Cellular and Molecular Control of Lipid Metabolism in Idiopathic Pulmonary Fibrosis: Clinical Application of the Lysophosphatidic Acid Pathway

Abstract

Idiopathic pulmonary fibrosis (IPF) is a representative disease that causes fibrosis of the lungs. Its pathogenesis is thought to be characterized by sustained injury to alveolar epithelial cells and the resultant abnormal tissue repair, but it has not been fully elucidated. IPF is currently difficult to cure and is known to follow a chronic progressive course, with the patient’s survival period estimated at about three years. The disease occasionally exacerbates acutely, leading to a fatal outcome. In recent years, it has become evident that lipid metabolism is involved in the fibrosis of lungs, and various reports have been made at the cellular level as well as at the organic level. The balance among eicosanoids, sphingolipids, and lipid composition has been reported to be involved in fibrosis, with particularly close attention being paid to a bioactive lipid “lysophosphatidic acid (LPA)” and its pathway. LPA signals are found in a wide variety of cells, including alveolar epithelial cells, vascular endothelial cells, and fibroblasts, and have been reported to intensify pulmonary fibrosis via LPA receptors. For instance, in alveolar epithelial cells, LPA signals reportedly induce mitochondrial dysfunction, leading to epithelial damage, or induce the transcription of profibrotic cytokines. Based on these mechanisms, LPA receptor inhibitors and the metabolic enzymes involved in LPA formation are now considered targets for developing novel means of IPF treatment. Advances in basic research on the relationships between fibrosis and lipid metabolism are opening the path to new therapies targeting lipid metabolism in the treatment of IPF.

A Protective Effect of Pirfenidone in Lung Fibroblast–Endothelial Cell Network via Inhibition of Rho-Kinase Activity

“…Macrophages present in the respiratory tract are considered to be important in pulmonary fibrosis, as they produce various cytokines and chemokines and induce wound healing and immune responses [ 35 ]. Pirfenidone has also been reported to have an antifibrotic effect [ 18 ] via inhibiting interleukin-1, tumor necrosis factor α, TGF-β, and platelet-derived growth factor—all of which are inflammatory cytokines produced by alveolar macrophages [ 33 , 36 ]—as well as chemokines such as monocyte chemoattractant protein-1 [ 37 ].…”

“…These reports, together with our data demonstrating the activation of Rho-kinase by TGF-β, suggest that the LPA–TGF-β–Rho-kinase cascade may be involved in fibrosis. Furthermore, in BLM-induced interstitial pneumonia model mice, significantly increased levels of autotaxin, an enzyme that converts lysophosphatidylcholine (LPC) in BALF into LPA, has been observed [ 55 ], suggesting also that lipid metabolism may be associated with fibrosis [ 18 ]. As LPC has been reported to be important in angiogenesis as well [ 56 ], it is also possible that changes in the balance of the lipid composition (LPC, LPA metabolism) may affect vascular network formation.…”

“…Transforming growth factor β (TGF-β), which is produced by the respiratory epithelium and macrophages in response to injury, is an important profibrotic cytokine that is also involved in the pathogenesis of pulmonary fibrosis [ 17 ]. Stimulation by TGF-β induces both injury to epithelial cells in the airway and their differentiation into myofibroblasts; TGF-β also causes epithelial mesenchymal conversion and deposition of the extracellular matrix in tissue, leading to fibrosis [ 17 , 18 ].…”

“…In a previous study, we co-cultured vascular endothelial cells and fibroblasts and subsequently constructed a vascular endothelial cell network under culture conditions [ 25 ]. As vascular endothelial dysfunction, fibroblasts, and TGF-β stimulation are considered to be potentially involved in the pathogenesis of pulmonary fibrosis [ 17 , 18 , 19 , 20 ], this co-culture network cell sheet has the potential to provide a simpler model for evaluating the interstitial pathology of the lungs. This cell sheet may thus be useful as an experimental method for quantitatively evaluating such pathologic factors, including the interactions among these various types of cells.…”

How do sphingosine-1-phosphate affect immune cells to resolve inflammation?

“…The second-generation S1PRs modulators, ozanimod, estrasimod, and CBP-307, have been optimized for receptor isoform selectivity and have very low affinity for S1PR3. Therefore, side effects such as pro-inflammatory and pulmonary fibrosis are avoided to a certain extent (26,141). FTY720 has been approved and is currently used for MS treatment.…”