A Focus on the Pathophysiology of Adrenomedullin Expression: Endothelitis and Organ Damage in Severe Viral and Bacterial Infections

Abstract

Adrenomedullin (ADM) is a peptide hormone produced primarily in the adrenal glands, playing a crucial role in various physiological processes. As well as improving vascular integrity and decreasing vascular permeability, ADM acts as a vasodilator, positive inotrope, diuretic, natriuretic and bronchodilator, antagonizing angiotensin II by inhibiting aldosterone secretion. ADM also has antihypertrophic, anti-apoptotic, antifibrotic, antioxidant, angiogenic and immunoregulatory effects and antimicrobial properties. ADM expression is upregulated by hypoxia, inflammation-inducing cytokines, viral or bacterial substances, strength of shear stress, and leakage of blood vessels. These pathological conditions are established during systemic inflammation that can result from infections, surgery, trauma/accidents or burns. The ability to rapidly identify infections and the prognostic, predictive power makes it a valuable tool in severe viral and bacterial infections burdened by high incidence and mortality. This review sheds light on the pathophysiological processes that in severe viral or bacterial infections cause endothelitis up to the development of organ damage, the resulting increase in ADM levels dosed through its more stable peptide mid-regional proadrenomedullin (MR-proADM), the most significant studies that attest to its diagnostic and prognostic accuracy in highlighting the severity of viral or bacterial infections and appropriate therapeutic insights.

Keywords: adrenomedullin (ADM); biomarkers; endothelitis; mid-regional proadrenomedullin (MR-proADM); sepsis; viral infection.

Figure 1

Vasodilator effect of adrenomedullin at the intravascular and interstitial levels. At the intravascular level, ADM induces vasodilation of VSMCs by stimulating the production of endothelial nitric oxide synthase (eNOS) and acting directly on these cells by activating protein kinase A (PKA). It also maintains vascular integrity by acting on endothelial cell junctions, reducing actomyosin contraction and vascular permeability. The latter function is inhibited by ADM at the interstitial level. In addition, at the interstitial level, ADM causes vasodilation through nitric oxide production, inhibition of the RAAS system and oxidative stress, and suppression of excessive tissue proliferation and secretion of catecholamines, ACTH, and insulin. Abbreviations: ACTH—Adrenocorticotropic hormone; ADM—adrenomedullin; cAMP—cyclic adenosine monophosphate; eNOS—nitric oxide synthase; NO—Nitric oxide; PKA—protein kinase A; RAAS—renin-angiotensin-aldosterone system; VSMCs—Vascular Smooth Muscle Cells.

Figure 2

Pathophysiology of adrenomedullin expression: endothelitis. A noxa (viral or bacterial infection) can cause damage to ECs resulting in a dysregulation of the ADM system. This dysregulation leads to dysfunction of the activities guaranteed physiologically by the system, as shown in (A), light blue colored. This results in ((B) pink colored) hypotension, increased inflammation and infectious state, and vascular leakage leading to activation of the coagulation cascade and consequently to multiorgan failure. On the other hand ((C) light blue colored), the hypoxia that sets in with infection also results in increased ADM expression that teleologically stimulates lymphangiogenesis (with reduction of edema and fibrosis) and reduces cardiac remodeling, apoptosis and myocardiocyte viability. Abbreviations: ACTH—Adrenocorticotropic hormone; ADM—adrenomedullin; AVP—Arginine vasopressin; Cx43—Connexin 43; CNS—Central Nervous System; Endothelial cells (ECs); RAAS—renin-angiotensin-aldosterone system; RV—right ventricular; VSMCs—Vascular Smooth Muscle Cells.

Figure 3

Pathophysiology of severe viral and bacterial infections and the immune modulation in the intravascular compartment. A viral or bacterial infection causes damage in the intravascular compartment by adhering to the cell surface through the ACE2 receptor, which causes it to enter the cell. Inside the cell, Toll-like Receptors and outside the cell B lymphocytes, antigen-presenting cells (APCs), monocytes, and neutrophils activate the immune response and the coagulation cascade. Abbreviations: AA-AT1—anti AT1 autoantibodies; ACE2—angiotensin-converting enzyme 2; ACE2r—angiotensin-converting enzyme 2 receptor; APCs—antigen-presenting cells; CTL—Cytotoxic T lymphocytes; H3—Histones 3; H4—Histone 4; IL-1B—Interleukin-1β; IL-2—Interleukin-2; IL-18—Interleukin-18; MHCII—major histocompatibility complex class II; MPO—Myeloperoxidase; NE—Neutrophil elastase; PEVs—platelet-derived extracellular vesicles; PLTs—Platelets; PPR—pathogen recognition receptor; RAAS—renin-angiotensin-aldosterone system; RNA—RiboNucleic Acid; TF—Tissue factor; TFPI—Tissue factor pathway inhibitor I; Th—Helper T cells; TLR 3,4,7—Toll-like Receptor 3,4,7; TLR 4—Toll-like Receptor 4; TNFα—Tumor necrosis factor α; TNFSF14 Light—tumor necrosis factor ligand superfamily member 14.

Figure 4

Pathophysiology of severe viral or bacterial infections on endothelial cells: endothelitis and ADM expression. Severe viral or bacterial infections cause inflammation and oxidative stress, leading to damage of Endothelial cells (ECs), degradation of glycocalyx with creation of autoantibodies resulting in increased RAAS activity, disruption of the ADM system and Angiopoietin-Tie axis with dysregulation of junctional proteins (Jps), activation of coagulation until organ failure sets in. Also depicted in the figure are the process steps in which the inhibitors act: ACE inhibitors and ARB on the RAAS, adrecizumab on the ADM system, and ABTAA on the Ang/Tie axis. Abbreviations: AA-AT1—anti AT1 autoantibodies; ABTAA—Ang2-binding antibody; ACE—angiotensin-converting enzyme; ACEi—angiotensin-converting enzyme inhibitor; ACE2—angiotensin-converting enzyme 2; ADM—adrenomedullin; Ang-Tie—Angiopoietin-Tie; Ang 1-7—Angiotensin-(1-7); ARB—angiotensin receptor blocker; ECs—Endothelial cells; CRP—C-Reactive Protein; NOx—Nitric oxide; RAAS—renin-angiotensin-aldosterone system; RNS—reactive nitrogen species; ROS—reactive oxygen species.