Role of endothelin-1 in lung disease

Abstract

ARDS = acute respiratory distress syndrome; BAL = bronchoalveolar lavage; BO = bronchiolitis obliterans; ECE = endothelin converting enzyme; ETA = endothelin A; ETB = endothelin B; ET-1 = endothelin-1; FEV1 = forced expiratory volume in 1 s; NO = nitric oxide.Available online http://respiratory-research.com/content/2/2/090 Introduction ET-1, ET-2, and ET-3 are members of a peptide family that has been the subject of much interest in the past decade. Our laboratory and that of Highsmith identified this peptide vasoconstrictor secreted from endothelial cells [1][2][3] that was subsequently isolated, sequenced, cloned, and named by Yanagisawa in 1988 [4]. The many diverse and overlapping functions of these peptides have since implicated endothelins in both homeostatic mechanisms as well as diseases of the lungs. This review will focus on the role of endothelins (particularly ET-1), emphasizing the need to better understand endothelin biology and function in a wide variety of disorders including diseases of the airways and pulmonary vasculature, lung tumors, the acute respiratory distress syndrome, and fibrotic diseases (Table 1). Endothelin biochemistryThe endothelins are a family of 21 amino acid peptides, of which there are three distinct isoforms (ET-1, ET-2, and ET-3). The isoforms ET-2 and ET-3 differ from ET-1 by two and six amino acids, respectively, and share significant homology, especially at the carboxy terminus with sarafotoxins a-e (Fig. 1). Endothelin-1 is the most abundant isoform and has been best characterized. The lung has the highest levels of ET-1 secreted by endothelium, smooth muscle, airway epithelium, and a variety of other cells (Table 2). ET-1 also circulates in the plasma. In the normal lung, ET-1 mainly localizes to vascular endothelium, airway and vascular smooth muscle cells and, to a lesser degree, the epithelium. ET-2 has similar biologic functions as ET-1 and is found in the myocardium, kidney and placental tissues. ET-3 also circulates in plasma and is found in the central nervous system, gastrointestinal tract, lung, and kidney although the cellular source is not clear. The gene for ET-1 is located on chromosome 6, that for ET-2 on chromosome 1, and the gene for ET-3 on chromosome 20 [5].All three endothelins are synthesized as preprohormones and post-translationally processed to active peptides. ET-1 processing has been best characterized and begins with the 212 amino acid peptide (preproET-1), which is then proteolytically cleaved by endopeptidases to big ET-1 Review Role of endothelin-1 in lung disease AbstractEndothelin-1 (ET-1) is a 21 amino acid peptide with diverse biological activity that has been implicated in numerous diseases. ET-1 is a potent mitogen regulator of smooth muscle tone, and inflammatory mediator that may play a key role in diseases of the airways, pulmonary circulation, and inflammatory lung diseases, both acute and chronic. This review will focus on the biology of ET-1 and its role in lung disease.

Endothelin-1 Is Increased in the Breath Condensate of Patients with Non-Small-Cell Lung Cancer

“…We observed the highest concentrations of ET-1 in patients with metastasis (stage IV), in agreement with findings of some authors that supposed that ET-1 could play a role in the metastasis of the tumour [2]. This hypothesis of the significant role of ET-1 in determining metastasis could be confirmed by the involvement of ET-1 in neo-angiogenesis, on which metastases are dependent via induction of vascular-endothelial growth factor expression, and the sprouting of new vessels [2, 31, 32, 33].…”

“…The reason for this interest in the involvement of ET-1 in lung cancer results from the findings that pulmonary endothelium [17, 18], smooth muscle [19], airway epithelium [20]and a variety of other cells [2]secrete the highest levels of ET-1.…”

“…ET-1 is a member of a peptide family that has been the subject of extensive studies in the past decade, particularly for its mitogenic regulation [2]. Its involvement in the start and progression of tumours is confirmed by its production by several human cancer cells, such as breast, colon, pancreas [11], cervix and larynx [12], endometrium [13], prostate [14], gastric and ovary cancers [15].…”

“…Vasopressin has been the first mitogenic factor investigated [1]. At the moment, research focuses on endothelin-1 (ET-1), a 21-amino-acid peptide secreted by different cell types, including macrophages, monocytes, hepatocytes, endothelial cells, vascular smooth muscle cells, and various tumour cells [2, 3]. It stimulates the proliferation of vascular smooth muscle cells, fibroblasts, and keratinocytes and plays a role in the expression of proto-oncogenes (c- myc, c- fos ), which stimulate cell proliferation [3].…”

A virtual-system coupled multicanonical molecular dynamics simulation: Principles and applications to free-energy landscape of protein–protein interaction with an all-atom model in explicit solvent

“…ET1, which is a potent and long-lasting vasoconstrictor on smooth muscles of a vessel, [28][29][30][31] is thought to be an important drug target because it is related to many human diseases. [32][33][34][35][36] Because of its two intra-peptide disulfide bonds, ET1 has a compact tertiary structure in solution. In both the NMR [37][38][39] and X-ray 40 structures, the N-terminal region of ET1 adopts a somewhat distorted strand and the middle region forms a helix.…”