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Thyroid Hormone Receptor Repression Linked to Type I Pneumocyte Associated Respiratory Distress Syndrome

Although the lung is a defining feature of air-breathing animals, the pathway controlling the formation of the type I pneumocyte, the cell that mediates gas exchange, is poorly understood. In contrast, glucocorticoids and their cognate receptor (GR) have long been known to promote type II pneumocyte...

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Autores principales: Pei, Liming, Leblanc, Mathias, Barish, Grant, Atkins, Annette, Nofsinger, Russell, Whyte, Jamie, Gold, David, He, Mingxiao, Kawamura, Kazuko, Li, Hai-Ri, Downes, Michael, Yu, Ruth T., Powell, Harry, Lingrel, Jerry B., Evans, Ronald M.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2011
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210920/
https://www.ncbi.nlm.nih.gov/pubmed/22001906
http://dx.doi.org/10.1038/nm.2450
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author Pei, Liming
Leblanc, Mathias
Barish, Grant
Atkins, Annette
Nofsinger, Russell
Whyte, Jamie
Gold, David
He, Mingxiao
Kawamura, Kazuko
Li, Hai-Ri
Downes, Michael
Yu, Ruth T.
Powell, Harry
Lingrel, Jerry B.
Evans, Ronald M.
author_facet Pei, Liming
Leblanc, Mathias
Barish, Grant
Atkins, Annette
Nofsinger, Russell
Whyte, Jamie
Gold, David
He, Mingxiao
Kawamura, Kazuko
Li, Hai-Ri
Downes, Michael
Yu, Ruth T.
Powell, Harry
Lingrel, Jerry B.
Evans, Ronald M.
author_sort Pei, Liming
collection PubMed
description Although the lung is a defining feature of air-breathing animals, the pathway controlling the formation of the type I pneumocyte, the cell that mediates gas exchange, is poorly understood. In contrast, glucocorticoids and their cognate receptor (GR) have long been known to promote type II pneumocyte maturation; prenatal administration of glucocorticoids is commonly used to attenuate the severity of infant respiratory distress syndrome (RDS). Here we show that knock-in mutations of the nuclear corepressor SMRT in C57Bl6 mice (SMRT(mRID)) produces a novel respiratory distress syndrome due to prematurity of the type I pneumocyte. Though unresponsive to glucocorticoids, treatment with anti-thyroid hormone drugs (propylthiouracil or methimazole) completely rescues the SMRT-induced RDS, suggesting an unrecognized and essential role for the thyroid hormone receptor (TR) in lung development. We show that TR and SMRT control type I pneumocyte differentiation through Klf2, which in turn appears to directly activate the type I pneumocyte gene program. Conversely, mice without lung Klf2 lack mature type I pneumocytes and die shortly after birth, closely recapitulating the SMRT(mRID) phenotype. These results identify a second nuclear receptor, the TR, in type I pneumocyte differentiation and suggest a new type of therapeutic option in the treatment of glucocorticoid non-responsive RDS.
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spelling pubmed-32109202012-04-16 Thyroid Hormone Receptor Repression Linked to Type I Pneumocyte Associated Respiratory Distress Syndrome Pei, Liming Leblanc, Mathias Barish, Grant Atkins, Annette Nofsinger, Russell Whyte, Jamie Gold, David He, Mingxiao Kawamura, Kazuko Li, Hai-Ri Downes, Michael Yu, Ruth T. Powell, Harry Lingrel, Jerry B. Evans, Ronald M. Nat Med Article Although the lung is a defining feature of air-breathing animals, the pathway controlling the formation of the type I pneumocyte, the cell that mediates gas exchange, is poorly understood. In contrast, glucocorticoids and their cognate receptor (GR) have long been known to promote type II pneumocyte maturation; prenatal administration of glucocorticoids is commonly used to attenuate the severity of infant respiratory distress syndrome (RDS). Here we show that knock-in mutations of the nuclear corepressor SMRT in C57Bl6 mice (SMRT(mRID)) produces a novel respiratory distress syndrome due to prematurity of the type I pneumocyte. Though unresponsive to glucocorticoids, treatment with anti-thyroid hormone drugs (propylthiouracil or methimazole) completely rescues the SMRT-induced RDS, suggesting an unrecognized and essential role for the thyroid hormone receptor (TR) in lung development. We show that TR and SMRT control type I pneumocyte differentiation through Klf2, which in turn appears to directly activate the type I pneumocyte gene program. Conversely, mice without lung Klf2 lack mature type I pneumocytes and die shortly after birth, closely recapitulating the SMRT(mRID) phenotype. These results identify a second nuclear receptor, the TR, in type I pneumocyte differentiation and suggest a new type of therapeutic option in the treatment of glucocorticoid non-responsive RDS. 2011-10-16 /pmc/articles/PMC3210920/ /pubmed/22001906 http://dx.doi.org/10.1038/nm.2450 Text en Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
spellingShingle Article
Pei, Liming
Leblanc, Mathias
Barish, Grant
Atkins, Annette
Nofsinger, Russell
Whyte, Jamie
Gold, David
He, Mingxiao
Kawamura, Kazuko
Li, Hai-Ri
Downes, Michael
Yu, Ruth T.
Powell, Harry
Lingrel, Jerry B.
Evans, Ronald M.
Thyroid Hormone Receptor Repression Linked to Type I Pneumocyte Associated Respiratory Distress Syndrome
title Thyroid Hormone Receptor Repression Linked to Type I Pneumocyte Associated Respiratory Distress Syndrome
title_full Thyroid Hormone Receptor Repression Linked to Type I Pneumocyte Associated Respiratory Distress Syndrome
title_fullStr Thyroid Hormone Receptor Repression Linked to Type I Pneumocyte Associated Respiratory Distress Syndrome
title_full_unstemmed Thyroid Hormone Receptor Repression Linked to Type I Pneumocyte Associated Respiratory Distress Syndrome
title_short Thyroid Hormone Receptor Repression Linked to Type I Pneumocyte Associated Respiratory Distress Syndrome
title_sort thyroid hormone receptor repression linked to type i pneumocyte associated respiratory distress syndrome
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210920/
https://www.ncbi.nlm.nih.gov/pubmed/22001906
http://dx.doi.org/10.1038/nm.2450
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