Lysophosphatidic acid (LPA) and its receptors: Role in airway inflammation and remodeling

Abstract

Lysophosphatidic acid (LPA), a simple bioactive phospholipid, is present in biological fluids such as plasma and bronchoalveolar lavage (BAL). It appears to have both pro- and anti-inflammatory roles in inflammatory lung diseases. Exogenous LPA promotes inflammatory responses by regulating the expression of chemokines, cytokines, and cytokine receptors in lung epithelial cells. In addition to the modulation of inflammatory responses, LPA regulates cytoskeleton rearrangement and confers protection against lung injury by enhancing lung epithelial cell barrier integrity and remodeling. The biological effects of LPA are mediated through its cell surface G-protein coupled LPA1-7 receptors. The roles of LPA receptors in lung fibrosis, asthma, and acute lung injury have been investigated using genetically engineered LPA receptor deficient mice and there appears to be a definitive role for endogenous LPA and its receptors in the pathogenesis of pulmonary inflammatory diseases. This review summarizes recent reports on the role of LPA and its receptors in the regulation of lung epithelial inflammatory responses and remodeling.

Therapeutic Efficacy of Lysophosphatidylcholine in Severe Infections Caused by Acinetobacter baumannii

“…At the dose used in this study, the C max of LPC in the sera of the mice was 2-to 3-fold higher than the 10 to 30 M required to induce the chemotaxis of immune cells (24,26), and this treatment did not induce any apparent toxic effects in the mice. In the peritoneal sepsis model, we observed that 60% of the LPC-treated mice were negative for bacteremia and that 40% of the LPC-treated mice survived.…”

“…The decreased LPC concentration may reflect its enhanced and rapid conversion to lysophosphatidic acid (LPA) by a plasmatic lysophospholipase D (23). LPA is known to induce a multitude of cellular responses, including LPA-driven effects on proinflammatory cytokine production (24). Clinically, it was reported that plasma LPC was significantly decreased in septic patients (25,26), and patients with unfavorable sepsis outcomes had significantly lower plasma LPC-phosphorylcholine levels than patients who survived a septic episode (25,26).…”

Tomatoes, lysophosphatidic acid, and the small intestine: new pieces in the puzzle of apolipoprotein mimetic peptides?

“…It can be made intracellularly and also in the extracellular compartment, such as the plasma ( 16 ). It has a relatively short half-life of less than a few minutes due to catabolism by lipid phosphate phosphatases ( 19 ). Most extracellular LPA is bound to albumin, which, like S1P, may inhibit its cell signaling activity by reducing its bioavailability.…”

“…In general, LPA containing unsaturated fatty acids are more potent in their biological activity, which is consistent with the result found in this study showing that LPA 18:0 was relatively inert. Intracellular LPA can also generate cell signaling events by the stimulation of nuclear membrane receptors ( 19 ). For example, intracellular LPA can activate the nuclear receptor PPAR-γ ( 16 ), which is a well-known transcription factor involved in lipid metabolism and atherosclerosis.…”

Deficiency or inhibition of lysophosphatidic acid receptor 1 protects against hyperoxia-induced lung injury in neonatal rats

“…LPA is involved in many pathological processes, including neurological disorders, cardiovascular disease, inflammation, lung and renal fibrosis, and cancer (Choi et al 2010, Pyne et al 2013). Experimental and clinical evidence strongly suggests that LPA is involved in lung pathology and disease, including airway repair and remodeling, inflammation, and fibrosis via LPA receptor signaling (Oikonomou et al 2012, Shea & Tager 2012, Tager et al 2008, Toews et al 2002, Zhao & Natarajan 2013. LPAR1 or endothelial differentiation gene (EDG) family member 2 (EDG2), is the first identified LPA receptor with high affinity to LPA.…”