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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
1   Department of Pediatrics, Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Bronx, New York
,
Alfin G. Vicencio
1   Department of Pediatrics, Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Bronx, New York
,
Michael E. Yeager
2   University of Giessen Lung Center, Department of Medicine II, Giessen University School of Medicine, Giessen, Germany
,
Michael Kashgarian
3   Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, USA
,
Gabriel G. Haddad
1   Department of Pediatrics, Albert Einstein College of Medicine and Children’s Hospital at Montefiore, Bronx, New York
,
Oliver Eickelberg
2   University of Giessen Lung Center, Department of Medicine II, Giessen University School of Medicine, Giessen, Germany
› Author AffiliationsFinancial support: This study was supported by the Sofja Kovalevskaja Award from the Alexander von Humboldt Association (to O.E.), the German Research Foundation (DFG SFB547-N1) (to O.E.), and NIH-PO1–32573 HD (to G.G.H.)
Further Information

Publication History

Received 10 October 2004

Accepted after resubmission 07 May 2005

Publication Date:
05 December 2017 (online)

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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
 

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