Adrenomedullin and Adrenomedullin-Targeted Therapy As Treatment Strategies Relevant for Sepsis

Abstract

Sepsis remains a major medical challenge, for which, apart from improvements in supportive care, treatment has not relevantly changed over the last few decades. Vasodilation and vascular leakage play a pivotal role in the development of septic shock, with vascular leakage being caused by disrupted endothelial integrity. Adrenomedullin (ADM), a free circulating peptide involved in regulation of endothelial barrier function and vascular tone, is implicated in the pathophysiology of sepsis. ADM levels are increased during sepsis, and correlate with extent of vasodilation, as well as with disease severity and mortality. In vitro and preclinical in vivo data show that administration of ADM exerts anti-inflammatory, antimicrobial, and protective effects on endothelial barrier function during sepsis, but other work suggests that it may also decrease blood pressure, which could be detrimental for patients with septic shock. Work has been carried out to negate ADMs putative negative effects, while preserving or even potentiating its beneficial actions. Preclinical studies have demonstrated that the use of antibodies that bind to the N-terminus of ADM results in an overall increase of circulating ADM levels and improves sepsis outcome. Similar beneficial effects were obtained using coadministration of ADM and ADM-binding protein-1. It is hypothesized that the mechanism behind the beneficial effects of ADM binding involves prolongation of its half-life and a shift of ADM from the interstitium to the circulation. This in turn results in increased ADM activity in the blood compartment, where it exerts beneficial endothelial barrier-stabilizing effects, whereas its detrimental vasodilatory effects in the interstitium are reduced. Up till now, in vivo data on ADM-targeted treatments in humans are lacking; however, the first study in septic patients with an N-terminus antibody (Adrecizumab) is currently being conducted.

Adrenomedullin in heart failure: pathophysiology and therapeutic application

“…In two animal models, intranasal ADM completely attenuated the acute‐induced airway hyper‐responsiveness and mucosal plasma leakage . ADM acts on several pathways in order to stabilize the endothelial barrier, including the cAMP/protein kinase A (PKA) pathway that inhibits RhoA/ROCK and reduces subsequent myosin light chain kinase‐induced actomyosin contraction (the ‘pulling forces’ exerted on endothelial cell junctions), as well as the cAMP/PKA and possibly the PI3K/Akt pathway to promote production of (protective) cortical actin and stabilization of the VE‐cadherin/β‐catenin complex (part of adherens junctions) . Finally, ADM inhibits the renin–angiotensin–aldosterone system .…”

“…42,43 ADM acts on several pathways in order to stabilize the endothelial barrier, including the cAMP/protein kinase A (PKA) pathway that inhibits RhoA/ROCK and reduces subsequent myosin light chain kinase-induced actomyosin contraction (the 'pulling forces' exerted on endothelial cell junctions), as well as the cAMP/PKA and possibly the PI3K/Akt pathway to promote production of (protective) cortical actin and stabilization of the VE-cadherin/ -catenin complex (part of adherens junctions). 44 Finally, ADM inhibits the renin-angiotensin-aldosterone system. 45 Although ADM increases plasma renin activity, it induces reductions in the aldosterone/plasma renin activity ratio and attenuates angiotensin II-induced aldosterone secretion.…”

Deregulated hypoxic response in myeloid cells: A model for high‐altitude pulmonary oedema (HAPE)

“…Among the most upregulated genes, we found Egln3 and Arg1 to be present, confirming our earlier observations. Adm2 , gene encoding for Adrenomedullin 2, a signalling peptide known to cause vasodilation, hypotension, being involved in regulation of endothelial cell permeability and induced by hypoxia . These functions suggest that Adrenomedullin 2 could lead to pulmonary vasodilation, causing pulmonary hypotension that results in decreased stroke volume.…”

Sepsis diagnosis and monitoring – procalcitonin as standard, but what next?

“…ADM receptors are expressed by blood vessels, skeletal muscles, heart, lungs, nerve tissues and on a cellular level by ECs, cardiomyocytes, vascular smooth muscle cells, macrophages and dendritic cells. Circulating ADM has a half-life of approximately 22 minutes and is degraded by protease [42]. ADM is classified as "hormokine", because of a hormone-like activity profile in non-inflammatory conditions when its only source is endocrine cells, and by a cytokine-like activity profile in sepsis when it is ubiquitously overexpressed [41].…”

“…Loss of barrier integrity is responsible for the edema, decreased blood pressure and subsequent organ failure observed in sepsis/septic shock. Adrenomedullin is a key hormone involved in regulation of the endothelial barrier and vascular tone [42].…”