Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. The molecular mechanisms involved in the pathophysiology of IPF are incompletely defined. Several lung cell types including alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells have been implicated in the development and progression of fibrosis. Regardless of the cell types involved, changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast, deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis. Lipid mediators derived from phospholipids, sphingolipids, and polyunsaturated fatty acids play an important role in the pathogenesis of pulmonary fibrosis and have been described to exhibit pro- and anti-fibrotic effects in IPF and in preclinical animal models of lung fibrosis. This review describes the current understanding of the role and signaling pathways of prostanoids, lysophospholipids, and sphingolipids and their metabolizing enzymes in the development of lung fibrosis. Further, several of the lipid mediators and enzymes involved in their metabolism are therapeutic targets for drug development to treat IPF.
Highlights
Lipids are the principal constituents of cell membranes and play an essential role in several physiological and pathophysiological processes by mediating intracellular and extracellular cues
idiopathic pulmonary fibrosis (IPF) is a heterogeneous interstitial lung disease caused by abnormal host-defense, activation of immune and non-immune cells, and dysfunctional wound, male gender, cigarette-smoking, and mutations in MUC5B and Sftpc gene confer a predisposition to the development of IPF
In the last three decades, several target genes and proteins have been identified as key players in the pathophysiology healing and lung repair that result in lung fibrosis
Summary
Lipids are the principal constituents of cell membranes and play an essential role in several physiological and pathophysiological processes by mediating intracellular and extracellular cues. Recurrent injury to the lung epithelium triggers pro-inflammatory and pro-fibrotic signaling involving the alveolar epithelial cells (AECs), alveolar macrophages (AM), fibroblasts, and endothelial cells contributing to the fibrotic foci and progression of IPF [12,13,14,15] This pathogenesis is characterized by epithelial cell apoptosis, epithelial-to-mesenchymal cell-transition (EMT), endothelial-mesenchymal transition (EndMT), activation of fibroblasts which differentiates into contractile myofibroblasts leading to deposition of the extracellular matrix and scar tissue formation [12]. This review is focused on the role of lipid-derived mediators and their signaling pathways modulating pulmonary fibrosis, in humans, and preclinical models. It is beyond the scope of this review to touch on all aspects of the disease since several recent reviews do justice in this context and will sway the subject away from lipid signaling [9,10,12]
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