Mechanism of the inhibitory effect of ghrelin in sepsis

Abstract

Sepsis and septic shock are the leading causes of death in intensive care units. Approximately 40%-70% of the mortality is associated with severe sepsis and septic shock. Systemic antibiotic usage, surgical intervention, aggressive fluid resuscitation and careful monitoring are common measures currently used to treat sepsis. Despite the advances in the understanding of the pathophysiology of sepsis, very little progress has been made towards therapeutic interventions. Recently we have shown that ghrelin, a stomach-derived peptide which is an endogenous ligand for the growth hormone secretagogue receptor (GHSR-1a), is beneficial in attenuating the inflammatory response, organ injury and mortality in an experimental model of polymicrobial sepsis induced by cecal ligation and puncture (CLP). In this review, we describe the mechanism of action of ghrelin in sepsis, highlight the role ghrelin plays in attenuating the hepatic dysfunction induced by sepsis and septic shock and suggest in developing ghrelin as a potential therapy for sepsis.

Keywords: GHSR-1a; cecal ligation; ghrelin; inhibition septic shock; sepsis.

Figure 1

Polymicrobial sepsis induced by cecal ligation and puncture (CLP) activates the sympathetic nervous system (SNS) and causes the release of norepinephrine (NE) from the sympathetic fibers in the gut. The NE then enters into the circulation and travels through the portal vein into the liver. While in the liver, NE binds to the α_2A-adrenoceptors (α_2A-AR) and activates the signaling pathway(s) responsible for the production and release of TNF-α, IL-6 and other pro-inflammatory cytokines from Kupffer cells and thereby produces hepatic dysfunction. Ghrelin, a stomach-derived peptide, reaches the dorsal vagal complex (DVC) in the brain by crossing the blood-brain barrier, stimulates GHSR-1a receptors, activates the vagus nerve and in turn, through the cholinergic pathways, downregulates TNF-α and IL-6 release from macrophages such as Kupffer cells in the liver possibly by increasing cAMP levels and restoring MKP-1. While activating the cholinergic pathway, ghrelin can inhibit the SNS, decrease the release of the sympathetic neurotransmitter, NE, and cause the downregulation of TNF-α and IL-6 from the macrophages. Therefore, ghrelin’s beneficial effect in sepsis by inhibiting the TNF-α and iL-6 release from Kupffer cells in the liver is mediated by the concerted efforts of the sympathetic and the parasympathetic nervous systems.