Matrix metalloproteinase activity in the lung is increased in Hermansky-Pudlak syndrome.
Publication/Presentation Date
7-4-2019
Abstract
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.
Volume
14
Issue
1
First Page
162
Last Page
162
ISSN
1750-1172
Published In/Presented At
Summer, R., Krishna, R., Schriner, D., Cuevas-Mora, K., Sales, D., Para, R., Roman, J., Nieweld, C., Gochuico, B. R., & Romero, F. (2019). Matrix metalloproteinase activity in the lung is increased in Hermansky-Pudlak syndrome. Orphanet journal of rare diseases, 14(1), 162. https://doi.org/10.1186/s13023-019-1143-0
Disciplines
Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods
PubMedID
31272455
Department(s)
Administration and Leadership
Document Type
Article