thanks for posting

helvella profile image
helvella in reply toTSH110

A good question.

It was very much issues like that which came to my mind.

TSH110 profile image
TSH110 in reply tohelvella

I was told the bronchus is permanently scarred and this causes the weakness but this sounds more convincing to me

arTistapple profile image
arTistapple

Crikey helvella I can’t take any more today. Is anyone in endocrinology reading any of this stuff? If they are where are they filing it? The bin? Too much to cope with? Where are these brave new endocrinologists we so desperately need?

I think it was you some time ago referred to the “Janet and John” mentality of endocrinologists. Maybe is was not quite such a brutal reference.

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