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 pro-inflammatory and pro-fibrotic 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 co-receptor CD14, the association is suppressed by ki16425. LPS-induced phosphorylation of PKCδ and p38 MAPK in liver cells and IL-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-TLR4 receptor complex. This anti-inflammatory effect may represent a therapeutic strategy for the treatment of systemic inflammatory responses to infection of the abdominal cavity.

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

“…) and in Ki16425‐treated mice which are protected against LPS‐induced peritoneal sepsis (Zhao et al . ). Pro‐inflammatory properties of LPA have been demonstrated in human lung epithelial cells by the secretion of IL8 and activation of NFkappa B, P38 MAPK and AP1 (Cummings et al .…”

“…Furthermore, the additional blocking of LPAR3 by Ki16425 and the relatively low concentration of Ki16425 we used in this study with neonatal rats (5 mg kg −1 day −1 ) compared to adult rodents (up to 20 mg kg −1 ; Zhao et al . ) may also contribute to the differences in response between both experimental approaches. The absence of a beneficial effect on medial wall thickness and RVH in LPAR1‐mutant rats may be explained by the development of RVH in LPAR1‐mutant rats during neonatal development in RA.…”

Lysophosphatidic Acid Induces Ligamentum Flavum Hypertrophy Through the LPAR1/Akt Pathway

“…Several LPAR1 antagonists have been used for in vivo fibrosis treatments (Ki16425 [37], VPC-32183 [38], and AM966 [39]). LPAR1 deficiency attenuates pulmonary injury by reducing pulmonary inflammation and fibrosis [40].…”

Lysophospholipid mediators in the vasculature

“…The lack of LPA1 disrupts the endothelial barrier and results in increased vascular permeability in response to inflammatory stimuli in the lung [16] and the skin [17]. Conversely, LPA1 antagonists prevent inflammation in response to peritoneal injection of lipopolysaccharide [18]. Whether either a defect in smooth muscle or endothelial cell function accounts for the bleeding observed in the Lpar1−/− mice remains unknown.…”