Endothelin-1 in Acute Lung Injury and the Adult Respiratory Distress Syndrome

Abstract

Endothelial damage is a hallmark of acute lung injury. Endothelial mediators may increase pulmonary vascular tone and induce pulmonary arterial muscularization, thereby contributing to the pulmonary hypertension seen with acute lung injury. We measured plasma levels and net pulmonary clearance of endothelin-1, a potent endothelium-derived vasoconstrictor peptide and smooth muscle mitogen, in 26 patients with early acute lung injury, the adult respiratory distress syndrome, and pulmonary hypertension. Nineteen had another data collection at clinical improvement or worsening. Control subjects (n = 25) had no pulmonary hypertension or lung injury. Initial mixed venous and systemic arterial plasma endothelin-1 levels were elevated (4.6 +/- 0.6 SEM and 4.9 +/- 0.6 pg/ml, respectively) as compared with control subjects (0.9 +/- 0.1 and 0.6 +/- 0.1 pg/ml). The systemic arterial/venous endothelin-1 ratio was 1.1 +/- 0.1 (0.7 +/- 0.1 in control subjects), indicating a reduction in normal net pulmonary endothelin-1 clearance. With clinical improvement, as compared with clinical worsening, mean plasma endothelin-1 levels, arterial/venous ratio, and pulmonary arterial pressure fell significantly towards normal. Thus, patients with acute lung injury have marked early increases in circulating plasma endothelin-1 levels, associated with abnormal pulmonary endothelin-1 metabolism. These abnormalities reverse in patients who recover. Through its actions, endothelin-1 could contribute to the pulmonary hypertension seen in acute lung injury.

ETA receptors are the primary mediators of myofilament calcium sensitization induced by ET‐1 in rat pulmonary artery smooth muscle: a tyrosine kinase independent pathway

“…As mentioned previously, the second phase of acute HPV requires the release of a vasoconstrictor from the intact endothelium (Leach et al, 1994) and appears to develop in the presence of a constant cytoplasmic free Ca 2+ concentration . Moreover, recent investigations have suggested that ET-1 may play an important role in the regulation of pulmonary vascular tone and may promote the development of hypoxic pulmonary hypertension (Chen et al, 1997;Bonvallet et al, 1994;Prie et al, 1997;Langleben et al, 1993;Yoshibayashi et al, 1991). Our ®ndings suggest, therefore, that ET-1, or a related peptide, may be responsible for the increase in myo®lament Ca 2+ sensitivity associated with hypoxic pulmonary hypertension.…”

“…Recent investigations have suggested that ET-1 may play an important role in the regulation of pulmonary vascular tone and may promote the development of pulmonary hypertension (Chen et al, 1997;Bonvallet et al, 1994;Prie et al, 1997;Langleben et al, 1993;Yoshibayashi et al, 1991). During pulmonary hypoxia, plasma ET-1 levels are elevated due to increased expression of ET-1 mRNA, and release of ET-1 from pulmonary artery endothelial cells (Giaid et al, 1993;Elton et al, 1992;Li et al, 1994a;, and this is accompanied by an increase in endothelin receptor gene expression in human and rat pulmonary vasculature (Li et al, 1994a,b).…”

EndothelinB receptor‐mediated contraction in human pulmonary resistance arteries

“…However, all relevant studies are consistent in showing that the ET-1 levels are significantly increased in cases of pulmonary hypertension. The most dramatic increases in circulating ET-1 levels and ET-1 expression, appear to be associated with primary pulmonary hypertension (Stewart et al, 1991;Cacoub et al, 1993;Giaid et al, 1993;Nootens et al, 1995); although ET-1 levels are also significantly increased in pulmonary hypertension secondary to hypoxia (Stewart et al, 1991;Ferri et al, 1995), congenital heart defects (Yoshibayashi et al, 1991;Cacoub et al, 1993;Vincent et al, 1993), valvular heart disease (Stewart et al, 1991;Chang et al, 1993;Yamamoto et al, 1994;Zhu et al, 1994), chronic heart failure (Cody et al, 1992;Kiowski et al, 1995) and the adult respiratory distress syndrome (Langleben et al, 1993). Plasma ET-1 levels can be increased four fold in some of these studies.…”

Endothelin-1 production is associated with eosinophilic rather than neutrophilic airway inflammation

“…Interestingly, only a modest increase in ET-1 production was found during this inflammation. This is surprising, since ET-1 has been associated with ARDS [8,25] and the degree of ET-1 elevation in critically ill patients has been shown to correlate with outcome [26]. A modest, but significant, rise in BALF ET-1 was observed 3 h following LPS provocation, the elevation being maintained after 24 h. However, this rise appeared in the absence of a significant increase in ET-1 mRNA production.…”

“…ET-1 has also been claimed to be of importance in other inflammatory lung disorders [5,7,8]. Since the lungs have been shown to be a major source of ET-1 [9] in addition to having a very high receptor density for this peptide [9], it could be speculated that ET-1 would be of importance as a general pro-inflammatory mediator in this organ.…”