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Review
. 2008 Feb;10(2):343-54.
doi: 10.1089/ars.2007.1908.

Extracellular superoxide dismutase in pulmonary fibrosis

Fei Gao  1 , Vuokko L Kinnula, Marjukka Myllärniemi, Tim D Oury
Affiliations
Review

Extracellular superoxide dismutase in pulmonary fibrosis

Fei Gao et al. Antioxid Redox Signal. 2008 Feb.

Abstract

Disruption of the oxidant/antioxidant balance in the lung is thought to be a key step in the development of many airway pathologies. Hence, antioxidant enzymes play key roles in controlling or preventing pulmonary diseases related to oxidative stress. The superoxide dismutases (SOD) are a family of enzymes that play a pivotal role protecting tissues from damage by oxidant stress by scavenging superoxide anion, which prevents the formation of other more potent oxidants such as peroxynitrite and hydroxyl radical. Extracellular SOD (EC-SOD) is found predominantly in the extracellular matrix of tissues and is ideally situated to prevent cell and tissue damage initiated by extracellularly produced ROS. EC-SOD has been shown to be protective in several models of interstitial lung disease, including pulmonary fibrosis. In addition, alterations in EC-SOD expression are also present in human idiopathic pulmonary fibrosis (IPF). This review discusses EC-SOD regulation in response to pulmonary fibrosis in animals and humans and reviews possible mechanisms by which EC-SOD may protect against fibrosis.

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Figures

FIG. 1
FIG. 1. Potential roles of reactive oxygen species (ROS) in the pathogenesis of pulmonary fibrosis
Multiple factors create a redox imbalance, resulting in the production of ROS. ROS can degrade several components of the extracellular matrix, causing ECM remodeling. The ECM fragments produced can lead to inflammatory cell recruitment to the site and further increases ROS production. Meanwhile, persistent inflammation can also trigger the fibrogenic process. ROS and ROS-induced ECM fragmentation products can also activate fibrotic cytokines/growth factors such as TGF-β, thus enhancing this process. EC-SOD can significantly reduce the oxidative stress in the lung parenchyma both in experimental models of lung fibrosis and in human lung.
FIG. 2
FIG. 2. This schematic diagram illustrates the heparin-binding affinity patterns of EC-SOD as well as a naturally occurring EC-SOD mutation
Tissues contain predominantly type C EC-SOD, which consists of a tetramer in which all four subunits contain the carboxy terminal heparin/matrix-binding domain (underlined sequence). The intersubunit disulfide bond links the heparin/matrix-binding domains of the subunits together. Proteolytic removal of these domains does not alter the enzymatic activity of EC-SOD, but results in progressive reduction of it's affinity to the matrix and leads to clearance of the protein from the tissue into the plasma. There is a naturally occurring polymorphism/mutation within the coding sequence of the heparin/matrix binding domain (C760G), which results in an amino acid change from an arginine to a glycine at amino acid residue 213. This amino acid is in the center of the cluster of positive amino acids in the heparin/matrix-binding domain and results in a lower affinity of the enzyme to heparin. This decreased heparin affinity results in elevated serum levels of EC-SOD (adapted from Refs. 33, 102).
FIG. 3
FIG. 3
In a high resolution computerized tomography (HRCT), subpleural honeycombing as a marker of advanced lung damage/fibrosis is seen bilaterally in the basal areas of IPF lungs (left). In idiopathic pulmonary fibrosis, subpleural fibroblast proliferation and epithelial atypia are considered as hallmarks of the disease (right). Alpha-actin positive cells show red staining in photomicrographs (200× magnification). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).
FIG. 4
FIG. 4
Characteristic features of human idiopathic pulmonary fibrosis (usual interstitial pneumonia).
FIG. 5
FIG. 5
EC-SOD-positive activated epithelial cells (red) are seen on the top of an EC-SOD negative fibroblast focus (1000× magnification). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article at www.liebertonline.com/ars).
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