Matrix regulation of idiopathic pulmonary fibrosis: the role of enzymes

TLDR

Repair of lung tissue is normally protective, but excessive or dysregulated repair leads to fibrosis characterized by excess extracellular matrix deposition and loss of normal architecture. The review aims to elucidate how aberrant wound‑healing processes and matrix remodeling contribute to idiopathic pulmonary fibrosis to guide new therapies. Inflammatory mediators such as TGF‑β and IL‑13, platelet activation, and myofibroblast expansion driven by epithelial‑to‑mesenchymal transition and fibroblast activation promote ECM deposition, while enzymes emerging as key regulators modulate this remodeling. IPF lungs exhibit elevated expression of ECM‑modulating enzymes, and experimental modulation of these enzymes can influence fibrotic tissue remodeling.

Abstract

Repairing damaged tissues is an essential homeostatic mechanism that enables clearance of dead or damaged cells after injury, and the maintenance of tissue integrity. However, exaggeration of this process in the lung can lead to the development of fibrotic scar tissue. This is characterized by excessive accumulation of extracellular matrix (ECM) components such as fibronectin, proteoglycans, hyaluronic acid, and interstitial collagens. After tissue injury, or a breakdown of tissue integrity, a cascade of events unfolds to maintain normal tissue homeostasis. Inflammatory mediators are released from injured epithelium, leading to both platelet activation and inflammatory cell migration. Inflammatory cells are capable of releasing multiple pro-inflammatory and fibrogenic mediators such as transforming growth factor (TGF)β and interleukin (IL)-13, which can trigger myofibroblast proliferation and recruitment. The myofibroblast population is also expanded as a result of epithelial cells undergoing epithelial-to-mesenchymal transition and of the activation of resident fibroblasts, leading to ECM deposition and tissue remodeling. In the healthy lung, wound healing then proceeds to restore the normal architecture of the lung; however, fibrosis can develop when the wound is severe, the tissue injury persists, or the repair process becomes dysregulated. Understanding the processes regulating aberrant wound healing and the matrix in the chronic fibrotic lung disease idiopathic pulmonary fibrosis (IPF), is key to identifying new treatments for this chronic debilitating disease. This review focuses primarily on the emerging role of enzymes in the lungs of patients with IPF. Elevated expression of a number of enzymes that can directly modulate the ECM has been reported, and recent data indicates that modulating the activity of these enzymes can have a downstream effect on fibrotic tissue remodeling.