Beside its role in NF
Beside its role in NF-κB and IL-1β activation, the NRLP3 pathway is closely involved in another essential pathophysiologic mechanism such as the cellular calcium homeostasis. Full activation of the NRLP3 inflammasome requires decreased extracellular K concentrations resulting in decreased osmotic pressure with cell swelling. Cell swelling, in turn, induces a regulatory volume decrease response through transient receptor potential cation channels (TRPM2/7 and TRPV2) that trigger intracellular Ca mobilization. The mobilized Ca has many molecular targets including, in the pancreas, the premature activation of proteases, a hallmark of pancreatitis. Whether a NRLP3 inflammasome triggered disease mechanism and its lactate-induced, GPR81-mediated down-regulation is operative in the acinar cell itself is presently unknown. The study of Hoque et al have shown this regulation to apply to inflammatory cell, specifically macrophages/monocytes, and the required protein machinery may not be expressed in the epithelial STF 083010 of the liver or pancreas.
In both models investigated, the co-stimulatory signal for activation of the inflammasome was LPS. However, acute pancreatitis and hepatitis, at least in the initiating phase where fluid resuscitation with Ringer lactate is clinically indicated, are considered to be sterile, that is, non-bacterial, inflammatory processes. Although previous clinical trials suggest that treatment with Ringer lactate is beneficial in this early disease phase and can reduce the systemic pro-inflammatory response, it would be interesting to learn whether disease models of pancreatitis and hepatitis, that do not require bacterial LPS as co-stimulatory signal, also benefit from a lactate GPR81–mediated inhibition of the NLPR3 inflammasome. If this were the case, the pathophysiologic basis for the clinical use of Ringer lactate would be even sounder. At present, Paracelsus' principle that “the dose makes the poison” remains a consideration for the clinical use of Ringer lactate in patients with liver and pancreatic diseases. The hepatotoxic properties of lactate in animal models and the caveats from clinical trials that seem to confirm this potentially negative effect in liver disease warrants some caution. In the absence of data from controlled trials and in light of the study by Hoque et al a current recommendation would encourage the use of Ringer lactate solution where rapid fluid replacement is required in inflammatory disease of the liver and pancreas. After the initial disease phase and before serum lactate levels rise above physiologic levels or the pH is reduced, the fluid replacement should probably be continued with other crystalloids to avoid impairing liver function and disturbed coagulation.
Hoque et al have given us a much better understanding of how lactate works, through which mechanisms it transmits its anti-inflammatory function in monocytes, and why inflammatory disorders of the liver and pancreas may benefit from its clinical use.
GPR81 is a class B G coupled GPCR expressed mainly in adipocytes for which lactate is a known endogenous ligand. Activation of GPR81 in adipose tissue leads to inhibition of lipolysis and FFA release through a cAMP dependent mechanism. AZ13415538 and AZ13087136 are two novel GPR81 agonists also active on GPR109A and the ghrelin receptors. In anaesthetized Wistar rats both compounds, at efficacious doses, caused a transient increase in blood pressure and a transient decrease in heart rate when given iv. A tool compound, which is structurally similar to AZ13087136 and active on the ghrelin receptor but inactive on GPR81 and GPR109A, did not show any cardiovascular effects when tested at a dose 10-fold above the AZ13087136 ED for fatty acid lowering in the anaesthetized rat model. The GPR109A selective agonists' nicotinic acid, MK-0354 or SCH900271, was also tested in the same model and did not show CV effects at efficacious doses. In conscious Wistar rats, iv infusion of AZ13415538 resulted in an increase in blood pressure at a plasma concentration corresponding to efficacy on FFA in rat. These data suggest an association between GPR81 agonism and CV effects which will be further investigated in GRP81 KO mice using telemetry.