The Role of Lysophospholipid Metabolites LPC and LPA in the Pathogenesis of Chronic Obstructive Pulmonary Disease

Abstract

Chronic obstructive pulmonary disease (COPD) is a heterogeneous lung condition characterized by persistent respiratory symptoms and airflow limitation. While there are some available treatment options, the effectiveness of treatment varies depending on individual differences and the phenotypes of the disease. Therefore, exploring or identifying potential therapeutic targets for COPD is urgently needed. In recent years, there has been growing evidence showing that lysophospholipids, namely lysophosphatidylcholine (LPC) and lysophosphatidic acid (LPA), can play a significant role in the pathogenesis of COPD. Exploring the metabolism of lysophospholipids holds promise for understanding the underlying mechanism of COPD development and developing novel strategies for COPD treatment. This review primarily concentrates on the involvement and signaling pathways of LPC and LPA in the development and progression of COPD. Furthermore, we reviewed their associations with clinical manifestations, phenotypes, and prognosis within the COPD context and discussed the potential of the pivotal signaling molecules as viable therapeutic targets for COPD treatment.

Keywords: COPD; lipid metabolism; lysophosphatidic acid; lysophosphatidylcholine; lysophospholipids.

Figure 1

Lysophosphatidic acid (LPA) generation Phospholipids within biological membranes, such as phosphatidylcholine (PC), can be enzymatically hydrolyzed by phospholipase D (PLD) 1 or 2 to generate phosphatidic acid (PA). In an alternative pathway, intracellular diacylglycerol (DAG) undergoes conversion to PA catalyzed by DAG kinase (DAGK). Subsequently, PA produced through both of these pathways is transformed into LPA by PA-specific phospholipase (PL) A1 or PLA2 enzymes localized at the cell membrane surface. Moreover, intracellularly, LPA can be produced through acylglycerol kinase (AGK) acting on monoacylglycerol, and via acylation of glycerol-3-phosphate by glycerol-3-phosphate acyltransferase. Extracellularly, Phospholipids such as PC are converted to lysophospholipids such as lysophosphatidylcholine (LPC) by secretory PLA1 or PLA2. ATX then cleaves the choline of LPC to generate LPA. Additionally, LPA can be generated from phospholipids through a sequential process involving lecithin cholesterol acyltransferase (LCAT), followed by the action of autotaxin (ATX).

Figure 2

The role of lysophosphatidic acid (LPA) in airway inflammation. LPA can strongly stimulate the secretion of IL-8 in the various airway epithelial cells and increase the infiltration of airway neutrophils. LPA-induced IL-8 secretion is mediated through Gαi and Gα12/13-coupled LPAR1-3 in human bronchial epithelial cells, partially mediated by [Ca²⁺]i, IκB phosphorylation, and NF-κB activation Changes and regulation of transcriptional activation of IL-8 gene expression in human bronchial epithelial cells (HBEpC). In addition, LPA promotes the recruitment of monocytes and mediates the differentiation of monocytes into macrophages. This process is likely through the activation of peroxisome proliferators-activated receptor γ (PPARγ), a non-canonical LPA receptor. LPA also indirectly regulates monocyte and neutrophil migration through the production of chemokines monocyte chemotactic protein 1 (MCP1) and IL-8 by endothelial cells. In addition, LPA acts on LPAR5 to induce the release of macrophage inflammatory protein 1 β (MIP-1β), a potent chemoattractant and activator of monocytes, lymphocytes, and various immune cells. Simultaneously, LPA significantly upregulated Toll-like receptors 4 (TLR-4) expression and promoted NF-kB activation, thereby prompting THP-1 cells (a human monocytic cell line) to secrete the pro-inflammatory cytokine TNF-α.

Figure 3

The anti-inflammatory role of lysophosphatidic acid (LPA) in airway inflammation. LPA induces COX-2 expression and PGE(2) production through EGFR transactivation-independent activation of transcriptional factors NF-kappaB and c-Jun, and EGFR transactivation-dependent activation of C/EBPbeta in HBEpCs.