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

Abstract

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 neoangiogenesis 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.

Metalloproteinases in idiopathic pulmonary fibrosis

“…Several studies have suggested that there is an increase in MMPs, rather than a loss of MMPs, in IPF ( fig. 2) [9]. Elevated levels of MMP-1, MMP-2, MMP-3, MMP-7, MMP-8 and MMP-9 have been reported.…”

“…Together, these changes result in an increase in the permeability of the alveolar capillary barrier, which can be detected clinically by increased diethylene triamine penta-acetic acid clearance [8]. Increased alveolar capillary barrier permeability may also be associated with early mortality in IPF [9]. Therefore, at least two different cellular routes exist -an inflammatory pathway, represented by most ILDs, and an epithelial pathway, as seen in IPF -that lead to the development of lung fibrosis [10].…”

A therapeutic role for matrix metalloproteinase inhibitors in lung diseases?

“…Indeed, lavage fluid from IPF patients shows increased concentrations of several MMPs (e.g. MMP3, 7, 8 and 9), abnormal capillary permeability and increased VEGF levels [141][142][143][144]. Fibrocytes, which are progenitor cells characterised by the simultaneous expression of mesenchymal, monocytic and haematopoietic stem cell markers, were recently proposed to be an important source of MMPs during pulmonary fibrosis pathogenesis [145].…”

Recent advances in the pathogenesis and clinical evaluation of pulmonary fibrosis

“…MMPs are believed to participate in the pathogenesis of pulmonary fibrosis and, in fact, MMP-3, -7, -8 and -9 are elevated in the BAL of IPF patients who had worse outcome [108]. Serum levels of CCL-18, a chemokine produced by alveolar macrophages, is independently predictive of mortality in IPF [109].…”