Endothelin-1 Levels in Interstitial Lung Disease Patients During Sleep

Trakada, Georgia; Nikolaou, E.; Pouli, A.; Tsiamita, Maria; Spiropoulos, Kostas

doi:10.1007/s11325-003-0111-y

Cited by 31 publications

(21 citation statements)

References 30 publications

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“…23,24 In this study, both oxygen desaturation indices investigated were correlated with the RVSP measured with Doppler echocardiography, thus providing the link between intermittent oxygen desaturation and pulmonary hypertension as well as its associated mortality. The potential mechanisms linking sleep and exercise oxygen desaturation with the development of PH may relate to different mechanisms, such as the hypoxia-mediated endothelial dysfunction 25 and the rise in arterial endothelin-1 levels-a potent mediator of pulmonary vascular remodelling 26 -as well as to the resetting of peripheral chemoreceptors due to hypoxia and the resulting lowering of the hypoxic drive, which might aggravate sleep oxygen desaturation by delaying arousal. 27 Furthermore, the desaturation-reoxygenation sequence characterizing intermittent hypoxia constitutes a major stimulus, even more potent than continuous hypoxia, which leads to oxidative stress, systemic inflammation, and generalized vascular endothelial damage adversely affecting myocardial function.…”

Section: Discussionmentioning

confidence: 99%

Sleep Oxygen Desaturation Predicts Survival in Idiopathic Pulmonary Fibrosis

Kolilekas

Manali

Vlami

et al. 2013

Journal of Clinical Sleep Medicine

121

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background: Recent studies suggest poor sleep quality in patients with idiopathic pulmonary fi brosis (IPF). However, so far, the impact of IPF-related sleep breathing disorders (SBDs) on survival has not been extensively studied. Methods: In a cohort of 31 (24 males) treatment-naïve, newly diagnosed consecutive IPF patients, we prospectively investigated the relationship of SBD parameters such as apnea-hypopnea index (AHI), maximal difference in oxygen saturation between wakefulness and sleep (maxdiff SpO 2 ), and lowest sleep oxygen saturation (lowest SpO 2 ) with clinical (survival, dyspnea, daytime sleepiness), pulmonary function, submaximal (6-min walk test [6MWT]) and maximal exercise variables (cardiopulmonary exercise test [CPET]), and right ventricular systolic pressure (RVSP). Results: Sleep oxygen desaturation exceeded signifi cantly that of maximal exercise (p < 0.001). Maxdiff SpO 2 was inversely related to survival, DLCO%, and SpO 2 after 6MWT, and directly with dyspnea, AHI, and RVSP. The lowest SpO 2 was directly related to survival and to functional (TLC%, DLCO%) as well as submaximal and maximal exercise variables (6MWT

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Section: Discussionmentioning

confidence: 99%

Sleep Oxygen Desaturation Predicts Survival in Idiopathic Pulmonary Fibrosis

Kolilekas

Manali

Vlami

et al. 2013

Journal of Clinical Sleep Medicine

121

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“…Hypoxemia is a potent inducer of ET-1 in humans and experimental animals, 14,[32][33][34][35] and arterial pO 2 Ͻ65 mm Hg is associated with significant increases in plasma ET-1 in humans. 33 Furthermore, the degree of hypoxemia correlates with induction of pulmonary prepro-ET-1 mRNA expression in the AHR KO mice, although the levels remain significantly less than WT mice.…”

Section: Discussionmentioning

confidence: 99%

Loss of the Aryl Hydrocarbon Receptor Induces Hypoxemia, Endothelin-1, and Systemic Hypertension at Modest Altitude

et al. 2008

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Abstract-The aryl hydrocarbon receptor (AHR) is a basic helix-loop-helix Per-Arnt-Sim transcription factor that mediates induction of metabolic enzymes and toxicity of certain environmental pollutants. Although AHR knockout (KO) mice develop cardiac hypertrophy, conflicting reports associate this pathology with hypotension or endothelin (ET)-1-dependent hypertension. Because hypertension occurred at modest altitude, we tested the hypothesis that loss of AHR increases the sensitivity to hypoxia-induced ET-1, contributing to systemic hypertension. We found that AHR KO mice were hypertensive at modest altitude (1632 m) but hypotensive at low altitude (225 m). When AHR KO mice residing at 1632 m were exposed to the partial pressure of inspired oxygen (PIO 2 ) at sea level for 11 days, blood pressure declined to levels measured at 225 m. Although plasma ET-1 in AHR KO mice was significantly elevated at 1632 m and decreased at 225 m and sea level PIO 2 , pulmonary prepro-ET-1 mRNA was significantly reduced at 1632 m and decreased further at 225 m and sea level PIO 2 . Blood gas analysis revealed that AHR KO mice were hypoxemic, hypercapnic, and acidotic at 1632 m, values that were attenuated and normalized after 24 hours and 11 days under sea level PIO 2 , respectively. Lastly, AHR inactivation in endothelial cells by small interfering RNA significantly reduced basal prepro-ET-1 mRNA but did not alter hypoxia-induced expression. Our studies establish the AHR KO mouse as a model in which modest decreases in PIO 2 lead to hypoxemia, increased plasma ET-1, and systemic hypertension without increased pulmonary prepro-ET-1 mRNA expression. Key Words: blood pressure Ⅲ hypertension Ⅲ endothelin Ⅲ oxygen Ⅲ gene regulation T he aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor belonging to the basic helix-loophelix Per-Arnt-Sim family of DNA binding proteins, which also includes hypoxia-inducible factors. 1 Although the AHR is known to mediate induction of drug-metabolizing enzymes and toxicity after exposure to 2,3,7,8-tetrachlorodibenzo-pdioxin, recent evidence has revealed a physiological role for AHR in cardiovascular homeostasis. AHR knockout (KO) mice develop cardiac hypertrophy, 2,3 which is mediated, in part, by elevated plasma angiotensin II and endothelin-1 (ET-1). 4,5 There are conflicting reports, however, of whether the cardiac hypertrophy is associated with systemic hypertension. Lund et al 4,5 reported that cardiac hypertrophy in AHR KO mice is preceded by hypertension, whereas Vasquez et al 6 and Ichihara et al 7 reported that AHR KO mice are hypotensive and normotensive, respectively. The explanation for the disparate blood pressure values among these studies is unclear.AHR and hypoxia-inducible factor-1␣ share a common dimerization partner, AHR nuclear translocator (hypoxiainducible factor-1␤), as well as other transactivators, and studies have shown that these 2 signal transduction pathways can exhibit reciprocal inhibitory cross-talk. 8,9 The mechanism by which this functional inter...

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“…2) Formation of alveolar fibrin clots due to impaired intra-alveolar fibrinolysis providing a lead structure for fibroblast chemotactic migration and proliferation as well as for neovascularisation [29,30,43]. 3) Growth factors such as TGF-b, insulin-like growth factor-1, platelet-derived growth factor (PDGF) and CTGF play a crucial role in the expansion of connective tissue and vascular remodelling in the lungs [44][45][46][47][48][49][50][51]. 4) Epithelial cell apoptosis and impaired epithelial regeneration and epithelial-to-mesenchymal transdifferentiation linked to integrin signalling promotes fibrotic tissue remodelling [52,53].…”

Section: Basic Aspects Of Pulmonary Fibrosis and Phmentioning

confidence: 99%

Pulmonary hypertension in interstitial lung disease

Behr

Ryu

2008

European Respiratory Journal

240

173

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In the lungs, parenchymal and vascular remodelling share pathomechanisms that may explain the relatively high prevalence (30-40%) of pulmonary hypertension (PH) in interstitial lung disease (ILD) patients. Notably, PH significantly contributes to exercise limitation and dismal prognosis of ILD patients. The absence of specific clinical symptoms commonly leads to delayed diagnosis. Besides clinical judgment and out-of-proportion reduction in diffusing capacity, severe hypoxaemia or exercise oxygen desaturation, echocardiography and biomarkers such as B-type natriuretic peptide (BNP) and N-terminal pro-hormone BNP are potentially helpful tools in identifying PH. However, right heart catheterisation is still necessary to confirm the diagnosis. Management of PH in ILD comprises treatment of the underlying disease process and long-term oxygen therapy. Affected patients should be listed for lung transplantation without delay, when appropriate. However, due to age and comorbidities only a minority of ILD patients will be eligible for lung transplantation. In the absence of satisfactory therapies for many ILDs, and considering the clinical burden of PH in affected patients, specific vasomodulatory therapies presently approved for PAH may be promising options for ILD patients. Consequently, there is an urgent need for adequately designed clinical trials to assess the effectiveness of specific PH therapy in the context of ILDs.

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Endothelin-1 Levels in Interstitial Lung Disease Patients During Sleep

Abstract: According to our study, arterial ET-1 is markedly increased in ILD patients, especially in those with pulmonary hypertension.

Cited by 31 publications

References 30 publications

Sleep Oxygen Desaturation Predicts Survival in Idiopathic Pulmonary Fibrosis

Sleep Oxygen Desaturation Predicts Survival in Idiopathic Pulmonary Fibrosis

Loss of the Aryl Hydrocarbon Receptor Induces Hypoxemia, Endothelin-1, and Systemic Hypertension at Modest Altitude

Pulmonary hypertension in interstitial lung disease

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