Review articleEndothelin-1 and its role in the pathogenesis of infectious diseases
Graphical abstract
A schematic illustration of ET-1 effects on different cell types. Binding of ET-1 to its cognate receptors causes activation of monocytes, neutrophils, mast cells, and endothelial cells. ET-1 contributes to cytokine production, enhanced cellular adhesion molecule expression, as well as monocyte diapedesis. Additionally, ET receptor activation on vascular smooth muscle cells results in vasoconstriction, vascular permeability, and tissue remodeling.
Introduction
Since its discovery, endothelin-1 (ET-1) has been shown to exhibit mitogenic properties and to regulate several physiologic functions, including salt and water homeostasis, vascular tone, and inflammation (Carpenter et al., 2005, Speciale et al., 1998, Chauhan et al., 2007). ET-1 is one of three known isoforms of endothelin, each encoded by a distinct peptide, but produced via a similar two-step metabolic pathway. Endothelins act through two seven transmembrane G-protein coupled receptors, endothelin receptor A (ETA) (Arai et al., 1990) and endothelin receptor B (ETB) (Sakurai et al., 1990, Masaki, 2004), to exert their effects on physiological and pathological processes. ET-1 is the most abundant isoform in vivo. It is formed by conversion of pre-pro-ET-1 into the intermediate precursor big ET-1, which is then cleaved by the ET converting enzyme (ECE) to form the active 21-amino acid peptide. ET-1 is synthesized by a variety of cells including endothelial cells, macrophages, cardiomyocytes, and neurons (Table 1) (Schinelli, 2002, Vignon-Zellweger et al., 2012, Kedzierski and Yanagisawa, 2001, van Harmelen et al., 2008, Dai et al., 2012, Nakagomi et al., 2000, Davis et al., 1992, De Souza et al., 2004, Kuddus et al., 2000, Jamal and Schneider, 2002, Ehrenreich et al., 1992, Matsushima et al., 2004, Giaid et al., 1989, D'Orleans-Juste et al., 2012, Yu et al., 1995).
ET-1 is constitutively synthesized and acts in an autocrine and paracrine manner in tissues throughout the body; its physiological plasma concentration is ~ 1 pM (Kedzierski and Yanagisawa, 2001). Binding of ET-1 to the ETA receptor triggers an increase in intracellular concentrations of calcium, resulting in very potent vasoconstriction and smooth muscle contraction (Chauhan et al., 2007, Ehrenreich et al., 1990). ET-1 can also promote vasodilation by inducing the production of NO via its interaction with the ETB receptor on endothelial cells (Chauhan et al., 2007, Tsukahara et al., 1994). Under normal physiological conditions ET-1 effects are controlled by these different mechanisms; however, abnormal activation of these cellular signaling pathways can play a role in the progression of disease.
Although typically regarded as a smooth muscle spasmogen, ET-1 has also been shown to participate in many inflammatory processes. While constitutively expressed throughout the body in healthy individuals, expression of ET-1 is increased with stress to the endothelium in response to cytokines, reactive oxygen species, angiotensin II, and thrombin (Kedzierski and Yanagisawa, 2001). High levels of ET-1 have been found in alveolar macrophages, leukocytes (Sessa et al., 1991) and fibroblasts (Gu et al., 1991), and it has been demonstrated that TNF-α facilitates the release of ET-1 by endothelial and epithelial cells (Sibson et al., 2002). In addition, there is ample evidence which suggests that ET-1 regulates leukocyte trafficking and cytokine production. Studies have shown that ET-1 stimulates monocyte production of IL-8 and MCP-1, known neutrophil and monocyte chemoattractants (Helset et al., 1994). Moreover, ET-1 can act as a mast cell activator, and lead to degranulation and release of inflammatory cytokines such as TNF-α and IL-6 (Matsushima et al., 2004). The mechanisms by which these cells enter targeted tissue are also under the control of the ET system. shRNA knockdown of different components of the ET system has demonstrated ET-1, ETB receptor, and ECE involvement in monocyte diapedesis (Reijerkerk et al., 2012). Cellular adhesion molecules like ICAM-1, VCAM-1, and e-selectin facilitate the leukocyte recruitment, binding, and infiltration. Human brain microvascular endothelial cells exposed to ET-1 upregulate the expression of ICAM-1, VCAM-1, and e-selectin (McCarron et al., 1993). This cascade of ET-1 mediated inflammatory events potentiates inflammation and the subsequent trafficking of immunocompetent cells into injured tissue.
Increased levels of ET-1 in response to stress have been implicated in a variety of infectious processes (Dietmann et al., 2008, Wanecek et al., 2000, Petkova et al., 2001, Koedel et al., 1997). Clinical and experimental data indicate that ET-1 is involved in the pathogenesis of sepsis (Arai et al., 1990, Wanecek et al., 2000, Andrade et al., 2012), viral and bacterial pneumonia (Schuetz et al., 2008, Samransamruajkit et al., 2002), Rickettsia conorii infections (Davi et al., 1995), Chagas disease (Bouallegue et al., 2007, Petkova et al., 2001), and severe malaria (Briyal et al., 2011, Dietmann et al., 2008, Wenisch et al., 1996, Brauner et al., 2000). ET-1 is associated with vasospasms, vascular damage, blood brain barrier (BBB) permeability, cardiovascular remodeling, and inflammation (Speciale et al., 1998, Chauhan et al., 2007, McCarron et al., 1993, Lin et al., 2004, Stanimirovic et al., 1994). Septic patients have increased ET-1 plasma concentrations, which correlate with renal dysfunction and disease severity (Piechota et al., 2007). Levels of cerebral spinal fluid (CSF) ET-1 are significantly elevated in individuals with bacterial meningitis, which is associated with abnormalities in cerebral blood flow (CBF) (Koedel et al., 1997). Additionally, ET-1 has been shown to play a major role in the development of vascular disruption caused by infection. In this review we will summarize the role of the ET in infectious diseases.
Section snippets
CNS Infections
The endothelin system is widely distributed throughout the central nervous system (CNS). Brain microvascular endothelial cells, neurons, and glial cells synthesize ET-1 and express receptors for the ligand (Schinelli, 2002, Dai et al., 2012). During pathological processes of the CNS, in addition to its vasoactive actions, upregulated ET-1 has been shown to cause an increase in BBB permeability, activate astrocytes, enhance cell adhesion molecule expression, as well as act as a neurotransmitter (
Endothelin and pneumonia
ET-1 is a potent vasoconstrictor and in the endothelium its synthesis is induced by hypoxia and pulmonary infection (Carpenter et al., 2005). In the infected lung ET-1 may be synthesized by a variety of cell types including bronchial epithelial, smooth muscle cells, endothelial cells, and inflammatory cells such as monocytes and macrophages.
Community-acquired pneumonia (CAP) is an important cause of morbidity and mortality world-wide and the precise microbial etiology of an episode of CAP is
Sepsis and endothelin
Despite the advances in our understanding of the mechanisms and therapeutic strategies in managing this disease complex, bacterial sepsis and septic shock continue to be important contributors to morbidity and death in the industrialized world, especially in the hospital setting, (Mayr et al., 2013). The administration of antibiotics within the early hours of the recognition with broad-spectrum antibiotics is a "goal" of therapy and is considered good medical practice. Nevertheless, even when
Chagas disease and endothelin
Chagas disease is a neglected tropical disease that is a life-long persistent infection. It is caused by the protozoan parasite, Trypanosoma cruzi, and is a major cause of morbidity and mortality in endemic areas of Latin America stretching from the Texas–Mexican border to almost the tip of the South American continent. Due to increased immigration to the non-endemic areas of North America, Europe, Asia and Australia this disease can no longer be considered an esoteric disease or a medical
Conclusions
The role of endothelins in the pathogenesis of infectious diseases has been an important field of study almost immediately since the discovery of the peptide. Though ET-1 is implicated in the pathogenesis of several processes with infectious diseases, there is no unifying hypothesis as to how ET-1 effects its actions, rendering the precise elucidation of this role difficult; particularly since the signaling pathways involved are complex, interrelated and redundant. Several of these disease
Conflict of interest statement
None
Acknowledgements
Supported by United States National Institutes of Health Grants NS069577 (MSD), AI076248 (HBT), T32AI 070117 (BDF); Burroughs-Wellcome Fund Career Award for Medical Scientists (MSD), Conselho Nacional do Desenvolvimento Científico e Tecnológico (CNPq), Brasília, Brazil; and Fundação de Amparo à Pesquisa do Estado de Minas Gerais (FAPEMIG), Belo Horizonte, Brazil (FSM).
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