Leukotriene B4

Inhibition of leukotriene B4 receptor 1 attenuates lipopolysaccharide-induced cardiac dysfunction: role of AMPK-regulated mitochondrial function.[Pubmed:28290498]

Sci Rep. 2017 Mar 14;7:44352.

Leukotriene B4 (LTB4)-mediated leukocyte recruitment and inflammatory cytokine production make crucial contributions to chronic inflammation and sepsis; however, the role of LTB4 in lipopolysaccharide (LPS)-induced cardiac dysfunction remains unclear. Therefore, the present study addressed this issue using an LTB4 receptor 1 (BLT1) inhibitor. Administration of LPS to mice resulted in decreased cardiovascular function. Inhibition of LTB4/BLT1 with the BLT1 inhibitor U75302 significantly improved survival and attenuated the LPS-induced acute cardiac dysfunction. During LPS challenge, the phosphorylated AMPK/ACC signaling pathway was slightly activated, and this effect was enhanced by U75302. Additionally, pNF-kappaB, Bax and cleaved caspase-3 were upregulated by LPS, and Bcl-2, IkappaB-alpha, mitochondrial complex I, complex II, and OPA1 were downregulated; however, these effects were reversed by U75302. The results indicated that the BLT1 antagonist suppressed cardiac apoptosis, inflammation, and mitochondrial impairment. Furthermore, the protection provided by the BLT1 inhibitor against LPS-induced cardiac dysfunction was significantly reversed by the AMPK inhibitor Compound C. In conclusion, inhibiting the LTB4/BLT1 signaling pathway via AMPK activation is a potential treatment strategy for septic cardiac dysfunction because it efficiently attenuates cardiac apoptosis, which may occur via the inhibition of inflammation and mitochondrial dysfunction.

The leukotriene B4-leukotriene B4 receptor axis promotes cisplatin-induced acute kidney injury by modulating neutrophil recruitment.[Pubmed:28318626]

Kidney Int. 2017 Jul;92(1):89-100.

Cisplatin is an effective chemotherapeutic agent and widely used in treatment of various solid organ malignancies, including head and neck, ovarian, and testicular cancers. However, the induction of acute kidney injury (AKI) is one of its main side effects. Leukotriene B4 receptor 1 (BLT1) mediates the majority of physiological effects of Leukotriene B4 (LTB4), a potent lipid chemoattractant generated at inflammation sites, but the role of the LTB4-BLT1 axis in cisplatin-induced AKI remains unknown. Here we found upregulated LTB4 synthesis and BLT1 expression in the kidney after cisplatin administration. Cisplatin was found to directly upregulate gene expression of leukotriene A4 hydrolase and stimulate LTB4 production in renal tubular epithelial cells. Reduced kidney structural/functional damage, inflammation, and apoptosis were observed in BLT1(-/-) mice, as well as in wild-type mice treated with the LTA4H inhibitor SC-57461A and the BLT1 antagonist U-75302. Neutrophils were likely the target of this pathway, as BLT1 absence induced a significant decrease in infiltrating neutrophils in the kidney. Adoptive transfer of neutrophils from wild-type mice restored kidney injury in BLT1(-/-) mice following cisplatin challenge. Thus, the LTB4-BLT1 axis contributes to cisplatin-induced AKI by mediating kidney recruitment of neutrophils, which induce inflammation and apoptosis in the kidney. Hence, the LTB4-BLT1 axis could be a potential therapeutic target in cisplatin-induced AKI.

Low salivary resolvin D1 to leukotriene B4 ratio predicts carotid intima media thickness: A novel biomarker of non-resolving vascular inflammation.[Pubmed:28195518]

Eur J Prev Cardiol. 2017 Jun;24(9):903-906.

Background Different lipid mediators may have opposing effects on vascular inflammation. For example, whereas Leukotriene B4 (LTB4) transduces inflammation, resolvin D1 (RvD1), which is synthesized from the omega-3 fatty acid docosahexaenoic acid, facilitates the resolution of inflammation. The aim of this study was to determine the association of the RvD1/LTB4 ratio with subclinical atherosclerosis. Methods Saliva samples and ultrasound measurements of the intima media thickness of the carotid artery was obtained for 254 participants. The lipid mediators RvD1 and LTB4 were measured by enzyme-linked immunosorbent assay. Results Participants with a salivary RvD1/LTB4 ratio >1 had a significantly lower intima media thickness than those in whom LTB4 prevailed. The salivary RvD1/LTB4 ratio independently predicted carotid intima media thickness. Conclusions The ratio between the proresolving and proinflammatory salivary lipid mediators RvD1 and LTB4 may serve as a biomarker of non-resolving inflammation and its relation to intima media thickness in cardiovascular disease.

The leukotriene B4 receptors BLT1 and BLT2 form an antagonistic sensitizing system in peripheral sensory neurons.[Pubmed:28242764]

J Biol Chem. 2017 Apr 14;292(15):6123-6134.

Sensitization of the heat-activated ion channel transient receptor potential vanilloid 1 (TRPV1) through lipids is a fundamental mechanism during inflammation-induced peripheral sensitization. Leukotriene B4 is a proinflammatory lipid mediator whose role in peripheral nociceptive sensitization is not well understood to date. Two major G-protein-coupled receptors for Leukotriene B4 have been identified: the high-affinity receptor BLT1 and the low-affinity receptor BLT2. Transcriptional screening for the expression G-protein-coupled receptors in murine dorsal root ganglia showed that both receptors were among the highest expressed in dorsal root ganglia. Calcium imaging revealed a sensitization of TRPV1-mediated calcium increases in a relative narrow concentration range for Leukotriene B4 (100-200 nm). Selective antagonists and neurons from knock-out mice demonstrated a BLT1-dependent sensitization of TRPV1-mediated calcium increases. Accordingly, Leukotriene B4-induced thermal hyperalgesia was mediated through BLT1 and TRPV1 as shown using the respective knock-out mice. Importantly, higher Leukotriene B4 concentrations (>0.5 mum) and BLT2 agonists abolished sensitization of the TRPV1-mediated calcium increases. Also, BLT2 activation inhibited protein kinase C- and protein kinase A-mediated sensitization processes through the phosphatase calcineurin. Consequently, a selective BLT2-receptor agonist increased thermal and mechanical withdrawal thresholds during zymosan-induced inflammation. In accordance with these data, immunohistochemical analysis showed that both Leukotriene B4 receptors were expressed in peripheral sensory neurons. Thus, the data show that the two Leukotriene B4 receptors have opposing roles in the sensitization of peripheral sensory neurons forming a self-restricting system.