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Endothelin antagonists: new bullets against lung injury?


Acute lung injury is a syndrome of inflammation and of increased permeability of the blood–gas barrier. Endothelins are thought to exert proinflammatory effects. Kuklin and colleagues show that the endothelin receptor antagonist tezosentan reduces pulmonary edema in endotoxemic sheep, in parallel with a prevention of protein kinase C-α activation. In turn, the level of some cytokines increased after tezosentan treatment. Whether these contrasting effects of endothelin blockade on inflammatory mechanisms have clinical relevance and whether these agents might benefit patients with acute lung injury is unknown.

In the search for new agents to protect the lung from injury, Kuklin and colleagues [1] report that tezosentan, a non-selective endothelin-1 receptor antagonist, reduces pulmonary edema in endotoxemic sheep, in parallel with a prevention of protein kinase C-α activation.

Mechanisms of acute lung injury

Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS), are syndromes of acute respiratory failure secondary to permeability, non-cardiogenic, pulmonary edema. Common causes are sepsis, pneumonia, aspiration and trauma. ALI/ARDS is a major cause of morbidity, death and cost in intensive care units [2, 3]. Alveolar edema accumulates in ALI/ARDS mainly because the permeability of the capillary (endothelium)–alveolar (epithelium) barrier is increased. This mechanism allows edema formation at normal capillary pressures and greatly increases the rate of edema formation at elevated capillary pressures [2, 3]. In addition, pressure elevation in the pulmonary circulation and mechanical stresses applied to the lung (during mechanical ventilation, for example) may cause "stress failure" in lung capillaries and alveoli, as evident in the formation of breaks and discontinuities in the endothelial and epithelial membranes of the blood–gas barrier [4].

The American–European consensus conference on ARDS defined ALI/ARDS as a "syndrome of inflammation and increased permeability". Hence, it is now widely accepted that the pathophysiology of ALI/ARDS is driven by an aggressive inflammatory reaction that damages the alveolocapillary unit [2, 3, 5, 6]. The inflammatory response includes both cellular and humoral components. After rapid recruitment of leukocytes to the inflamed site, there is activation of mediator cascades including the production of cytokines, chemokines, acute phase proteins, free radicals, complement, coagulation pathway components and focal upregulation of adhesion molecule expression units [5, 6]. Several cytokines, such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-1, IL-6 and IL-8, have been found in bronchoalveolar lavage fluid and plasma of patients with ARDS [3, 5]. Inflammatory mediators amplify endothelial injury directly or by recruiting inflammatory cells into the vascular, interstitial and alveolar spaces [3, 5].

In addition, some mediators may also alter endothelial permeability by disturbing intracellular signaling pathways. TNF-α and α-thrombin have been shown to activate protein kinase C-mediated mechanisms that participate in the pulmonary endothelial response to agents involved in lung injury [3, 7]. Protein kinase C is a ubiquitously expressed family of kinases that have a key role in regulating multiple cellular activities. Activation of specific protein kinase C isoforms, most probably protein kinase C-α, may cause lung endothelial dysfunction through several mechanisms [1, 3, 7].

Endothelins and inflammation

Endothelins are a family of 21-amino-acid isopeptides. Initially described as strong vasoconstrictors, endothelins are now believed also to exert potent proinflammatory effects. For example, transgenic mice overexpressing endothelin-1 release increased amounts of TNF-α, interferon-γ, IL-1 and IL-6 [8]. The endothelin system is activated in clinical lung injury and in various types of experimental lung injury [9], and several endothelin receptor antagonists have been reported to exert protective effects in some models of ALI/ARDS [10]. Endothelins may thus play a pathophysiologic role in ALI/ARDS and promote pulmonary edema by increasing the filtration pressure (as postcapillary vasoconstrictors), and also by increasing capillary permeability (as inflammatory mediators). The results of Kuklin and colleagues [1] are in accordance with this hypothesis and provide further insight into an intracellular effect of endothelin receptor antagonists (i.e. prevention of protein kinase C-α activation).

Endothelin receptor antagonists have been made available recently for clinical use in the treatment of pulmonary arterial hypertension [11]. These drugs may therefore offer new and attractive opportunities for the management of patients with ALI/ARDS, especially because, to date, no pharmacologic agent has been convincingly shown to improve the prognosis of these patients [12]. The data of Kuklin and colleagues [1] suggest that endothelin receptor antagonists might benefit patients with ALI/ARDS.

There is, however, the other side of the coin. As expected from the use of a receptor antagonist, the level of the ligand increased; that is, the plasma concentration of endothelin-1 was elevated after tezosentan treatment [1]. As also expected from the proinflammatory properties of endothelin-1 [8], plasma levels of TNF-α and IL-8 increased after tezosentan treatment [1]. The clinical relevance of these observations is unknown, but production of these cytokines might counteract the benefits expected from endothelin blockade. In other experimental models of ALI/ARDS, endothelin receptor antagonists did not decrease intrapulmonary shunt [13], lung lymph flow or the histologically evaluated degree of parenchymal injury [14], despite a reduction in pulmonary vascular resistance.


The work of Kuklin and colleagues [1] provides important information on the complex effects of endothelin blockers on inflammatory processes. From a clinical point of view, given the prolific nature of the inflammatory cascade causing ALI/ARDS and the angel/devil effects of endothelin receptor antagonists on inflammatory mechanisms, it is unlikely that these single agents could reverse or terminate such a complex process [12].



acute lung injury


acute respiratory distress syndrome




tumor necrosis factor alpha.


  1. Kuklin V, Kirov M, Sovershaev M, Andreasen T, Ingebretsen OC, Ytrehus K, Bjertnaes L: Tezosentan-induced attenuation of lung injury in endotoxemic sheep is associated with reduced activation of protein kinase C. Crit Care 2005, 9: R211-R217. 10.1186/cc3497

    Article  PubMed Central  PubMed  Google Scholar 

  2. Matthay MA, Zimmerman GA, Esmon C, Bhattacharya J, Coller B, Doerschuk CM, Floros J, Gimbrone MA, Hoffman E, Hubmayr RD, et al.: Future research directions in acute lung injury. Summary of a National Heart, Lung, and Blood Institute Working Group. Am J Respir Crit Care Med 2003, 167: 1027-1035. 10.1164/rccm.200208-966WS

    Article  PubMed  Google Scholar 

  3. Piantadosi CA, Schwartz DA: The acute respiratory distress syndrome. Ann Intern Med 2004, 141: 460-470.

    Article  PubMed  Google Scholar 

  4. Bhattacharya J: Pressure-induced capillary stress failure: is it regulated? Am J Physiol Lung Cell Mol Physiol 2003, 284: L701-L702.

    Article  CAS  PubMed  Google Scholar 

  5. Bellingan GJ: The pulmonary physician in critical care (part 6): the pathogenesis of ALI/ARDS. Thorax 2002, 57: 540-546. 10.1136/thorax.57.6.540

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Puneet P, Moochhala S, Bhatia M: Chemokines in acute respiratory distress syndrome. Am J Physiol Lung Cell Mol Physiol 2005, 288: L3-L15. 10.1152/ajplung.00405.2003

    Article  CAS  PubMed  Google Scholar 

  7. Siflinger-Birnboim A, Johnson A: Protein kinase C modulates pulmonary endothelial permeability: a paradigm for acute lung injury. Am J Physiol Lung Cell Mol Physiol 2003, 284: L435-L451.

    Article  CAS  PubMed  Google Scholar 

  8. Yang LL, Gros R, Kabir G, Sadi A, Gotlieb AI, Husain M, Stewart DJ: Conditional cardiac overexpression of endothelin-1 induces inflammation and dilated cardiomyopathy in mice. Circulation 2004, 109: 255-261. 10.1161/01.CIR.0000105701.98663.D4

    Article  CAS  PubMed  Google Scholar 

  9. Michael JR, Markewitz BA: Endothelins and the lung. Am J Respir Crit Care Med 1996, 154: 555-581.

    Article  CAS  PubMed  Google Scholar 

  10. Fujii Y, Magder S, Cernacek P, Goldberg P, Guo Y, Husain SN: Endothelin receptor blockade attenuates lipopolysaccharide-induced pulmonary nitric oxide production. Am J Respir Crit Care Med 2000, 161: 982-989.

    Article  CAS  PubMed  Google Scholar 

  11. Humbert M, Sitbon O, Simmoneau G: Treatment of pulmonary arterial hypertension. N Engl J Med 2004, 351: 1425-1436. 10.1056/NEJMra040291

    Article  CAS  PubMed  Google Scholar 

  12. Cranshaw J, Griffiths MJD, Evans TW: The pulmonary physician in critical care (part 9): non-ventilatory strategies in ARDS. Thorax 2002, 57: 823-829. 10.1136/thorax.57.9.823

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Hubloue I, Biarent D, Abdel Kafi S, Bejjani G, Mélot C, Naeije R, Leeman M: Endothelin receptor blockade in canine oleic acid lung injury. Intensive Care Med 2003, 29: 1003-1006.

    PubMed  Google Scholar 

  14. Cox RA, Enkhabaatar P, Burke AS, Katahira J, Shimoda K, Chandra A, Traber LD, Herndon DN, Hawkins HK, Traber DL: Effects of a dual endothelin-1 antagonist on airway obstruction and acute lung injury in sheep following smoke inhalation and burn injury. Clin Sci (Lond) 2005, 108: 265-272.

    Article  CAS  Google Scholar 

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Correspondence to Marc Leeman.

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Leeman, M. Endothelin antagonists: new bullets against lung injury?. Crit Care 9, 245 (2005).

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