title: Lysophosphatidic acid receptor 1 antagonist ki16425 blunts abdominal and systemic inflammation in a mouse model of peritoneal sepsis.
abstract: Lysophosphatidic acid (LPA) is a bioactive lipid mediator of inflammation via the LPA receptors 1-6. We and others have previously described proinflammatory and profibrotic activities of LPA signaling in bleomycin- or lipopolysaccharide (LPS)-induced pulmonary fibrosis or lung injury models. In this study, we investigated if LPA signaling plays a role in the pathogenesis of systemic sepsis from an abdominal source. We report here that antagonism of the LPA receptor LPA1 with the small molecule ki16425 reduces the severity of abdominal inflammation and organ damage in the setting of peritoneal endotoxin exposure. Pretreatment of mice with intraperitoneal ki16425 eliminates LPS-induced peritoneal neutrophil chemokine and cytokine production, liver oxidative stress, liver injury, and cellular apoptosis in visceral organs. Mice pretreated with ki16425 are also protected from LPS-induced mortality. Tissue myeloperoxidase activity is not affected by LPA1 antagonism. We have shown that LPA1 is associated with LPS coreceptor CD14 and the association is suppressed by ki16425. LPS-induced phosphorylation of protein kinase C δ (PKCδ) and p38 mitogen-activated protein kinase (p38 MAPK) in liver cells and interleukin 6 production in Raw264 cells are likewise blunted by LPA1 antagonism. These studies indicate that the small molecule inhibitor of LPA1, ki16425, suppresses cytokine responses and inflammation in a peritoneal sepsis model by blunting downstream signaling through the LPA1-CD14-toll-like receptor 4 receptor complex. This anti-inflammatory effect may represent a therapeutic strategy for the treatment of systemic inflammatory responses to infection of the abdominal cavity.
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhao
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA; Vascular Medical Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Jianxin
authors.initials: J
authors.lastname: Wei
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Weathington
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA; Vascular Medical Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Anastasia M
authors.initials: AM
authors.lastname: Jacko
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Hai
authors.initials: H
authors.lastname: Huang
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA.
authors.forename: Allan
authors.initials: A
authors.lastname: Tsung
authors.affiliation: Department of Medicine, Acute Lung Injury Center of Excellence, University of Pittsburgh School of Medicine, Pittsburgh, PA; Vascular Medical Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA; Department of Cell Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA. Electronic address: zhaoy3@upmc.edu.
authors.forename: Yutong
authors.initials: Y
authors.lastname: Zhao
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D007555:Isoxazoles / Q000494:pharmacology*; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010538:Peritonitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009195:Peroxidase / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D049368:Receptors, Lysophosphatidic Acid / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018805:Sepsis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D015398:Signal Transduction / Q000187:drug effects; D057170:Translational Research, Biomedical
chemical_list: C477898:3-(4-(4-((1-(2-chlorophenyl)ethoxy)carbonyl amino)-3-methyl-5-isoxazolyl) benzylsulfanyl) propanoic acid; D016207:Cytokines; D007555:Isoxazoles; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D011422:Propionates; D049368:Receptors, Lysophosphatidic Acid; D009195:Peroxidase; D000410:Alanine Transaminase