Effects of Endothelin-1 on Epithelial Ion Transport in Human Airways

Blouquit, Sabine; Lombet, Alain; D'herbomez, Michelle; Naline, Emmanuel; Matran, Régis; Chinet, Thierry

doi:10.1165/rcmb.2002-0104oc

Cited by 22 publications

(12 citation statements)

References 35 publications

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“…Although VX-770 had some effect on unstimulated HBE, likely because of endogenous levels of cAMP in these cells (47), the maximal pharmacological effect of VX-770 on ion and fluid transport required stimulation of the cAMP/PKA signaling pathway by either forskolin or VIP. It is likely that the situation is more dynamic in vivo, where neuronal pathways and mechanical forces exerted on the airway regulate the epithelial cellular signaling pathways to control the activity of CFTR and other ion transport pathways to regulate fluid transport (48,49).…”

Section: Discussionmentioning

confidence: 98%

Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770

Goor

Hadida

Grootenhuis

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

1,067

817

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Cystic fibrosis (CF) is a fatal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR), a protein kinase A (PKA)-activated epithelial anion channel involved in salt and fluid transport in multiple organs, including the lung. Most CF mutations either reduce the number of CFTR channels at the cell surface (e.g., synthesis or processing mutations) or impair channel function (e.g., gating or conductance mutations) or both. There are currently no approved therapies that target CFTR. Here we describe the in vitro pharmacology of VX-770, an orally bioavailable CFTR potentiator in clinical development for the treatment of CF. In recombinant cells VX-770 increased CFTR channel open probability (Po) in both the F508del processing mutation and the G551D gating mutation. VX-770 also increased Cl ؊ secretion in cultured human CF bronchial epithelia (HBE) carrying the G551D gating mutation on one allele and the F508del processing mutation on the other allele by Ϸ10-fold, to Ϸ50% of that observed in HBE isolated from individuals without CF. Furthermore, VX-770 reduced excessive Na ؉ and fluid absorption to prevent dehydration of the apical surface and increased cilia beating in these epithelial cultures. These results support the hypothesis that pharmacological agents that restore or increase CFTR function can rescue epithelial cell function in human CF airway.

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Section: Discussionmentioning

confidence: 98%

Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770

Goor

Hadida

Grootenhuis

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

1,067

817

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“…The proliferative response to ET-1 (10 )7 M) was significantly inhibited by BQ-123 (10 )6 M), an ET A antagonist, and TAK044 (10 )6 M), an ET A /ET B antagonist, but not by BQ-788 (10 )6 M), an ET B antagonist, suggesting that the ET-1stimulated proliferation was mediated via ET A receptors, as shown in Figure 5. The dose of antagonists were within the common limits [25,26].…”

Section: Effects Of Et Receptor Antagonists On Proliferative Responsementioning

confidence: 92%

Inhibition of angiotensin II‐ and endothelin‐1‐stimulated proliferation by selective MEK inhibitor in cultured rabbit gingival fibroblasts†

Ohsawa

Ohuchi

Taniguchi³

et al. 2005

Fundamemntal Clinical Pharma

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We investigated the implication of extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) in the proliferation stimulated by angiotensin II (Ang II) and endothelin-1 (ET-1) in cultured rabbit gingival fibroblasts (CRGF). Ang II stimulated activation of ERK1/2 and the activation was inhibited by CV-11974, an AT1 antagonist, and saralasin, an AT1/AT2 antagonist, but not by PD123,319, an AT2 antagonist in the CRGF. Ang II-stimulated proliferation was inhibited by PD98059 or U0126, selective MEK inhibitors. Furthermore, ET-1 stimulated proliferation via G-protein-coupled ETA receptors, which were identified by Western blot analysis of membrane protein from the CRGF. ET-1 also stimulated activation of ERK1/2 and the activation was inhibited by BQ-123, an ETA inhibitor, and TAK044, an ETA/ETB inhibitor, but not by BQ-788, an ETB inhibitor. ET-1-stimulated proliferation was inhibited by PD98059 or U0126. These findings suggest that ERK1/2 play a role in the signaling process leading to proliferation stimulated by Ang II and ET-1 via G-protein-coupled receptors, AT1 and ETA in CRGF.

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“…Its activity contributes to the maintenance of endogenous vasomotor tone by producing a long-lasting vasoconstriction of the underlying smooth muscle cells 24. In addition, ET-1 is also produced by smooth muscle cells,25 cardiomyocites,26 leukocytes,26 macrophages,27 mesangial cells,28,29 airway epithelium,30–32 and alveolar epithelial cells (AECs) 33,34. ET-1 is released during various injurious stimuli, including shear stress, thrombin, angiotensin II, cytokines, and free radicals, whereas atrial natriuretic peptide, prostacyclin, and NO inhibit its synthesis and release 35,36…”

Section: Endothelin Systemmentioning

confidence: 99%

Role of endothelin-1 in acute lung injury

Comellas

Briva

2009

Translational Research

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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...

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Effects of Endothelin-1 on Epithelial Ion Transport in Human Airways

Cited by 22 publications

References 35 publications

Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770

Rescue of CF airway epithelial cell function in vitro by a CFTR potentiator, VX-770

Inhibition of angiotensin II‐ and endothelin‐1‐stimulated proliferation by selective MEK inhibitor in cultured rabbit gingival fibroblasts†

Role of endothelin-1 in acute lung injury

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