Since the first identification of a vasoconstrictor activity present in endothelial cell supernatants (1) and the subsequent isolation of endothelin (ET)-1 in 1988 (2), there has been tremendous interest in the biology of endothelins. In addition to ET-1, further studies have demonstrated the existence of two other endothelins, ET-2 and ET-3, which differ from ET-1 with two and six amino acid residues, respectively (3). The family of endothelins has been an object of intensive research for scientists from many disciplines. The majority of research has focused on the cardiovascular system (for review see References 4 and 5), but there has also been a significant accumulation of data indicating the mediator role of endothelins in a variety of lung disorders (for further review see References 6 and 7). However, despite intense investigation and the identification of ET-1 expression under a number of pathologic conditions related to the lungs, such as pulmonary vascular disease, asthma, and pulmonary fibrosis, a direct link between ET-1 activity and a disease state has been elusive. This Perspective will focus on aspects of endothelin biology that pertain to the pulmonary system. Endothelins are synthesized from precursors known as preproendothelins (ppET), comprising 212 amino acid residues. The large precursors undergo an intermediate cleavage by endopeptidases to form the 38-amino-acid biologically inactive proendothelins, also called big endothelins. Endothelin-converting enzymes are membrane-bound metalloendopeptidases that further cleave proendothelins. The biologically active endothelins are 21-amino-acid peptides, with two disulfide bridges joining cysteins in positions 1-15 and 3-11 in the N-terminal half, and a cluster of hydrophobic amino acid residues at the C-terminal end of the structure. The structure of the N-terminal domain determines the affinity to the receptor, while the C-terminal domain contains the binding site of the peptide to the receptor (for review see Reference 8). Most tissues contain more ET-1 than ET-2 or ET-3, with the highest levels of ET-1 found in lung. ET-1 is secreted by endothelial cells (2, 9), epithelial cells (10, 11), alveolar macrophages (12, 13), polymorphonuclear leukocytes (14), and fibroblasts (15). Release of endothelins is regulated at the level of gene expression and peptide synthesis because cells do not store endothelins. The expression of the gene is induced by a variety of factors including thrombin, angiotensin II, adrenalin, cytokines, and growth factors. The calcium-dependent protein kinase C (PKC) is involved in this stimulation, and the expression of ET-1 is reduced in the presence of PKC inhibitors. The most potent physiologic factor in regulating ET-1 production and release from endothelial cells seems to be blood flow. An increase in blood flow elicits vasodilatation via activation of the shear stress receptors of endothelial cells that, in turn, produce and release nitric oxide and decrease the production and release of ET-1. The multitude of stimuli that influence the release of ET-1 have made the precise biologic significance of ET-1 elusive. Approximately 80% of the synthesized amount of ET-1 is secreted into the basolateral compartment toward the surrounding smoothmuscle cells and interstitium where it acts in an autocrine and paracrine manner. The concentration detected in vascular tissue is approximately 100 times higher than that in plasma, with the vast majority receptor bound and only minute amounts remaining in a free form. ET-1 has a halflife of approximately 4 to 7 min in the blood because of quick binding to tissues and rapid metabolization by a specific endothelin-degrading enzyme (for further …