Therapeutic effects of lysophosphatidylcholine in experimental sepsis

Abstract

Sepsis represents a major cause of death in intensive care units. Here we show that administration of lysophosphatidylcholine (LPC), an endogenous lysophospholipid, protected mice against lethality after cecal ligation and puncture (CLP) or intraperitoneal injection of Escherichia coli. In vivo treatment with LPC markedly enhanced clearance of intraperitoneal bacteria and blocked CLP-induced deactivation of neutrophils. In vitro, LPC increased bactericidal activity of neutrophils, but not macrophages, by enhancing H(2)O(2) production in neutrophils that ingested E. coli. Incubation with an antibody to the LPC receptor, G2A, inhibited LPC-induced protection from CLP lethality and inhibited the effects of LPC in neutrophils. G2A-specific antibody also blocked the inhibitory effects of LPC on certain actions of lipopolysaccharides (LPS), including lethality and the release of tumor necrosis factor-alpha (TNF-alpha) from neutrophils. These results suggest that LPC can effectively prevent and treat sepsis and microbial infections.

Lysophospholipids of Different Classes Mobilize Neutrophil Secretory Vesicles and Induce Redundant Signaling through G2A

“…These findings corroborate earlier studies in which lyso-PC enhanced neutrophil superoxide production, adherence, chemotaxis, and degranulation (5,8). Of note, neutrophil responses to lyso-PC appear to depend both on fatty acid chain length (5,7) and on the method of presentation (dissolved in organic solvents or water, or presented on albumin or in liposomes) (2,5).…”

“…Given previous reports of neutrophil expression of the G protein-linked receptor, G2A, and lyso-PC signaling through this receptor (2, 7), signaling in the presence of blocking Abs to G2A was tested. As shown, and as in the investigation of Yan et al (7), blocking Abs to G2A (but not isotype control Abs) inhibited calcium flux in response to C18: 1/OH lyso-PC (Fig. 2B).…”

“…Recently, it was shown that early administration of lysophosphatidylcholine (lyso-PC) in vivo significantly enhanced survival during murine sepsis (7). Mechanistically, improved survival was related to enhanced neutrophil function with regard to oxidant production and clearance of bacteria (7). These findings corroborate earlier studies in which lyso-PC enhanced neutrophil superoxide production, adherence, chemotaxis, and degranulation (5,8).…”

“…Recently, it was shown that early administration of lysophosphatidylcholine (lyso-PC) in vivo significantly enhanced survival during murine sepsis (7). Mechanistically, improved survival was related to enhanced neutrophil function with regard to oxidant production and clearance of bacteria (7).…”

“…Signaling through G2A, a member of the lysolipid-sensitive, proton-sensing G protein-coupled receptor (GPCR) family (9), has been implicated in lyso-PC stimulation in neutrophils, and blocking Ab to G2A prevented lyso-PC enhancement of neutrophil function in vitro and sepsis survival in vivo (7). Although lyso-PC was originally thought to be a ligand of the G2A receptor (10), more recent data suggest that rather than acting directly as a ligand, lyso-PC alters receptor G2A distribution and signaling by preventing its reuptake or altering its residency on the cell surface (11,12).…”