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MMP expression and abnormal lung permeability are important determinants of outcome in IPF

¹ Respiratory Medicine Research Group, The Queen's University of Belfast, Belfast, and ² Lung Injury and Fibrosis Treatment Programme, Dept of Medical Sciences, Medical School, University of Birmingham, Birmingham, UK.

CORRESPONDENCE: D. R. Thickett, c/o Lung Investigation Unit, 1st floor Nuffield House, Birmingham, B15 2TH, UK. Fax: 44 1216272012. E-mail: d.thickett{at}bham.ac.uk

Keywords: Idiopathic pulmonary fibrosis, matrix metalloproteinase, vascular endothelial growth factor

Received: April 21, 2008
Accepted September 15, 2008

Matrix metalloproteinases (MMPs) degrade all of the extracellular matrix components of the intersititium and may play a role in abnormal alveolar permeability, which is a feature of idiopathic pulmonary fibrosis (IPF). The aims of the present study were to evaluate MMP protein levels in patients with IPF and determine any relationship to treatment and markers of permeability.

In total, 20 patients with IPF and eight normal controls underwent bronchoalveolar lavage. MMP, tissue inhibitor of metalloproteinase, and vascular endothelial growth factor (VEGF) levels were related to clinical outcome and protein permeability index.

MMP-3, -7, -8 and -9 were elevated in IPF lavage fluid and levels remained high despite treatment. Levels of MMP-3, -7, -8 and -9, VEGF and protein permeability index were higher in those who died early during follow-up. VEGF, and MMP-8 and -9 levels were higher in those with a rapidly declining lung function over 1 yr. Levels of MMP-3, -7, -8 and -9 correlated with an increased permeability index.

Matrix metalloproteinase levels were elevated in idiopathic pulmonary fibrosis patients and were not modulated by current standard treatment. Matrix metalloproteinase production through an interaction with the known vascular permogen, vascular endothelial growth factor, was potentially associated with abnormal capillary permeability and may have potentiated the neo-angiogenesis seen in idiopathic pulmonary fibrosis. The changes were greatest in those who died or progressed during follow-up, suggesting that drugs targeting vascular endothelial growth factor or matrix metalloproteinase activity warrant assessment as novel therapy for idiopathic pulmonary fibrosis.