Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function

[helvella]

For anyone who is interested, the full article should be available on PubMed Central from 2018-06-04.

Yet another paper which identifies thyroid hormone as a possible treatment for something that is not classically thought of as hypothyroidism.

Nat Med. 2018 Jan;24(1):39-49. doi: 10.1038/nm.4447. Epub 2017 Dec 4.

Thyroid hormone inhibits lung fibrosis in mice by improving epithelial mitochondrial function.

Yu G1, Tzouvelekis A1,2, Wang R1, Herazo-Maya JD1, Ibarra GH1, Srivastava A1, de Castro JPW3,4, DeIuliis G1, Ahangari F1, Woolard T1, Aurelien N1, Arrojo E Drigo R5, Gan Y1, Graham M6, Liu X6, Homer RJ7,8, Scanlan TS9, Mannam P1, Lee PJ1, Herzog EL1, Bianco AC3, Kaminski N1.

Author information

1 Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut, USA.

2 Division of Immunology, Biomedical Sciences Research Center "Alexander Fleming", Athens, Greece.

3 Division of Endocrinology/Metabolism, Rush University Medical Center, Chicago, Illinois, USA.

4 Biophysics Institute, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil.

5 The Salk Institute for Biological Studies, Molecular and Cell Biology Laboratory, La Jolla, California, USA.

6 CCMI Electron Microscopy Core Facility, Yale University School of Medicine, New Haven, Connecticut, USA.

7 Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA.

8 Pathology and Laboratory Medicine Service, VA Connecticut HealthCare System, West Haven, Connecticut, USA.

9 Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon, USA.

Abstract

Thyroid hormone (TH) is critical for the maintenance of cellular homeostasis during stress responses, but its role in lung fibrosis is unknown. Here we found that the activity and expression of iodothyronine deiodinase 2 (DIO2), an enzyme that activates TH, were higher in lungs from patients with idiopathic pulmonary fibrosis than in control individuals and were correlated with disease severity. We also found that Dio2-knockout mice exhibited enhanced bleomycin-induced lung fibrosis. Aerosolized TH delivery increased survival and resolved fibrosis in two models of pulmonary fibrosis in mice (intratracheal bleomycin and inducible TGF-β1). Sobetirome, a TH mimetic, also blunted bleomycin-induced lung fibrosis. After bleomycin-induced injury, TH promoted mitochondrial biogenesis, improved mitochondrial bioenergetics and attenuated mitochondria-regulated apoptosis in alveolar epithelial cells both in vivo and in vitro. TH did not blunt fibrosis in Ppargc1a- or Pink1-knockout mice, suggesting dependence on these pathways. We conclude that the antifibrotic properties of TH are associated with protection of alveolar epithelial cells and restoration of mitochondrial function and that TH may thus represent a potential therapy for pulmonary fibrosis.

PMID: 29200204

PMCID: PMC5760280 [Available on 2018-06-04]

DOI: 10.1038/nm.4447

ncbi.nlm.nih.gov/pubmed/292...

[Aurealis]

Do they specify which thyroid hormone?

[helvella Administrator in reply to Aurealis]

You and I are both limited to seeing exactly what I posted - unfortunately. But if anyone does have access... ?

That was my first question as well.

[helvella Administrator in reply to Aurealis]

They did mention Sobetirome which is classed as a thyroid hormone analog.

pubchem.ncbi.nlm.nih.gov/co...

[crimple]

Interesting, thanks for posting

[thyras]

They are using T3 in a gas form,

"

<strong>Thyroid hormone blunts lung fibrosis in two mouse models

</strong>

Systemic administration of T4 (100 μg per kg body weight, μg/kg) at days 10, 12, 14 and 16 after bleomycin administration significantly blunted fibrosis but caused a significant increase in serum T3 levels (Supplementary Fig. 1). To avoid the side effects of systemic administration of T4 and maximize therapeutic efficacy, we focused on pulmonary delivery by aerosol of the physiologically active T3 hormone. Therapy with aerosolized T3 (40 μg/kg), given every other day starting at the stage of established fibrosis (days 10–20 after bleomycin administration), caused a significant decrease in hydroxyproline levels (2.25-fold, P < 0.05) (Fig. 2a) and reduction of histological evidence of fibrosis (Fig. 2b), without affecting serum T3 levels (Fig. 2c). The effects were comparable to those observed with oral administration of pirfenidone (100 mg per kg body weight, mg/kg) or nintedanib (60 mg/kg), the two drugs currently approved by the US Food and Drug Administration (FDA) for treatment of human IPF15 (Fig. 2a,b).

"

From this type of studies I get the impression that the effects of T3 in compared to medicines that are under developent or as in this case, are already are in use.

[helvella Administrator in reply to thyras]

Thank you once again.

[thyras in reply to helvella]

Thank you.

The argument that the standards treatment with T4 caused elevated levels of T3 and to avoid side effects and therefore was not used but T3 instead - was strange since the T3-treatment was kind of boosted. Hm...

[helvella Administrator in reply to thyras]

Yes, but...

That approach avoids high T3 blood levels and consequent systemic effects. But achieves relatively high T3 levels in the cells forming the lung lining - where it is needed.