Turn Up the HETE on Septic Shock

Abstract

Septic shock is life-threatening organ dysfunction due to a dysregulated response to infection. It is a leading cause of death caused by the excessive release of cytokines and inflammatory mediators in response to bacterial endotoxins. It produces hypotension refractory to vasoconstrictors leading to tissue hypoperfusion and multiple organ failure. Despite intensive investigation, there still are no specific pharmacologic treatments. Current therapy relies on supportive care, including antibiotics, fluid resuscitation, corticosteroids, and pressor agents. This commentary summarizes little-known previous observations that inhibition of vascular 20-hydroxyeicosatetraenoic acid (20-HETE) by nitric oxide plays a key role in sepsis. It also highlights the new and exciting current report by Tunctan et al (2022) in this issue of Journal of Cardiovascular Pharmacology that administration of a 20-HETE mimetic can prevent lipopolysaccharide-induced vascular hyporeactivity, hypotension, and tachycardia in rats by activating the recently discovered GPR75/20-HETE receptor. Overall, these results provide a compelling case for initiating 20-HETE clinical trials to prevent hypotension, multiple organ failure, and death in septic shock.

Figure 1:. Central Role of iNOS and 20-HETE deficiency in septic shock.

Lipopolysaccharide-LPS is released from bacterial cell membranes by macrophages. LPS stimulates the release of various cytokines, including tumor necrosis factor-TNFα, interferon-gamma- IFNγ, interleukins-1, 6 and12- IL1, IL6, and IL12. These cytokines activate coagulation pathways leading to disseminated intravascular coagulation- DIC, upregulation of the expression of inducible nitric oxide synthase- iNOS and the formation of nitric oxide- NO, and increased formation of leukotriene B₄- LTB₄, and prostaglandins- PGs that promote fever, inflammation, and vasodilation. NO binds to heme in cytochrome P4504A - CYP4A enzymes and inhibits the formation of 20-hydroxyeicosatetraenoic acid- 20-HETE in arteries and arterioles. The fall in 20-HETE levels reduces the activity of the newly discovered G protein 75/20-HETE receptor- GPR75. This increases the activity of the large-conductance, Ca²⁺-activated potassium channel- K_Ca, causing membrane hyperpolarization, and vasodilation. The vasodilation and LTB4-induced capillary leakage reduce venous return and cardiac output. Reduced cardiac output in conjunction with peripheral vasodilation causes severe refractory hypotension and tissue hypoperfusion leading to multiorgan dysfunction, especially in the liver, kidney, heart, and GI tract. Further details regarding the downstream GPR75/20-HETE signaling pathways can be found in the current study of Tunctan and previous studies by others.^,