Endothelin-1 Secretion by Alveolar Macrophages in Systemic Sclerosis

Odoux, Christine; Crestani, Bruno; Lebrun, Gaëlle; Rolland, Corinne; Aubin, Philippe; Seta, Nathalie; Kahn, Marcel-Francis; Fiet, Jean; Aubier, Michel

doi:10.1164/ajrccm.156.5.96-11004

Cited by 34 publications

(18 citation statements)

References 28 publications

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“…In scleroderma-associated fibrotic lung disease, ET-1 immunoreactivity is increased, and a reduction in ET A with a slight increase in ET B expression has been noted in the diseased lung (1). Furthermore, in systemic sclerosis, alveolar macrophage ET-1 expression is increased upon stimulation with LPS (22). Thus, it is known that alveolar macrophages from diseased lungs demonstrate alterations in the ET-1 cascade.…”

Section: Discussionmentioning

confidence: 99%

“…Although vascular endothelial cells express and secrete the majority of ET-1, lung macrophages also show increased expression of the ET-1 cascade under various pathological conditions (1,9,22,37,39). Infiltration of various inflammatory cells, including macrophages, has been found in the plexiform lesions in IPAH (38) and in CD8 ϩ lymphocytes in the lung periphery (2).…”

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confidence: 99%

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BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension

Talati¹,

West²,

Blackwell³

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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Macrophage derived-endothelin-1 (ET-1) has been suggested to contribute to a number of chronic lung diseases. Whether the ET-1 cascade from non-vascular sources (inflammatory cells) also contributes to pulmonary artery hypertension (PAH) and in particular to heritable PAH (HPAH) with known bone morphogenetic protein type 2 receptor (BMPR2) mutations is not known. We tested this notion using bone marrow-derived macrophages (BMDM; precursors of tissue macrophages) isolated from ROSA26rtTAXTetO(7)-tet-BMPR2(R899X) mice (model of PAH with universal expression of a mutated BMPR2 gene) with and without activation by LPS and in human lung tissue from HPAH with BMPR2 mutations and idiopathic PAH (IPAH). At baseline ET(A) and ET(B) receptors and endothelin converting enzyme (ECE) gene expression was reduced in BMPR2 mutant BMDM compared with controls. In control BMDM, LPS resulted in increased ppET-1 gene expression and ET-1 in culture media, whereas ET(A) and ET(B) receptor and ECE gene expression was decreased. These findings were more severe in BMPR2 mutant BMDM. Antagonism of the ET(B) receptor resulted in increased ET-1 in the media, suggesting that decreased ET-1 uptake by the ET(B) receptor contributes to the elevation. While ET-1 expression was demonstrated in lung macrophages from controls and IPAH and HPAH patients, ET(A) and ET(B) expression was decreased in the HPAH, but not IPAH, patients compared with controls. We conclude that reduced expression of macrophage ET-1 receptors in HPAH increases lung ET-1 and may contribute to the pathogenesis and maintenance of HPAH. This is the first description of protein expression that distinguishes HPAH from IPAH in patients.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension

Talati¹,

West²,

Blackwell³

et al. 2010

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…The presence of these markers has been investigated in different biological samples, such as plasma [13, 14], supernatant of dermal fibroblasts [26], BAL fluid [27], cell culture supernatants from monocyte and alveolar macrophages [10]and urine [24]of patients with pulmonary fibrosis where concentrations of vitronectin and ET-1 have been found elevated compared to healthy subjects.…”

Section: Discussionmentioning

confidence: 99%

“…Endothelin-1 (ET-1) also has been involved in the pathogenesis of both NSIP and FASSc for its fibrogenic properties [9, 10]. ET-1 was first identified as a potent vasoconstrictor.…”

Section: Introductionmentioning

confidence: 99%

Increased Vitronectin and Endothelin-1 in the Breath Condensate of Patients with Fibrosing Lung Disease

Carpagnano

Kharitonov²,

Wells³

et al. 2003

Respiration

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Background: Non-specific interstitial pneumonia (NSIP) and fibrosing alveolitis associated with systemic sclerosis (FASSc) are diseases of unknown aetiology that are characterised by the accumulation of mononuclear cells, followed by the progressive deposition of collagen within the interstitium and subsequent destruction of lung airspace. Better understanding of mediators involved in fibrosis may be useful for early diagnosis and in clinical monitoring of disease progression. Objective: The aim of this study was to investigate the presence of two profibrotic markers, the vitronectin and the endothelin-1 (ET-1) in the airways of NSIP and FASSc patients. Methods: Ten NSIP (6 males, age 57 ± 2 years) and 15 FASSc (8 males, age 55 ± 4 years) patients were recruited along with 10 normal subjects (4 male, age 52 ± 2 years). Vitronectin and ET-1 concentrations were measured in their breath condensate, using a specific enzyme immunoassay. Results: Higher levels of vitronectin and ET-1 were observed in NSIP and FASSc patients [median 92.8 (91.7–93.9) µg/ml; median 8.3 (7.9–9.3) pg/ml] than in control subjects [median 80.3 (89.3–91.4) µg/ml; p < 0.01; median 5.3 (4.9–5.9) pg/ml, p < 0.0001]. We also found increased concentrations of vitronectin in patients with clinical deterioration compared to those remaining stable and in ex-smokers compared to non-smokers and, increased vitronectin and ET-1 in patients treated with steroids compared to untreated patients. Conclusion: These findings justify further studies of vitronectin and ET-1 levels in exhaled breath condensate, as a means of monitoring activity and predicting progression of pulmonary fibrosis.

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“…There are several lines of evidence suggesting that EDN1 may play a role in the development of chronic airway obstruction in asthma [7,8]. EDN1 is strongly expressed in the lung and is synthesised by many different cells including epithelial cells, inflammatory cells and smooth muscle cells [6,9,10]. Increased concentrations of EDN1 have been found in the bronchial lavage of asthmatics [11], and overexpression of EDN1 in the airways of asthmatic patients has been demonstrated [12].…”

Section: Introductionmentioning

confidence: 99%

ETBreceptor polymorphism is associated with airway obstruction

et al. 2007

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BackgroundEndothelin-1 (EDN1) has been involved in the development of airway obstruction and inflammation in asthma. Several polymorphisms have been identified among the genes encoding for preproET1, an inactive precursor of ET-1, and for ETA (EDNRA) and ETB (EDNRB), the two receptors for EDN1. In the present work, we hypothesised that molecular variation in these genes could be a major determinant of the degree of bronchial obstruction. The purpose of this study was to investigate whether the genetic polymorphisms of preproET-1, EDNRA and EDNRB genes were associated with the degree of airway obstruction, assessed by FEV1.MethodsPolymorphisms of preproET-1, EDNRA and EDNRB were first studied in a population of adult asthmatic patients. Results were confirmed in a large population of adults from the general population from the ECRHS II study.ResultsIn our population of adult asthmatic patients, the EDNRB-30G>A (Leu277Leu) polymorphism (GG genotype) is strongly associated with a low FEV1 and with a higher percentage of patients with FEV1 < 80% of predicted value. No relationship was found between pulmonary function and EDNRA-1363C>T (His323His) or preproET-1-595G>T (Lys198Asp) polymorphism. In the adult population from the ECRHS II, we found a similar association between GG genotype and a low FEV1 or a higher percentage of subjects with FEV1 < 80% predicted, especially in the subgroups of asthmatics subjects (OR = 4.31 (95%CI 1.03 – 18.04)) and smokers (OR = 7.42 (95%CI 1.69 – 32.6)).Conclusionthe EDNRB-30G>A polymorphism could be a determinant of airway obstruction in humans with predisposing factors such as tobacco smoke exposure or asthma.

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Endothelin-1 Secretion by Alveolar Macrophages in Systemic Sclerosis

Cited by 34 publications

References 28 publications

BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension

BMPR2 mutation alters the lung macrophage endothelin-1 cascade in a mouse model and patients with heritable pulmonary artery hypertension

Increased Vitronectin and Endothelin-1 in the Breath Condensate of Patients with Fibrosing Lung Disease

ETBreceptor polymorphism is associated with airway obstruction

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