Effect of endothelin antagonism on the production of cytokines in eosinophilic airway inflammation

Finsnes, Finn; Lyberg, Torstein; Christensen, Geir; Skjønsberg, Ole Henning

doi:10.1152/ajplung.2001.280.4.l659

Cited by 53 publications

(47 citation statements)

References 44 publications

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“…40 The beneficial effect of ET A R antagonism in our studies is further corroborated by data from other laboratories showing that ET-1, ET A R, and/or ET B R levels are rapidly upregulated after LPS administration. 41,42 In contrast to other studies, 12,18,19 our study failed to demonstrate significant anti-inflammatory effects of ET A R antagonism. However, in a different endotoxemia study, while attenuating lung injury and decreasing protein kinase C activation, ET-1 receptor blockade increased plasma TNF-α and IL-8 levels.…”

Section: Discussioncontrasting

confidence: 99%

“…12 ET-1 is also a potent proinflammatory mediator that directly stimulates production of other proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), interferon-γ, inducible nitric oxide synthase (iNOS), and IL-4. 18 Of note, several of these cytokines (e.g., IL-1β, iNOS) have also been implicated in endotoxin-induced PA dysfunction, 6 and in this context, inhibition of ET-1 signaling has been demonstrated to improve outcomes in experimental sepsis. 19 ET-1 acts via two receptors that are highly expressed in the pulmonary vasculature: endothelin receptor A (ET A R) and endothelin receptor B (ET B R).…”

Section: Introductionmentioning

confidence: 99%

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Selective Endothelin‐A Receptor Blockade Attenuates Endotoxin‐Induced Pulmonary Hypertension and Pulmonary vascular dysfunction

et al. 2014

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Endothelin-1 is a potent mediator of sepsis-induced pulmonary hypertension (PH). The pulmonary vascular effects of selective blockade of endothelin receptor subtype A (ET A R) during endotoxemia remain unknown. We hypothesized that selective ET A R antagonism attenuates endotoxin-induced PH and improves pulmonary artery (PA) vasoreactivity. Adult male Sprague-Dawley rats (250-450 g) received lipopolysaccharide (LPS; Salmonella typhimurium; 20 mg/kg intraperitoneally) or vehicle 6 hours before hemodynamic assessment and tissue harvest. The selective ET A R antagonist sitaxsentan (10 or 20 mg/kg) or vehicle was injected intravenously 3 hours after receipt of LPS. Right ventricular systolic pressure, mean arterial pressure (MAP), cardiac output (CO), oxygenation (P/F ratio), and serum bicarbonate were measured. Bronchoalveolar lavage (BAL) cell differential and lung wet-to-dry ratios were obtained. Endothelium-dependent and endothelium-independent vasorelaxations were determined in isolated PA rings. PA interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α), and inducible nitric oxide synthase (iNOS) messenger RNA (mRNA) were measured. LPS caused PH, decreased MAP, CO, and serum bicarbonate, and increased PA IL-1β, IL-6, TNF-α, and iNOS mRNA. Sitaxsentan attenuated sepsis-induced PH and increased MAP. The P/F ratio, CO, serum bicarbonate, and BAL neutrophilia were not affected by sitaxsentan. In isolated PA rings, while not affecting phenylephrine-induced vasocontraction or endothelium-dependent relaxation, sitaxsentan dosedependently attenuated LPS-induced alterations in endothelium-independent relaxation. PA cytokine mRNA levels were not significantly attenuated by ET A R blockade. We conclude that ET A R blockade attenuates endotoxin-induced alterations in systemic and PA pressures without negatively affecting oxygenation. This protective effect appears to be mediated not by attenuation of sepsis-induced cardiac dysfunction, acidosis, or alveolar inflammation but rather by improved endothelium-independent vasorelaxation.

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Section: Discussioncontrasting

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Selective Endothelin‐A Receptor Blockade Attenuates Endotoxin‐Induced Pulmonary Hypertension and Pulmonary vascular dysfunction

et al. 2014

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“…Both conditions have been shown to be associated with increased plasma levels of ET-1 (12,15,22) as observed in SCD. In patients with pulmonary hypertension, a pilot study has shown therapeutic efficacy of selective antagonists to ET-1 receptors (1).…”

Section: Discussionmentioning

confidence: 91%

“…In addition, in a mouse model of pulmonary hypertension, this therapy showed benefits in both prevention and reversal of hypoxia-induced pulmonary vascular remodeling. Furthermore, treatment with bosentan, a nonselective blocker of ET-1 receptors, has been reported to reduce the levels of proinflammatory molecules that are associated with the development of asthma (15). A clinical trial is currently underway to assess the effect of bosentan on pulmonary vascular resistance and exercise capacity in SCD patients (http://clinicaltrials.gov/ct/show/NCT00313196) (5).…”

Section: Discussionmentioning

confidence: 99%

Reduced sickle erythrocyte dehydration in vivo by endothelin-1 receptor antagonists

Rivera¹

2007

American Journal of Physiology-Cell Physiology

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Elevated plasma levels of cytokines such as endothelin-1 (ET-1) have been shown to be associated with sickle cell disease (SCD). However, the role of ET-1 in the pathophysiology of SCD is not entirely clear. I now show that treatment of SAD mice, a transgenic mouse model of SCD, with BQ-788 (0.33 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 intraperitoneally for 14 days), an ET-1 receptor B (ET B) antagonist, induced a significant decrease in Gardos channel activity (1.7 Ϯ 0.1 to 1.0 Ϯ 0.4 mmol ⅐ 10 13 cell Ϫ1 ⅐ h Ϫ1 , n ϭ 3, P ϭ 0.019) and reduced the erythrocyte density profile by decreasing the mean density (D50; n ϭ 4, P ϭ 0.012). These effects were not observed in mice treated with BQ-123, an ET-1 receptor A (ET A) antagonist. A mixture of both antagonists induced a similar change in density profile as with BQ-788 alone that was associated with an increase in mean cellular volume and a decrease in corpuscular hemoglobin concentration mean. I also observed in vitro effects of ET-1 on human sickle erythrocyte dehydration that was blocked by BQ-788 and a mixture of ET B/ETA antagonists but not by ETA antagonist alone. These results show that erythrocyte hydration status in vivo is mediated via activation of the ET B receptor, leading to Gardos channel modulation in SCD. cellular dehydration; Gardos channel; transgenic sickle mice ACUTE CHEST SYNDROME AND STROKE are the leading causes of morbidity and mortality among sickle cell disease (SCD) patients. One major clinical manifestation of this disease is the onset of recurrent episodes of severe pain called vaso-occlusive crises. These crises are caused by the occlusion within blood vessels of dehydrated sickle erythrocytes and the ischemia that follows (18). Epidemiological data indicate that 5% of the patients with SCD experience 3-10 crises a year (24,25). It is believed that crises are initiated by the interaction among the endothelium, sickle cells, and plasma factors (33).Patients with SCD have been shown to have elevated levels of cytokines such as ET-1 (16, 31), transforming growth factor-␤, stem cell factor, soluble transferrin receptor (7), IL-8 (11), and platelet-activating factor (PAF) (20). These vasoactive molecules control a variety of physiological processes, which are mediated by cell surface receptors, reactive oxygen species, H 2 O 2 , and nitric oxide. However, the mechanisms for their interaction with the vasoactive molecules and their pathophysiological roles in SCD are not completely understood. Nonetheless, it is believed that they play an important role in the adhesion of sickle erythrocytes to the endothelium and in the pathogenesis of vaso-occlusive crises (2, 7).Sickle erythrocytes have been shown to interact with vascular endothelial cells, stimulating the release of ET-1 and regulating the expression of the ET-1 gene in cultured endothelial cells (17). My coworkers and I have recently shown that the Gardos channel is coupled to ET-1, C-X-C (cytokines), and C-C (chemokines) receptors in both human (27) and mouse sickle erythrocytes (28). ET-1 acts via two ma...

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“…Such accumulating data supports the potential for endothelin-1 as a possible therapeutic target of asthma. Several antagonists, including bosentan, a dual antagonist of the endothelin receptors ETA and ETB, have been shown to repress airway in ammation, hyper-reactivity, and remodeling in a murine asthma model 28,29 . However, to our knowledge, only a few clinical studies have targeted endothelin-1 in patients with asthma.…”

Section: Discussionmentioning

confidence: 99%

Tumor Necrosis Factor-alpha and Transforming Growth Factor-beta Synergistically Upregulate Endothelin-1 Expression in Human Bronchial Epithelial Cells BEAS-2B

Tsuchiya

Wakabayashi

Matsukura

et al. 2016

Showa Univ J Med Sci

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: Endothelin-1 is a peptide with many functions including bronchoconstriction and the stimulation of fibroblasts, and myofibroblasts, and airway smooth muscle cell proliferation. These functions are related to airway remodeling and endothelin-1 is known to be upregulated in the epithelium of patients with severe asthma. We thus sought to elucidate the mechanisms underlying endothelin-1 expression in bronchial epithelial cells in vitro. The human bronchial epithelial cell line BEAS-2B was grown in culture and then treated with tumor necrosis factoralpha TNF-, interleukin-4 IL-4 , interleukin-13 IL-13 , and transforming growth factor-beta TGF-. Expression of endothelin-1 mRNA and protein was quantified by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. We also repressed expression of the key transcription factor in the pathogenesis of severe asthma, nuclear factor-kappa B NF-B , using small interfering RNA siRNA . TNF-and TGF-signi cantly increased the release of endothelin-1 protein into the culture medium of BEAS-2B cells at 24 h after treatment compared to untreated cells ; however, the Th2 cytokines, IL-4 and IL-13, had no effect. Endothelin-1 mRNA expression was also upregulated by TNFand TGFwith a peak time point at 4 h after stimulation. Finally, the combination of TNF-and TGF-synergistically increased both endothelin-1 protein secretion and mRNA expression, and this upregulation was signi cantly suppressed in cells transfected with siRNA to repress NF-B expression. TNF-and TGF-synergistically upregulate the expression of endothelin-1 in human bronchial epithelial cells, possibly via the activity of NF-B. Our ndings thus suggest NFBa as a potential therapeutic target for the regulation of airway remodeling.

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Effect of endothelin antagonism on the production of cytokines in eosinophilic airway inflammation

Cited by 53 publications

References 44 publications

Selective Endothelin‐A Receptor Blockade Attenuates Endotoxin‐Induced Pulmonary Hypertension and Pulmonary vascular dysfunction

Selective Endothelin‐A Receptor Blockade Attenuates Endotoxin‐Induced Pulmonary Hypertension and Pulmonary vascular dysfunction

Reduced sickle erythrocyte dehydration in vivo by endothelin-1 receptor antagonists

Tumor Necrosis Factor-alpha and Transforming Growth Factor-beta Synergistically Upregulate Endothelin-1 Expression in Human Bronchial Epithelial Cells BEAS-2B

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