Modulation and roles of the endothelins in the pathophysiology of pulmonary embolism.
Recent research on the endothelins (ETs) and their pathways in acute pulmonary embolism (APE) has led to significant advances in the understanding of this disease. ETs are potent vasoconstrictors and bronchoconstrictors found abundantly in the lung and can be released by stimuli such as endothelial injury, hypoxia, or thrombin, a key product in the coagulation cascade. Many studies using different approaches and methods of inducing pulmonary embolization, both in vitro and in vivo in various species, have mostly shown that ETs play an important role in the pathophysiology of APE. These results were obtained by comparing the hemodynamic data in the presence or absence of various ETs inhibitors, but also by assessing the modulation of the ET-related elements of this system by molecular, cell biology, and pharmacological methods. Based on the current understanding, a mechanism involving the ET pathway in the pathophysiology of APE is proposed for the reader's considerations. We postulate that ETs are primary mediators in APE based on the following: (i) their source from pulmonary endothelial cells where the primary injury takes place; (ii) their direct vasconstrictive, bronchoconstrictive, and promitogenic effects via distinct ET receptors; and (iii) their indirect effects associated with the secondary release of thromboxane and other mediators, which are released from inflammatory cells and platelets, which together can potentiate the overall hemodynamic response, most specifically the pulmonary vascular bed. Such combined effects of ETs on bronchomotor and vasomotor tone in the lung can adversely affect ventilation perfusion matching and lead to severe hypoxemia without causing significant changes in the chest X-ray of these patients. Thus, we may consider ET inhibitors as future current therapeutic agents in patients with PE.
Battistini
Bruno
B
Laval Hospital Research Center, Quebec Heart and Lung Institute, Department of Medicine, Laval University, 2725 Chemin Ste-Foy, Sainte-Foy, QC G1V 4G5, Canada. bruno.battistini@med.ulaval.ca
D000818:Animals; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000502:physiology*; D006801:Humans; D011655:Pulmonary Embolism / Q000188:drug therapy* / Q000503:physiopathology*; D017466:Receptors, Endothelin / Q000502:physiology
D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D017466:Receptors, Endothelin