Differential expression of matrix metalloproteinases and their inhibitors in human and mouse lung development

Julie Ryu; Alfin G. Vicencio; Michael E. Yeager; Michael Kashgarian; Gabriel G. Haddad; Oliver Eickelberg

doi:10.1160/TH04-10-0656

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 94(01): 175-183
DOI: 10.1160/TH04-10-0656

Endothelium and Vascular Development

Schattauer GmbH

Differential expression of matrix metalloproteinases and their inhibitors in human and mouse lung development

Julie Ryu

¹Department of Pediatrics, Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Bronx, New York

,

Alfin G. Vicencio

¹Department of Pediatrics, Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Bronx, New York

,

Michael E. Yeager

²University of Giessen Lung Center, Department of Medicine II, Giessen University School of Medicine, Giessen, Germany

,

Michael Kashgarian

³Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA

,

Gabriel G. Haddad

¹Department of Pediatrics, Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Bronx, New York

,

Oliver Eickelberg

²University of Giessen Lung Center, Department of Medicine II, Giessen University School of Medicine, Giessen, Germany

› Author Affiliations

Abstract

Summary

Lung development is a highly orchestrated process characterized by timed expression and activation of growth factor and protease/antiprotease systems. This interplay is essential in regulating vasculogenesis, alveolarization, and epithelial to mesenchymal transition during lung development. Alterations in the proteolytic/antiproteolytic balance of the lung have been associated with several respiratory diseases characterized by changes in the lung extracellular matrix (ECM). Here, we characterized the expression pattern of matrix metalloproteases (MMP) and their inhibitors, the tissue inhibitors of metalloproteases (TIMP), in human and mouse lung development. Using MMP/TIMP expression arrays, RT-PCR, Western Blotting, and ELISA analyses, we demonstrate that fetal human lung is characterized by a dominant proteolytic profile with high MMP-2 and little TIMP-3 expression. Adult human lung, in contrast, exhibits a more anti-proteolytic profile with decreased MMP-2 and increasedTIMP-3 expression. MMP-14, MMP-20,TIMP-1, and TIMP-2 were constitutively expressed, irrespective of the developmental stage. Similar results were obtained using mouse lungs of different developmental stages, with the addition that in mouse lung, TIMP-2 and TIMP-3 were upregulated as lung development progressed. Exposure of neonatal mice to chronic hypoxia (10% O₂), a stimulus that leads to an arrest of lung development, resulted in upregulation of MMP-2 with a concomitant downregulation of TIMP-2.These results provide a comprehensive analysis of MMP and TIMP expression during human and mouse lung development. MMP-2, TIMP-2, and TIMP-3 may be key regulatory enzymes during lung development, possibly through their complex action on ECM components, membrane receptor ectodomain shedding, and growth factor bioactivity.

Keywords

MMP - TIMP - lung development - ECM - remodeling

Full Text

References

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