A Tale of Two Proteolytic Machines: Matrix Metalloproteinases and the Ubiquitin–Proteasome System in Pulmonary Fibrosis

Abstract

Pulmonary fibrosis is a chronic and progressive lung disease characterized by the activation of fibroblasts and the irreversible deposition of connective tissue matrices that leads to altered pulmonary architecture and physiology. Multiple factors have been implicated in the pathogenesis of lung fibrosis, including genetic and environmental factors that cause abnormal activation of alveolar epithelial cells, leading to the development of complex profibrotic cascade activation and extracellular matrix (ECM) deposition. One class of proteinases that is thought to be important in the regulation of the ECM are the matrix metalloproteinases (MMPs). MMPs can be up- and down- regulated in idiopathic pulmonary fibrosis (IPF) lungs and their role depends upon their location and function. Furthermore, alterations in the ubiquitin-proteosome system (UPS), a major intracellular protein degradation complex, have been described in aging and IPF lungs. UPS alterations could potentially lead to the abnormal accumulation and deposition of ECM. A better understanding of the specific roles MMPs and UPS play in the pathophysiology of pulmonary fibrosis could potentially drive to the development of novel biomarkers that can be as diagnostic and therapeutic targets. In this review, we describe how MMPs and UPS alter ECM composition in IPF lungs and mouse models of pulmonary fibrosis, thereby influencing the alveolar epithelial and mesenchymal cell behavior. Finally, we discuss recent findings that associate MMPs and UPS interplay with the development of pulmonary fibrosis.

Impact of Human Cytomegalovirus and Human Herpesvirus 6 Infection on the Expression of Factors Associated with Cell Fibrosis and Apoptosis: Clues for Implication in Systemic Sclerosis Development

“…By summarizing the results obtained in this in vitro study on the modulation of several pro-fibrotic factors induced by HCMV and/or HHV-6A, it is worthy to note that although a number of them are often altered in different autoimmune diseases [ 89 ], most of them have been described to be up- or downregulated in SSc, as already highlighted above [ 15 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 , 87 , 88 ].…”

“…A dysregulated expression of MMPs has been observed in subjects with pulmonary fibrosis [ 67 ], where they have been shown to have a profound impact on the mechanisms involved in fibrosis development. In particular, MMP1 overexpression has been associated to the pathogenesis of fibrosis, MMP3 is induced in epithelial to mesenchymal transition, MMP9 is induced by TGF-β and has a pro-fibrotic action, and MMP13 has a controversial pro- and anti-fibrotic action on fibroblasts [ 68 ].…”

DR7dA, a Novel Antioxidant Peptide Analog, Demonstrates Antifibrotic Activity in Pulmonary Fibrosis In Vivo and In Vitro

“…MMPs can degrade ECM components, but their activity is blocked by tissue inhibitors of MMPs. Many MMPs are involved in fibrosis, such as MMP2, MMP7, MMP9, and MMP28 (Roque et al, 2020). MMP2 is mainly expressed in alveolar epithelial cells in PF, which may be related to basement membrane rupture (Dancer et al, 2011).…”

Progress in understanding and treating idiopathic pulmonary fibrosis: recent insights and emerging therapies

“…MMPs are proactive contributors to pulmonary fibrosis ( Todd et al, 2020 ). This family of endopeptidases, including MMP-3, MMP-7, and MMP-8, is integral to regulating EMT degradation in IPF ( Roque et al, 2020b ; Bormann et al, 2022 ). EMT activation in the lungs is believed to be one of the mechanisms associated with the loss of alveolar cells and the formation of pulmonary fibrosis.…”