MicroRNA let-7 downregulates ligand-independent estrogen receptor–mediated male-predominant pulmonary fibrosis

Sharon Elliot, Simone Periera-Simon, Xiaomei Xia, Paola Catanuto, Gustavo Rubio, Shahriar Shahzeidi, Fadi El Salem, Josh Shapiro, Karoline Briegel, Kenneth S. Korach, Marilyn K. Glassberg

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Rationale: The relevance of hormones in idiopathic pulmonary fibrosis (IPF), a predominantly male lung disease, is unknown. Objectives: To determine whether the ER (estrogen receptor) facilitates the development of pulmonary fibrosis and is mediated in part through microRNA regulation of ERa and ERa-activated profibrotic pathways. Methods: ER expression in male lung tissue and myofibroblasts from control subjects (n = 6) and patients with IPF (n = 6), aging bleomycin (BLM)-treated mice (n = 7), and BLM-treated AF2ERKI mice (n = 7) was determined. MicroRNAs that regulate ER and fibrotic pathways were assessed. Transfections with a reporter plasmid containing the 39 untranslated region of the gene encoding ERa (ESR1) with and without miRNA let-7 mimics or inhibitors or an estrogen response element–driven reporter construct (ERE) construct were conducted. Measurements and Main Results: ERa expression increased in IPF lung tissue, myofibroblasts, or BLM mice. In vitro treatment with let-7 mimic transfections in human myofibroblasts reduced ERa expression and associated fibrotic pathways. AF2ERKI mice developed BLM-induced lung fibrosis, suggesting a role for growth factors in stimulating ER and fibrosis. IGF-1 (insulin-like growth factor 1) expression was increased and induced a fourfold increase of an ERE construct. Conclusions: Our data show 1) a critical role for ER and let-7 in lung fibrosis, and 2) that IGF may stimulate ER in an E2-independent manner. These results underscore the role of sex steroid hormones and their receptors in diseases that demonstrate a sex prevalence, such as IPF.

Original languageEnglish (US)
Pages (from-to)1246-1257
Number of pages12
JournalAmerican journal of respiratory and critical care medicine
Volume200
Issue number10
DOIs
StatePublished - Nov 15 2019

Fingerprint

Pulmonary Fibrosis
MicroRNAs
Estrogen Receptors
Idiopathic Pulmonary Fibrosis
Estrogens
Down-Regulation
Bleomycin
Ligands
Myofibroblasts
Lung
Fibrosis
Transfection
Untranslated Regions
Insulin-Like Growth Factor II
Gonadal Steroid Hormones
Somatomedins
Lung Diseases
Intercellular Signaling Peptides and Proteins
Plasmids
Hormones

Keywords

  • Estrogen receptor
  • MicroRNA let-7
  • Pulmonary fibrosis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine

Cite this

MicroRNA let-7 downregulates ligand-independent estrogen receptor–mediated male-predominant pulmonary fibrosis. / Elliot, Sharon; Periera-Simon, Simone; Xia, Xiaomei; Catanuto, Paola; Rubio, Gustavo; Shahzeidi, Shahriar; El Salem, Fadi; Shapiro, Josh; Briegel, Karoline; Korach, Kenneth S.; Glassberg, Marilyn K.

In: American journal of respiratory and critical care medicine, Vol. 200, No. 10, 15.11.2019, p. 1246-1257.

Research output: Contribution to journalArticle

Elliot, S, Periera-Simon, S, Xia, X, Catanuto, P, Rubio, G, Shahzeidi, S, El Salem, F, Shapiro, J, Briegel, K, Korach, KS & Glassberg, MK 2019, 'MicroRNA let-7 downregulates ligand-independent estrogen receptor–mediated male-predominant pulmonary fibrosis', American journal of respiratory and critical care medicine, vol. 200, no. 10, pp. 1246-1257. https://doi.org/10.1164/rccm.201903-0508OC
Elliot, Sharon ; Periera-Simon, Simone ; Xia, Xiaomei ; Catanuto, Paola ; Rubio, Gustavo ; Shahzeidi, Shahriar ; El Salem, Fadi ; Shapiro, Josh ; Briegel, Karoline ; Korach, Kenneth S. ; Glassberg, Marilyn K. / MicroRNA let-7 downregulates ligand-independent estrogen receptor–mediated male-predominant pulmonary fibrosis. In: American journal of respiratory and critical care medicine. 2019 ; Vol. 200, No. 10. pp. 1246-1257.
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abstract = "Rationale: The relevance of hormones in idiopathic pulmonary fibrosis (IPF), a predominantly male lung disease, is unknown. Objectives: To determine whether the ER (estrogen receptor) facilitates the development of pulmonary fibrosis and is mediated in part through microRNA regulation of ERa and ERa-activated profibrotic pathways. Methods: ER expression in male lung tissue and myofibroblasts from control subjects (n = 6) and patients with IPF (n = 6), aging bleomycin (BLM)-treated mice (n = 7), and BLM-treated AF2ERKI mice (n = 7) was determined. MicroRNAs that regulate ER and fibrotic pathways were assessed. Transfections with a reporter plasmid containing the 39 untranslated region of the gene encoding ERa (ESR1) with and without miRNA let-7 mimics or inhibitors or an estrogen response element–driven reporter construct (ERE) construct were conducted. Measurements and Main Results: ERa expression increased in IPF lung tissue, myofibroblasts, or BLM mice. In vitro treatment with let-7 mimic transfections in human myofibroblasts reduced ERa expression and associated fibrotic pathways. AF2ERKI mice developed BLM-induced lung fibrosis, suggesting a role for growth factors in stimulating ER and fibrosis. IGF-1 (insulin-like growth factor 1) expression was increased and induced a fourfold increase of an ERE construct. Conclusions: Our data show 1) a critical role for ER and let-7 in lung fibrosis, and 2) that IGF may stimulate ER in an E2-independent manner. These results underscore the role of sex steroid hormones and their receptors in diseases that demonstrate a sex prevalence, such as IPF.",
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T1 - MicroRNA let-7 downregulates ligand-independent estrogen receptor–mediated male-predominant pulmonary fibrosis

AU - Elliot, Sharon

AU - Periera-Simon, Simone

AU - Xia, Xiaomei

AU - Catanuto, Paola

AU - Rubio, Gustavo

AU - Shahzeidi, Shahriar

AU - El Salem, Fadi

AU - Shapiro, Josh

AU - Briegel, Karoline

AU - Korach, Kenneth S.

AU - Glassberg, Marilyn K.

PY - 2019/11/15

Y1 - 2019/11/15

N2 - Rationale: The relevance of hormones in idiopathic pulmonary fibrosis (IPF), a predominantly male lung disease, is unknown. Objectives: To determine whether the ER (estrogen receptor) facilitates the development of pulmonary fibrosis and is mediated in part through microRNA regulation of ERa and ERa-activated profibrotic pathways. Methods: ER expression in male lung tissue and myofibroblasts from control subjects (n = 6) and patients with IPF (n = 6), aging bleomycin (BLM)-treated mice (n = 7), and BLM-treated AF2ERKI mice (n = 7) was determined. MicroRNAs that regulate ER and fibrotic pathways were assessed. Transfections with a reporter plasmid containing the 39 untranslated region of the gene encoding ERa (ESR1) with and without miRNA let-7 mimics or inhibitors or an estrogen response element–driven reporter construct (ERE) construct were conducted. Measurements and Main Results: ERa expression increased in IPF lung tissue, myofibroblasts, or BLM mice. In vitro treatment with let-7 mimic transfections in human myofibroblasts reduced ERa expression and associated fibrotic pathways. AF2ERKI mice developed BLM-induced lung fibrosis, suggesting a role for growth factors in stimulating ER and fibrosis. IGF-1 (insulin-like growth factor 1) expression was increased and induced a fourfold increase of an ERE construct. Conclusions: Our data show 1) a critical role for ER and let-7 in lung fibrosis, and 2) that IGF may stimulate ER in an E2-independent manner. These results underscore the role of sex steroid hormones and their receptors in diseases that demonstrate a sex prevalence, such as IPF.

AB - Rationale: The relevance of hormones in idiopathic pulmonary fibrosis (IPF), a predominantly male lung disease, is unknown. Objectives: To determine whether the ER (estrogen receptor) facilitates the development of pulmonary fibrosis and is mediated in part through microRNA regulation of ERa and ERa-activated profibrotic pathways. Methods: ER expression in male lung tissue and myofibroblasts from control subjects (n = 6) and patients with IPF (n = 6), aging bleomycin (BLM)-treated mice (n = 7), and BLM-treated AF2ERKI mice (n = 7) was determined. MicroRNAs that regulate ER and fibrotic pathways were assessed. Transfections with a reporter plasmid containing the 39 untranslated region of the gene encoding ERa (ESR1) with and without miRNA let-7 mimics or inhibitors or an estrogen response element–driven reporter construct (ERE) construct were conducted. Measurements and Main Results: ERa expression increased in IPF lung tissue, myofibroblasts, or BLM mice. In vitro treatment with let-7 mimic transfections in human myofibroblasts reduced ERa expression and associated fibrotic pathways. AF2ERKI mice developed BLM-induced lung fibrosis, suggesting a role for growth factors in stimulating ER and fibrosis. IGF-1 (insulin-like growth factor 1) expression was increased and induced a fourfold increase of an ERE construct. Conclusions: Our data show 1) a critical role for ER and let-7 in lung fibrosis, and 2) that IGF may stimulate ER in an E2-independent manner. These results underscore the role of sex steroid hormones and their receptors in diseases that demonstrate a sex prevalence, such as IPF.

KW - Estrogen receptor

KW - MicroRNA let-7

KW - Pulmonary fibrosis

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