Role of endothelin-1 in acute lung injury

Abstract

The alveolar-capillary membrane serves as a barrier that prevents the accumulation of fluid in the alveolar space and restricts the diffusion of large solutes while facilitating an efficient gas exchange. When this barrier becomes dysfunctional, patients develop acute lung injury (ALI), which is characterized by pulmonary edema and increased lung inflammation that leads to a lifethreatening impairment of gas exchange. In addition to the increase of inflammatory cytokines, plasma levels of endothelin-1 (ET-1), which is a primarily endothelium-derived vasoconstrictor, are increased in patients with ALI. As patients recover, ET-1 levels decrease, which suggests that ET-1 may not only be a marker of endothelial dysfunction but may have a role in the pathogenesis of ALI. While pulmonary edema accumulates, alveolar fluid clearance (AFC) is of critical importance, as failure to return to normal clearance is associated with poor prognosis in patients with pulmonary edema. AFC involves active transport mechanisms where sodium (Na + ) is actively transported from the alveolar airspaces, across the alveolar epithelium, and into the pulmonary circulation, which creates an osmotic gradient that is responsible for the clearance of lung edema. In this article, we review the relevance of ET-1 in the development of ALI, not only as a vasoconstrictor molecule but also by inhibiting AFC via the activation of endothelial ET-B receptors and generation. Furthermore, this review highlights the therapeutic role of drugs such as beta-adrenergic agonists and, in particular, of endothelin receptor antagonists in patients with ALI.The alveolar-capillary barrier facilitates efficient gas exchange and restricts the accumulation of fluid and large solutes in the alveolar space. When this barrier becomes dysfunctional, patients develop acute lung injury (ALI), which is clinically defined by a ratio of arterial partial pressure of oxygen to a fraction of inspired oxygen (PaO 2 /FiO2) of up to 300 and bilateral infiltrates on chest radiographs in the absence of left atrial hypertension. The more severe form of ALI is known as acute respiratory distress syndrome (ARDS), which has a similar definition as ALI except for a PaO 2 /FiO 2 ratio of up to 200. 1,2 This syndrome of acute respiratory failure affects ~190,000 patients per year in the United States with a mortality rate of 40% to 50%. 3 Moreover, the costs of care for ALI in the United States per patient was approximately $48,000 in 2005. 4 It is now widely accepted that the pathophysiology of ALI is driven by an aggressive inflammatory reaction that increases the permeability of the alveolo-capillary unit after events such as sepsis, pneumonia, aspiration, and trauma. [5][6][7][8] Several cytokines, such as tumor necrosis factor alpha, interleukin (IL)-1, IL-6, and IL-8, have been found to be increased in bronchoalveolar lavage (BAL) fluid and in the plasma of patients with ALI. [9][10][11] The development of lung injury seems to include the activation of the coagulation and infl...

Endotelina-1: vasoconstrictor intrínseco del endotelio vascular

“…Cada endotelina es sintetizada en diferentes células, tejidos, y órganos, cabe señalar que esta síntesis va-Neil Flores Valdez ría dependiendo de la estructura, órgano y tejido en estudio. En la tabla 1 se presentan las diversas células implicadas en la síntesis de cada endotelina, de esta tabla se destaca que ET-1 se produce en mayor concentración en células endoteliales, la ET-2 mayormente en células epiteliales renales y células del estroma y ET-3 en el cerebro fundamentalmente en las neuronas y células de la glía (3,13,21,22,23). Cada uno de los péptidos: endotelina-1 (ET-1), endotelina-2(ET-2) y endotelina-3(ET-3), es codificado por un gen independiente en un cromosoma determinado 6, 1 y 20 respectivamente (7).…”

“…La movilización de calcio intracelular y la entrada del mismo a la célula, así como las vías de señalización dependientes de fosfatidilinositol 3-cinasa (PI3K) y la subunidad β/ γ de la Proteína G, se producen posterior a la interacción de ET-1 y ETB (13,22). Cuando ET-1 toma contacto con receptor ETB a nivel de las células endoteliales va a producir relajación del endotelio a expensas del incremento del GMPc, esto producirá liberación del óxido nítrico (NO) y EDHF.…”

Endothelin Receptor Down-Regulation Mediated Ligand Regulation Mechanisms Protect Against Cellular Hypoxia Injury in Rat Vascular Endothelial Cells

“…There are three known subtypes of ET: ET-1, ET-2 and ET-3. ET-1 is mainly produced by endothelial cells, and its expression is significantly increased after renal ischemia reperfusion [6]. ET implies its biological effects by combining with endothelin receptors (ETR), including endothelin A receptors (ETaR) and endothelin B receptors (ETbR).…”

The Endothelin System Has a Significant Role in the Pathogenesis and Progression of Mycobacterium tuberculosis Infection

“…Its activity contributes to endogenous tonic vasomotor maintenance by homeostatically balancing the vasodilation activity of NO. In addition, ET-1 also is produced by many cell types and released during various injurious stimuli, whereas atrial natriuretic peptide, prostacyclin, and nitric oxide (NO) inhibit its synthesis and release (10,11). ET-1 binds to two distinct subtype receptors (ETA and ETB), which are presented in several cell types.…”