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Airway epithelial transcription factor NK2 homeobox 1 inhibits mucous cell metaplasia and Th2 inflammation

Airway epithelial transcription factor NK2 homeobox 1 inhibits mucous cell metaplasia and Th2 inflammation
Airway epithelial transcription factor NK2 homeobox 1 inhibits mucous cell metaplasia and Th2 inflammation
Rationale: Airway mucous cell metaplasia and chronic inflammation are pathophysiological features that influence morbidity and mortality associated with asthma and other chronic pulmonary disorders. Elucidation of the molecular mechanisms regulating mucous metaplasia and hypersecretion provides the scientific basis for diagnostic and therapeutic opportunities to improve the care of chronic pulmonary diseases.

Objectives: To determine the role of the airway epithelial–specific transcription factor NK2 homeobox 1 (NKX2-1, also known as thyroid transcription factor-1 [TTF-1]) in mucous cell metaplasia and lung inflammation.

Methods: Expression of NKX2-1 in airway epithelial cells from patients with asthma was analyzed. NKX2-1+/? gene targeted or transgenic mice expressing NKX2-1 in conducting airway epithelial cells were sensitized to the aeroallergen ovalbumin. In vitro studies were used to identify mechanisms by which NKX2-1 regulates mucous cell metaplasia and inflammation.

Measurements and Main Results: NKX2-1 was suppressed in airway epithelial cells from patients with asthma. Reduced expression of NKX2-1 in heterozygous NKX2-1+/? gene targeted mice increased mucous metaplasia in the small airways after pulmonary sensitization to ovalbumin. Conversely, mucous cell metaplasia induced by aeroallergen was inhibited by expression of NKX2-1 in the respiratory epithelium in vivo. Genome-wide mRNA analysis of lung tissue from ovalbumin-treated mice demonstrated that NKX2-1 inhibited mRNAs associated with mucous metaplasia and Th2-regulated inflammation, including Spdef, Ccl17, and Il13. In vitro, NKX2-1 inhibited SPDEF, a critical regulator of airway mucous cell metaplasia, and the Th2 chemokine CCL26.

Conclusions: The present data demonstrate a novel function for NKX2-1 in a gene network regulating mucous cell metaplasia and allergic inflammation in the respiratory epithelium.
asthma, goblet cell, respiratory epithelium, NK2 homeobox 1
1073-449X
421-429
Maeda, Yutaka
93d2b566-1f36-4c02-a1a4-8cc8a7e89e9b
Chen, Gang
83a5c46f-13cc-4be3-ad5b-698a69e82b8e
Xu, Yan
2b4952f1-3855-4a5d-a8b0-777561a292e1
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
Du, Lingling
89d358e6-4497-4a27-b571-e79782a227d7
Keiser, Angela R.
cef98368-5930-4040-830b-fafec02f714e
Howarth, Peter H.
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Davies, Donna E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Holgate, Stephen T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b
Maeda, Yutaka
93d2b566-1f36-4c02-a1a4-8cc8a7e89e9b
Chen, Gang
83a5c46f-13cc-4be3-ad5b-698a69e82b8e
Xu, Yan
2b4952f1-3855-4a5d-a8b0-777561a292e1
Haitchi, Hans Michael
68dadb29-305d-4236-884f-e9c93f4d78fe
Du, Lingling
89d358e6-4497-4a27-b571-e79782a227d7
Keiser, Angela R.
cef98368-5930-4040-830b-fafec02f714e
Howarth, Peter H.
ff19c8c4-86b0-4a88-8f76-b3d87f142a21
Davies, Donna E.
7de8fdc7-3640-4e3a-aa91-d0e03f990c38
Holgate, Stephen T.
2e7c17a9-6796-436e-8772-1fe6d2ac5edc
Whitsett, Jeffrey A.
84fb8fc3-212e-4741-8934-d4083cd6549b

Maeda, Yutaka, Chen, Gang, Xu, Yan, Haitchi, Hans Michael, Du, Lingling, Keiser, Angela R., Howarth, Peter H., Davies, Donna E., Holgate, Stephen T. and Whitsett, Jeffrey A. (2011) Airway epithelial transcription factor NK2 homeobox 1 inhibits mucous cell metaplasia and Th2 inflammation. American Journal of Respiratory and Critical Care Medicine, 184 (4), 421-429. (doi:10.1164/rccm.201101-0106OC). (PMID:21562130)

Record type: Article

Abstract

Rationale: Airway mucous cell metaplasia and chronic inflammation are pathophysiological features that influence morbidity and mortality associated with asthma and other chronic pulmonary disorders. Elucidation of the molecular mechanisms regulating mucous metaplasia and hypersecretion provides the scientific basis for diagnostic and therapeutic opportunities to improve the care of chronic pulmonary diseases.

Objectives: To determine the role of the airway epithelial–specific transcription factor NK2 homeobox 1 (NKX2-1, also known as thyroid transcription factor-1 [TTF-1]) in mucous cell metaplasia and lung inflammation.

Methods: Expression of NKX2-1 in airway epithelial cells from patients with asthma was analyzed. NKX2-1+/? gene targeted or transgenic mice expressing NKX2-1 in conducting airway epithelial cells were sensitized to the aeroallergen ovalbumin. In vitro studies were used to identify mechanisms by which NKX2-1 regulates mucous cell metaplasia and inflammation.

Measurements and Main Results: NKX2-1 was suppressed in airway epithelial cells from patients with asthma. Reduced expression of NKX2-1 in heterozygous NKX2-1+/? gene targeted mice increased mucous metaplasia in the small airways after pulmonary sensitization to ovalbumin. Conversely, mucous cell metaplasia induced by aeroallergen was inhibited by expression of NKX2-1 in the respiratory epithelium in vivo. Genome-wide mRNA analysis of lung tissue from ovalbumin-treated mice demonstrated that NKX2-1 inhibited mRNAs associated with mucous metaplasia and Th2-regulated inflammation, including Spdef, Ccl17, and Il13. In vitro, NKX2-1 inhibited SPDEF, a critical regulator of airway mucous cell metaplasia, and the Th2 chemokine CCL26.

Conclusions: The present data demonstrate a novel function for NKX2-1 in a gene network regulating mucous cell metaplasia and allergic inflammation in the respiratory epithelium.

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More information

e-pub ahead of print date: 11 May 2011
Published date: 15 August 2011
Keywords: asthma, goblet cell, respiratory epithelium, NK2 homeobox 1
Organisations: Faculty of Medicine, Infection Inflammation & Immunity

Identifiers

Local EPrints ID: 188617
URI: http://eprints.soton.ac.uk/id/eprint/188617
ISSN: 1073-449X
PURE UUID: e3af11f1-92fe-4dd1-a418-5d1e04d94d9d
ORCID for Hans Michael Haitchi: ORCID iD orcid.org/0000-0001-8603-302X
ORCID for Donna E. Davies: ORCID iD orcid.org/0000-0002-5117-2991

Catalogue record

Date deposited: 26 May 2011 08:54
Last modified: 26 Nov 2019 02:08

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Contributors

Author: Yutaka Maeda
Author: Gang Chen
Author: Yan Xu
Author: Lingling Du
Author: Angela R. Keiser
Author: Donna E. Davies ORCID iD
Author: Jeffrey A. Whitsett

University divisions

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