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.
Highlights
Sepsis remains a major health problem in the twenty-first century, with an increasing incidence and high mortality in intensive care units worldwide [1, 2]
The profound inflammatory response observed in sepsis plays a pivotal role in this phenomenon, which is accompanied by endothelial cell (EC) death and loss of barrier integrity [5, 7, 8]
In vitro studies demonstrated potent vasodilatory effects of ADM on isolated blood vessels [42, 55] and in isolated organs [56], and in vivo studies showed that direct infusion of ADM resulted in decreased blood pressure and induced a compensatory increase of heart rate, endogenous noradrenaline, and renin concentrations in various mammalian species, which coincided with increased cardiac output (CO) [14, 57,58,59,60,61,62]
Summary
Sepsis remains a major health problem in the twenty-first century, with an increasing incidence and high mortality in intensive care units worldwide [1, 2]. Loss of barrier integrity leads to extravascular accumulation of fluids and molecules, causing edema, a decreased blood pressure and subsequent organ failure. The removal of all introns results in the formation of a mature mRNA molecule (form A) which is eventually translated and processed into ADM as detailed below. Due to the presence of a stop codon in this intron, a smaller prohormone is produced that does not result in the production of ADM [19] It remains unknown which factors regulate the splicing of this third intron and whether this is altered during sepsis. Translation of the form A mRNA molecule leads to a 185 amino acid long preprohormone (prepro-ADM) that undergoes a multistep cleavage process. On a more organ-specific level, the lungs appear to be involved as a site of clearance [53, 54]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
