A cytokine reborn? Endothelin-1 in pulmonary inflammation and fibrosis.

摘要: Since the first identification of a vasoconstrictor activity present in endothelial cell supernatants (1) and subsequent isolation endothelin (ET)-1 1988 (2), there has been tremendous interest biology endothelins. In addition to ET-1, further studies have demonstrated existence two other endothelins, ET-2 ET-3, which differ from ET-1 with six amino acid residues, respectively (3). The family endothelins an object intensive research for scientists many disciplines. majority focused on cardiovascular system (for review see References 4 5), but also significant accumulation data indicating mediator role variety lung disorders 6 7). However, despite intense investigation expression under number pathologic conditions related lungs, such as pulmonary vascular disease, asthma, fibrosis, direct link between disease state elusive. This Perspective will focus aspects that pertain system. Endothelins are synthesized precursors known preproendothelins (ppET), comprising 212 residues. large undergo intermediate cleavage by endopeptidases form 38-amino-acid biologically inactive proendothelins, called big Endothelin-converting enzymes membrane-bound metalloendopeptidases cleave proendothelins. active 21-amino-acid peptides, disulfide bridges joining cysteins positions 1-15 3-11 N-terminal half, cluster hydrophobic residues at C-terminal end structure. structure domain determines affinity receptor, while contains binding site peptide receptor Reference 8). Most tissues contain more than or highest levels found lung. is secreted cells (2, 9), epithelial (10, 11), alveolar macrophages (12, 13), polymorphonuclear leukocytes (14), fibroblasts (15). Release regulated level gene synthesis because do not store induced factors including thrombin, angiotensin II, adrenalin, cytokines, growth factors. calcium-dependent protein kinase C (PKC) involved this stimulation, reduced presence PKC inhibitors. most potent physiologic factor regulating production release seems be blood flow. An increase flow elicits vasodilatation via activation shear stress receptors that, turn, produce nitric oxide decrease ET-1. multitude stimuli influence made precise biologic significance Approximately 80% amount into basolateral compartment toward surrounding smoothmuscle interstitium where it acts autocrine paracrine manner. concentration detected tissue approximately 100 times higher plasma, vast bound only minute amounts remaining free form. halflife 7 min quick rapid metabolization specific endothelin-degrading enzyme references Two endothelin-specific cloned humans: some selective isoforms (ET A ) (16), nonisoform B (17). Homology these 60%, both subtypes. three isopeptides ET can described . .. ET-3. humans, 1,000-fold compared ET-3 (18). similar all isoforms, recognizes identical end. Both associated vasoconstriction when localized smooth-muscle cells, whereas mediates commonly endothelium. third isolated Xenopus laevis (19). Pulmonary fibrosis common outcome interstitial diseases, etiologically heterogeneous group diffuse inflammatory affecting parenchyma 20). Despite myriad potential mechanisms injury, pathway injury structures wall. response influx mediators, recruitment mesenchymal turnover extracellular matrix (ECM). ( Received original May 19, 2000