Fine-tuning the ubiquitin-proteasome system to treat pulmonary fibrosis.

Publication/Presentation Date

1-1-2019

Abstract

Idiopathic pulmonary fibrosis (IPF) is an extremely aggressive lung disease that develops almost exclusively in older individuals, carries a very poor prognosis, and lacks any truly effective therapies. The current conceptual model is that IPF develops because of an age-related decline in the ability of the lung epithelium to regenerate after injury, largely due to death or senescence of epithelial progenitor cells in the distal airways. This loss of regenerative capacity is thought to initiate a chronic and ineffective wound-healing response, characterized by persistent, low-grade lung inflammation and sustained production of collagen and other extracellular matrix materials. Despite recent advances in our understanding of IPF pathobiology, there remains a pressing need to further delineate underlying mechanisms to develop more effective therapies for this disease. In this review, we build the case that many of the manifestations of IPF result from a failure of cells to effectively manage their proteome. We propose that epithelial progenitor cells, as well as immune cells and fibroblasts, become functionally impaired, at least in part, because of an accumulation or a loss in the expression of various crucial proteins. Further, we propose that central to this defect is the dysregulation of the ubiquitin-proteasome system (UPS), which is the major protein-degradation system in eukaryotic cells. Lastly, borrowing concepts from other fields, we discuss how targeting the UPS system could be employed as a novel treatment for IPF and perhaps for other fibrotic lung diseases as well.

Volume

60

Issue

1

First Page

50

Last Page

61

ISSN

1607-8438

Disciplines

Business Administration, Management, and Operations | Health and Medical Administration | Management Sciences and Quantitative Methods

PubMedID

30343604

Department(s)

Administration and Leadership

Document Type

Article

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