In vitro induction of myofibroblast characteristics via acetaminophen toxicity in pulmonary tissue model cell lines: Implications for pulmonary fibrosis

Abstract

Idiopathic pulmonary fibrosis (IPF) is a degenerative lung disease characterized by extensive fibrosis and impaired lung capacity. IPF is often fatal and its origin is as yet unknown. However, recent in vivo and in vitro data point to oxidative stress as an initiator and facilitator of IPF symptoms via structural changes to cellular membranes and the apparent capacity for oxidants and reactive oxygen species (ROS) to favor myofibroblast differentiation. Myofibroblasts are key components of IPF pathogenesis as they are responsible for depositing the extra-cellular matrix (ECM) in response to alveolar epithelial cell (AEC) damage, an initiating event in IPF. Aberrant repair mechanisms, also favored by an oxidative environment induce ECM dysregulation and permanent deposition of its major components, namely collagen. This tissue deposition is responsible for the impaired lung capacity indicative of IPF. Researchers have long posited different common oxidants as capable of fostering the oxidative environment that favors a fibrotic response in the lungs. One such oxidant, which has also recently been linked to airway restriction disorders such as asthma, is the common pain reliever acetaminophen (APAP), which has also been indicated in fibrotic processes in other tissues such as the liver and kidneys. Thus, the purpose of this research is to ascertain whether APAP can induce structural and biochemical characteristics indicative of IPF in pulmonary model cell lines. Ultimately, we found that APAP could induce structural changes in cell membranes comparable to a myofibroblast phenotype and also that APAP was associated with increased expression of the myofibroblast-associated protein, alphasmooth muscle actin in a pulmonary fibroblast model cell line.