MMP3 and lung fibrosis

An increase in MMP3 was found in IPF lung tissue. Mmmp3–/– mice were protected from bleomycin induced lung fibrosis, through beta-catenin mediated EMT.


References:
Am J Pathol. 2011 Oct;179(4):1733-45. Epub 2011 Aug 24.
Matrix metalloproteinase 3 is a mediator of pulmonary fibrosis.
Yamashita CM, Dolgonos L, Zemans RL, Young SK, Robertson J, Briones N, Suzuki T, Campbell MN, Gauldie J, Radisky DC, Riches DW, Yu G, Kaminski N, McCulloch CA, Downey GP.
Source
Department of Medicine, University of Western Ontario, London, Ontario, Canada; Division of Pulmonary and Critical Care Medicine, Departments of Medicine and Pediatrics, National Jewish Health, Denver, Colorado.
Abstract
Idiopathic pulmonary fibrosis (IPF) may be triggered by epithelial injury that results in aberrant production of growth factors, cytokines, and proteinases, leading to proliferation of myofibroblasts, excess deposition of collagen, and destruction of the lung architecture. The precise mechanisms and key signaling mediators responsible for this aberrant repair process remain unclear. We assessed the importance of matrix metalloproteinase-3 (MMP-3) in the pathogenesis of IPF through i) determination of MMP-3 expression in patients with IPF, ii) in vivo experiments examining the relevance of MMP-3 in experimental models of fibrosis, and iii) in vitro experiments to elucidate possible mechanisms of action. Gene expression analysis, quantitative RT-PCR, and Western blot analysis of explanted human lungs revealed enhanced expression of MMP-3 in IPF, compared with control. Transient adenoviral vector-mediated expression of recombinant MMP-3 in rat lung resulted in accumulation of myofibroblasts and pulmonary fibrosis. Conversely, MMP-3-null mice were protected against bleomycin-induced pulmonary fibrosis. In vitro treatment of cultured lung epithelial cells with purified MMP-3 resulted in activation of the β-catenin signaling pathway, via cleavage of E-cadherin, and induction of epithelial-mesenchymal transition. These processes were inhibited in bleomycin-treated MMP-3-null mice, as assessed by cytosolic translocation of β-catenin and cyclin D1 expression. These observations support a novel role for MMP-3 in the pathogenesis of IPF, through activation of β-catenin signaling and induction of epithelial-mesenchymal transition.
Copyright © 2011 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
PMID: 21871427 [PubMed - in process] PMCID: PMC3181358 [Available on 2012/10/1]

Plasma proteins predict IPF

With a cohort of 241 IPF patients, a recent study found that high concentrations of MMP7, ICAM1, IL8, VCAM1, and S100A12 predicted poor overall survival, poor transplant free survival and poor progression free survival in the derivation cohort.



References:
Am J Respir Crit Care Med. 2011 Oct 20. [Epub ahead of print]
Peripheral Blood Proteins Predict Mortality in Idiopathic Pulmonary Fibrosis.
Richards TJ, Kaminski N, Baribaud F, Flavin S, Brodmerkel C, Horowitz D, Li K, Choi J, Vuga LJ, Lindell KO, Klesen M, Zhang Y, Gibson KF.
Source
Medicine/PACCM, University of Pittsburgh, Pittsburgh, Pennsylvania, United States.
Abstract
Introduction/

BACKGROUND:
Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease of unknown etiology with a variable and unpredictable course. The aim of this study was to identify and validate plasma proteins that are predictive of outcome in IPF.

METHODS:
Plasma samples were available for 241 IPF patients (140 - derivation and 101 validation). In derivation cohort, concentrations of 92 proteins were analyzed using a multiplex bead-based immunoassay and concentrations of MMP7, MMP1, and SPD were assessed by ELISA. In the validation cohort concentrations of ICAM1, IL8, VCAM1 were assessed by bead-based multiplex assay, and S100A12 and MMP7 by ELISA. Associations of biomarkers with mortality, transplant free survival, and disease progression were tested in derivation and validation cohorts using nonparametric methods of survival analysis and the Cox proportional hazards model, and an integrated risk prediction score was derived and tested.

RESULTS:
High concentrations of MMP7, ICAM1, IL8, VCAM1, and S100A12 predicted poor overall survival, poor transplant free survival and poor progression free survival in the derivation cohort. In the independent validation cohort high concentrations of all five were predictive of poor transplant free survival, MMP7, ICAM1, and IL8 of overall survival and ICAM1 of poor progression free survival. The personal clinical and molecular mortality prediction index (PCMI) derived in the derivation cohort was highly predictive of mortality in the validation cohort.

CONCLUSIONS:
Our results suggest that plasma proteins should be evaluated as a tool for prognosis determination in prioritization of patients for lung transplantation and stratification in drug studies.

PMID: 22016448 [PubMed - as supplied by publisher]