Adrenomedullin and endothelial barrier function

Abstract

SummaryAlthough loss of endothelial barrier function is a hallmark of every acute inflammation and contributes to fatal loss of organ function during severe infections, there is no sufficient therapy for stabilization of endothelial barrier function. Endogenous peptide adrenomedullin (AM) serum levels were shown to be increased during severe infection including sepsis and septic shock. In different in-vitro and in-vivo models AM acted as a potent therapeutic endothelial barrier function-stabilizing agent. Activation of specific receptors by AM results in elevation of second messenger cAMP. AM inhibits actin-myosin based endothelial cell contraction and junctional disassembly, thereby preventing paracellular permeability and oedema formation. The peptide furthermore possesses several protective cardiovascular qualities, including protection of the microcirculation during inflammation, and was proven as an efficient counter-regulatory molecule in various models of sepsis and septic shock. Overall, AM may be an attractive molecule to combat against cardiovascular malfunction during severe infection.

Therapeutic strategies in pneumonia: going beyond antibiotics

“…Adrenomedullin is derived from the precursor prepro-adrenomedullin and binds to the calcitonin receptor-like receptor (CRLR). In endothelial cells, receptor ligation by adrenomedullin causes intracellular accumulation of the second messenger cAMP, thereby activating various kinases such as protein kinase (PK) A, PKC and mitogen-activated protein kinases [61,62]. The crucial role of adrenomedullin in protecting vascular barrier integrity was underscored by demonstrating that mice deficient in adrenomedullin, CRLR or other components of the adrenomedullin signalling pathway die prematurely due to hydrops fetalis [63][64][65][66].…”

The prognostic blood biomarker proadrenomedullin for outcome prediction in patients with chronic obstructive pulmonary disease (COPD): a qualitative clinical review

“…ADM is ubiquitously expressed in pulmonary, cardiovascular, renal, gastrointestinal, and endocrine tissue and by endothelial cells, vascular smooth muscle cells, cardiomyocytes, fibroblasts, leukocytes, and placental trophoblast cells, among others [49][50][51][52]. In pulmonary tissue, ADM expression has been found in endothelial cells including type II pneumocytes, chondrocytes, smooth muscle cells, the columnar epithelium, alveolar macrophages, monocytes, T cells, and neurons of the pulmonary parasympathetic nervous system, as well as small-cell and non-small-cell neoplasia [42,53].…”

“…It acts systemically and in autocrine and paracrine fashion [54,55], exerting or mediating vasodilatory, natriuretic, diuretic, antioxidative, anti-inflammatory, antimicrobial, and metabolic effects [42,50,[56][57][58]. Upregulated by hypoxia, inflammatory cytokines, bacterial products, and shear stress, ADM has in preclinical and animal models been shown to reduce hypoxic pulmonary vascular structural remodeling and fibrosis and to inhibit bronchoconstriction; the molecule also has been shown to stabilize barrier function in the lungs by downregulating pro-inflammatory factors and reactive oxidative species [42,50,51,[59][60][61][62]. Circulating ADM elevation, e.g., in end-stage pulmonary disease [63], is believed to reflect "high demand" for these compensatory/counter-regulatory effects [28,42].…”

Blood cells and endothelial barrier function

“…Endothelial cells are also able to synthesize and release factors, such as adrenomedullin, that act to stabilize the endothelial barrier thereby opposing the actions of inflammatory mediators on vascular permeability. 64 However, when mediator release from these other cell populations is excessive, endothelial barrier dysfunction or failure may result. There is also mounting evidence that blood cells are capable of exerting a similar influence on endothelial barrier function, and may account for the barrier failure evidenced in different pathological conditions.…”