Aging, antagonistic pleiotropy and fibrotic disease

Abstract

Tissue fibrosis is most often referred to in its pathological context and is a major cause of progressive organ failure and death. Here, we consider fibrosis as an evolutionarily conserved, adaptive tissue response to injury. The role of NADPH oxidase 4 (Nox4) as a novel pro-fibrogenic mediator is highlighted. The concept that Nox4 may function as an antagonistically pleiotropic gene in age-associated fibrotic disorders is discussed.

Figure 1. The proposed role of Nox4 in myofibroblast differentiation/activation and factors that influence alveolar epithelial cell injury-repair

Injury to the alveolar epithelium is typically accompanied by a regenerative response involving the differentiation of “cuboidal” alveolar type II cells to “squamous” alveolar type I cells that constitute >95% of the alveolar surface lining. This regenerative response is facilitated by a provisional extracellular matrix elaborated by tissue-resident mesenchymal cells. Myofibroblasts are a distinct subpopulation of mesenchymal cells with contractile properties and that differentiate in response to transforming growth factor-β1 (TGF-β1)-induced activation of NADPH oxidase isoform 4 (Nox4). Apoptosis and clearance of myofibroblasts facilitate the resolution of the repair process, leading to restitution of normal alveolar structure/function. The persistence of activated myofibroblasts (due to the acquisition of apoptosis-resistant and/or proliferative phenotypes) leads to progressive fibrosis that characterizes a number of human fibrotic diseases, including idiopathic pulmonary fibrosis. The inability to “deactivate” myofibroblasts may be related to a number of host (age, epigenetic and genetic factors) and environmental factors. Age may also influence the susceptibility of the alveolar epithelium to injury/apoptosis, thus impairing normal alveolar regeneration.