KA-1002, a Novel Lysophosphatidic Acid Signaling Antagonist, Alleviates Bovine Tracheal Cell Disruption and Inflammation

Abstract

The industrial livestock environment can cause stress and weakened immunity in cattle, leading to microbial infections which reduce productivity. As such, there is a need for an effective therapeutic agent that can alleviate uncontrolled destructive respiratory inflammation. We found that lysophosphatidic acid (LPA), a potent endogenous stress-induced inflammatory agent, causes respiratory tissue damage and triggers inflammation in bovine bronchial cells. LPA also inflames pulmonary bovine blood vessel cells to produce inflammatory cytokines. These findings strongly suggest that LPA is a highly important endogenous material exacerbating bovine respiratory diseases. We further identified a novel LPA-signaling antagonist, KA-1002, and showed that it alleviated LPA-mediated bovine tracheal cell disruption and inflammation. Therefore, KA-1002 could potentially serve as a novel therapeutic agent to maintain physiologically healthy and balanced conditions in bovine respiratory tracts.

A Novel Therapeutic Reagent, KA-1002 for Alleviating Lysophosphatidic Acid-Mediated Inflammation Related Gene Expression in Swine Macrophages

“…These transcriptome results suggest that LPA induce suppression of T cell responses and upregulation of innate immune cells-mediated inflammation. Multiple previous reports [12][13][14] support our hypothesis. Mathew D et al showed that LPA suppresses CD8+T cell cytotoxicity function via disruption of early TCR signaling [13].…”

“…For example, LPA strongly induced inflammatory angiogenesis and the production of inflammatory cytokine [14]. Furthermore, we found a novel LPA-antagonistic molecule, KA-1002 [13], which strongly alleviated LPA-induced inflammatory responses from bovine respiratory cells and blood endothelial cells. However, we did not understand the effect of the LPA antagonistic molecule, KA-1002 on swine cells.…”

“…Thus, LPA signaling antagonists have been attracting therapeutic targets for multiple inflammatory diseases [24]. Even though the pathological roles of LPA in livestock animals are not fully investigated in vivo study until now, many in vitro studies and several important in vivo animal models such as cows strongly suggest that LPA importantly works in multiple inflammatory diseases in livestock animals [13,16]. For example, In vivo studies of cattle for reproductive diseases might support the importance of LPA in livestock animals [25,26].…”

“…LPA signaling is mediated by its receptors, LPARs and there are needs for LPA antagonists for therapeutic reagents [11,12]. In our previous report [13], we showed that LPA triggered inflammatory responses from bovine respiratory cells and bovine blood endothelial cell lines. For example, LPA strongly induced inflammatory angiogenesis and the production of inflammatory cytokine [14].…”

“…Thus, the investigation about the LPA mediated inflammatory condition in swine macrophages should be helpful for understanding the therapeutic mechanism of LPA-antagonistic therapeutics on porcine inflammatory diseases related abnormally upregulated LPA condition. In this study, we tried to understand LPA mediated inflammation and our previously reported LPA-antagonistic compound KA-1002, which could be used for therapeutic reagents [13] through the genome-scale transcriptional expression analysis on swine macrophages. For those goals, we investigated the genome-scale transcriptional expression pattern on swine macrophages differentially regulated by LPA treatment and the transcriptional regulation by KA-1002 on LPA induced inflammatory conditioned swine macrophages.…”