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Matrix metalloproteinase activity in the lung is increased in Hermansky-Pudlak syndrome

BACKGROUND: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and platelet dysfunction and can sometimes lead to a highly aggressive form of pulmonary fibrosis that mimics the fatal lung condition called idiopathic pulmonary fibrosis (IPF...

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Autores principales: Summer, Ross, Krishna, Rachana, Schriner, DeLeila, Cuevas-Mora, Karina, Sales, Dominic, Para, Rachel, Roman, Jesse, Nieweld, Carl, Gochuico, Bernadette R., Romero, Freddy
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610946/
https://www.ncbi.nlm.nih.gov/pubmed/31272455
http://dx.doi.org/10.1186/s13023-019-1143-0
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author Summer, Ross
Krishna, Rachana
Schriner, DeLeila
Cuevas-Mora, Karina
Sales, Dominic
Para, Rachel
Roman, Jesse
Nieweld, Carl
Gochuico, Bernadette R.
Romero, Freddy
author_facet Summer, Ross
Krishna, Rachana
Schriner, DeLeila
Cuevas-Mora, Karina
Sales, Dominic
Para, Rachel
Roman, Jesse
Nieweld, Carl
Gochuico, Bernadette R.
Romero, Freddy
author_sort Summer, Ross
collection PubMed
description BACKGROUND: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and platelet dysfunction and can sometimes lead to a highly aggressive form of pulmonary fibrosis that mimics the fatal lung condition called idiopathic pulmonary fibrosis (IPF). Although the activities of various matrix metalloproteinases (MMPs) are known to be dysregulated in IPF, it remains to be determined whether similar changes in these enzymes can be detected in HPS. RESULTS: Here, we show that transcript and protein levels as well as enzymatic activities of MMP-2 and -9 are markedly increased in the lungs of mice carrying the HPS Ap3b1 gene mutation. Moreover, immunohistochemical staining localized this increase in MMP expression to the distal pulmonary epithelium, and shRNA knockdown of the Ap3b1 gene in cultured lung epithelial cells resulted in a similar upregulation in MMP-2 and -9 expression. Mechanistically, we found that upregulation in MMP expression associated with increased activity of the serine/threonine kinase Akt, and pharmacological inhibition of this enzyme resulted in a dramatic suppression of MMP expression in Ap3b1 deficient lung epithelial cells. Similarly, levels and activity of different MMPs were also found to be increased in the lungs of mice carrying the Bloc3 HPS gene mutation and in the bronchoalveolar lavage fluid of subjects with HPS. However, an association between MMP activity and disease severity was not detected in these individuals. CONCLUSIONS: In summary, our findings indicate that MMP activity is dysregulated in the HPS lung, suggesting a role for these proteases as biological markers or pathogenic players in HPS lung disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13023-019-1143-0) contains supplementary material, which is available to authorized users.
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spelling pubmed-66109462019-07-16 Matrix metalloproteinase activity in the lung is increased in Hermansky-Pudlak syndrome Summer, Ross Krishna, Rachana Schriner, DeLeila Cuevas-Mora, Karina Sales, Dominic Para, Rachel Roman, Jesse Nieweld, Carl Gochuico, Bernadette R. Romero, Freddy Orphanet J Rare Dis Research BACKGROUND: Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder characterized by oculocutaneous albinism and platelet dysfunction and can sometimes lead to a highly aggressive form of pulmonary fibrosis that mimics the fatal lung condition called idiopathic pulmonary fibrosis (IPF). Although the activities of various matrix metalloproteinases (MMPs) are known to be dysregulated in IPF, it remains to be determined whether similar changes in these enzymes can be detected in HPS. RESULTS: Here, we show that transcript and protein levels as well as enzymatic activities of MMP-2 and -9 are markedly increased in the lungs of mice carrying the HPS Ap3b1 gene mutation. Moreover, immunohistochemical staining localized this increase in MMP expression to the distal pulmonary epithelium, and shRNA knockdown of the Ap3b1 gene in cultured lung epithelial cells resulted in a similar upregulation in MMP-2 and -9 expression. Mechanistically, we found that upregulation in MMP expression associated with increased activity of the serine/threonine kinase Akt, and pharmacological inhibition of this enzyme resulted in a dramatic suppression of MMP expression in Ap3b1 deficient lung epithelial cells. Similarly, levels and activity of different MMPs were also found to be increased in the lungs of mice carrying the Bloc3 HPS gene mutation and in the bronchoalveolar lavage fluid of subjects with HPS. However, an association between MMP activity and disease severity was not detected in these individuals. CONCLUSIONS: In summary, our findings indicate that MMP activity is dysregulated in the HPS lung, suggesting a role for these proteases as biological markers or pathogenic players in HPS lung disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s13023-019-1143-0) contains supplementary material, which is available to authorized users. BioMed Central 2019-07-04 /pmc/articles/PMC6610946/ /pubmed/31272455 http://dx.doi.org/10.1186/s13023-019-1143-0 Text en © The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Summer, Ross
Krishna, Rachana
Schriner, DeLeila
Cuevas-Mora, Karina
Sales, Dominic
Para, Rachel
Roman, Jesse
Nieweld, Carl
Gochuico, Bernadette R.
Romero, Freddy
Matrix metalloproteinase activity in the lung is increased in Hermansky-Pudlak syndrome
title Matrix metalloproteinase activity in the lung is increased in Hermansky-Pudlak syndrome
title_full Matrix metalloproteinase activity in the lung is increased in Hermansky-Pudlak syndrome
title_fullStr Matrix metalloproteinase activity in the lung is increased in Hermansky-Pudlak syndrome
title_full_unstemmed Matrix metalloproteinase activity in the lung is increased in Hermansky-Pudlak syndrome
title_short Matrix metalloproteinase activity in the lung is increased in Hermansky-Pudlak syndrome
title_sort matrix metalloproteinase activity in the lung is increased in hermansky-pudlak syndrome
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6610946/
https://www.ncbi.nlm.nih.gov/pubmed/31272455
http://dx.doi.org/10.1186/s13023-019-1143-0
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