Oxidative stress and pulmonary fibrosis

Abstract

Oxidative stress is implicated as an important molecular mechanism underlying fibrosis in a variety of organs, including the lungs. However, the causal role of reactive oxygen species (ROS) released from environmental exposures and inflammatory/interstitial cells in mediating fibrosis as well as how best to target an imbalance in ROS production in patients with fibrosis is not firmly established. We focus on the role of ROS in pulmonary fibrosis and, where possible, highlight overlapping molecular pathways in other organs. The key origins of oxidative stress in pulmonary fibrosis (e.g. environmental toxins, mitochondria/NADPH oxidase of inflammatory and lung target cells, and depletion of antioxidant defenses) are reviewed. The role of alveolar epithelial cell (AEC) apoptosis by mitochondria- and p53-regulated death pathways is examined. We emphasize an emerging role for the endoplasmic reticulum (ER) in pulmonary fibrosis. After briefly summarizing how ROS trigger a DNA damage response, we concentrate on recent studies implicating a role for mitochondrial DNA (mtDNA) damage and repair mechanisms focusing on 8-oxoguanine DNA glycosylase (Ogg1) as well as crosstalk between ROS production, mtDNA damage, p53, Ogg1, and mitochondrial aconitase (ACO2). Finally, the association between ROS and TGF-β1-induced fibrosis is discussed. Novel insights into the molecular basis of ROS-induced pulmonary diseases and, in particular, lung epithelial cell death may promote the development of unique therapeutic targets for managing pulmonary fibrosis as well as fibrosis in other organs and tumors, and in aging; diseases for which effective management is lacking. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.

Figure 1. Hypothetical model of environmental stress/oxidant induced pulmonary fibrosis

Environmental toxins/oxidants may induce the generation of ROS via induction of ER stress, NOX4 and uncoupling of mitochondrial electron transport or Rac 1 mediated activation of macrophages and/or PMNs. In conjunction with DNA damage and p53 activation, ROS promote apoptosis of airway epithelial cells, and elicit the production of cytokines and growth factors that may be important for invasive myofibroblastic differentiation and collagen deposition and may alter antioxidant defenses. The susceptibility of epithelial cells to apoptosis may be affected by mutations in surfactant, telomerase and mucin genes.

Figure 2. Asbestos-induced pulmonary fibrosis is blocked in Rac-1 null mice

Wild-type (WT) and Rac1 null mice were intratracheally exposed to chrysotile asbestos (100 µg). Micro-CT scan images were obtained on live mice (in vivo) 21 days after exposure. Images are representative of three WT (A) and three Rac1 null (B) mice. Twenty one days after exposure, the mice were euthanized and the lungs were removed and processed for collagen deposition using Masson's trichrome staining. Micrographs are representative of 10 WT (C) and 10 Rac1 null (D) mice. (E), mice were euthanized 21 days after exposure, and lungs were removed and homogenized for hydroxyproline assay. WT (n = 4) and Rac1 null (n = 4); *p < 0.0208. Experimental data from Osborn-Heaford et.al (reference 16) was used with permission.

Figure 3. Hypothetical model of AEC ER-mitochondria crosstalk-induced apoptosis and fibrosis

Exposure of AEC cells to environmental toxins induces ER that can lead to the release of ROS from the mitochondria that promotes apoptosis and pulmonary fibrosis (see text for details).

Figure 4. Hypothetical model of p53-dependent cytosolic and mitochondrial apoptotic pathways

In response to stressors such as oxidative stress, nuclear-localized p53 induces the transcription of target genes that mediate p53’s function (see text for details).