Suppression of adrenomedullin contributes to vascular leakage and altered epithelial repair during asthma

Hagner, Stefanie; Welz, H. G.; Kicic, Anthony; Alrifai, Mohammed; Marsh, Leigh M.; Sutanto, Erika N.; Ling, Kak-Ming; Stick, Stephen M.; Müller, Bernd; Weißmann, Norbert; Renz, Harald

doi:10.1111/j.1398-9995.2012.02851.x

Cited by 12 publications

(12 citation statements)

References 38 publications

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“…Since ACOT1 is upregulated by PPAR-␣ activation, reduced ACOT1 expression in vitamin D deficiency may demonstrate a reduction in PPAR-␣ activation, which is then associated with increased inflammation following HDM exposure. ADM is an anti-inflammatory peptide, and its expression in the lung has previously been shown to be decreased during allergen-induced airway inflammation (17). Thus, in addition to MID1, downregulation of ACOT1 and ADM may lead to the increase in inflammation we observed in BAL of vitamin D-deficient mice.…”

Section: Discussionsupporting

confidence: 47%

“…There may be a role for ADM in modulating AHR, as, in addition to its anti-inflammatory properties, ADM also has bronchodilating effects, and reduced ADM increased allergen-induced AHR in mice (41). ADM expression has also been shown to be lower in asthmatic airway epithelium and is associated with impaired epithelial repair (17), which may also contribute to AHR.…”

Section: Discussionmentioning

confidence: 99%

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Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease

Foong

Bosco

Troy

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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Vitamin D deficiency is associated with asthma risk. Vitamin D deficiency may enhance the inflammatory response, and we have previously shown that airway remodeling and airway hyperresponsiveness is increased in vitamin D-deficient mice. In this study, we hypothesize that vitamin D deficiency would exacerbate house dust mite (HDM)-induced inflammation and alterations in lung structure and function. A BALB/c mouse model of vitamin D deficiency was established by dietary manipulation. Responsiveness to methacholine, airway smooth muscle (ASM) mass, mucus cell metaplasia, lung and airway inflammation, and cytokines in bronchoalveolar lavage (BAL) fluid were assessed. Gene expression patterns in mouse lung samples were profiled by RNA-Seq. HDM exposure increased inflammation and inflammatory cytokines in BAL, baseline airway resistance, tissue elastance, and ASM mass. Vitamin D deficiency enhanced the HDM-induced influx of lymphocytes into BAL, ameliorated the HDM-induced increase in ASM mass, and protected against the HDM-induced increase in baseline airway resistance. RNA-Seq identified nine genes that were differentially regulated by vitamin D deficiency in the lungs of HDM-treated mice. Immunohistochemical staining confirmed that protein expression of midline 1 (MID1) and adrenomedullin was differentially regulated such that they promoted inflammation, while hypoxia-inducible lipid dropletassociated, which is associated with ASM remodeling, was downregulated. Protein expression studies in human bronchial epithelial cells also showed that addition of vitamin D decreased MID1 expression. Differential regulation of these genes by vitamin D deficiency could determine lung inflammation and pathophysiology and suggest that the effect of vitamin D deficiency on HDM-induced allergic airways disease is complex. airway remodeling; airway hyperresponsiveness; mouse model; RNASeq; house dust mite VITAMIN D DEFICIENCY IS PREVALENT all over the world and is a public health concern. Epidemiological studies have linked vitamin D deficiency to respiratory diseases, including lung cancer, chronic obstructive pulmonary disease, and asthma (16,26,43). However, while there is evidence that higher vitamin D levels may reduce the risk of asthma exacerbations, there is inconclusive evidence that vitamin D deficiency has the capacity to cause asthma (5,13,34).Asthma is an inflammatory disorder affecting the conducting airways (22). Allergic asthma is characterized by T helper (Th) 2 type inflammation, and persistent airway inflammation drives structural alterations in the lung (32). These structural changes, termed airway remodeling, lead to reversible airflow obstruction, deficits in lung function, and airway hyperresponsiveness (AHR) (32). These functional deficits are ultimately linked to asthma-related morbidity. Vitamin D has important immunomodulatory properties, as evidenced by the widespread expression of the vitamin D receptor on immune cells, including activated T and B cells, macrophages, and dendritic cells (18). Studies hav...

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Section: Discussionsupporting

confidence: 47%

Section: Discussionmentioning

confidence: 99%

Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease

Foong

Bosco

Troy

et al. 2016

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…Also, ADM dose‐dependently reduced experimentally induced endothelial hyperpermeability of cultured human umbilical vein endothelial cell and porcine pulmonary artery endothelial cell monolayers . Suppression of ADM contributes to vascular leakage and altered epithelial repair during asthma . In two animal models, intranasal ADM completely attenuated the acute‐induced airway hyper‐responsiveness and mucosal plasma leakage .…”

Section: Vascular Effects Of Adrenomedullinmentioning

confidence: 93%

“…Further support for the effects of ADM in maintaining vascular integrity comes from experimental studies showing that experimental overexpression of ADM inhibits systemic and pulmonary vascular leakage in animals . For example, in a rat model of Staphylococcus aureus ‐toxin induced systemic inflammation, accompanied by extensive vascular leakage, ADM infusion protected endothelial barrier function via cyclic adenosine monophosphate (cAMP) elevation .…”

Section: Vascular Effects Of Adrenomedullinmentioning

confidence: 99%

Adrenomedullin in heart failure: pathophysiology and therapeutic application

Voors

Kremer

Geven

et al. 2018

European J of Heart Fail

177

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Adrenomedullin (ADM) is a peptide hormone first discovered in 1993 in pheochromocytoma. It is synthesized by endothelial and vascular smooth muscle cells and diffuses freely between blood and interstitium. Excretion of ADM is stimulated by volume overload to maintain endothelial barrier function. Disruption of the ADM system therefore results in vascular leakage and systemic and pulmonary oedema. In addition, ADM inhibits the renin–angiotensin–aldosterone system. ADM is strongly elevated in patients with sepsis and in patients with acute heart failure. Since hallmarks of both conditions are vascular leakage and tissue oedema, we hypothesize that ADM plays a compensatory role and may exert protective properties against fluid overload and tissue congestion. Recently, a new immunoassay that specifically measures the biologically active ADM (bio‐ADM) has been developed, and might become a biomarker for tissue congestion. As a consequence, measurement of bio‐ADM might potentially be used to guide diuretic therapy in patients with heart failure. In addition, ADM might be used to guide treatment of (pulmonary) oedema or even become a target for therapy. Adrecizumab is a humanized, monoclonal, non‐neutralizing ADM‐binding antibody with a half‐life of 15 days. Adrecizumab binds at the N‐terminal epitope of ADM, leaving the C‐terminal side intact to bind to its receptor. Due to its high molecular weight, the antibody adrecizumab cannot cross the endothelial barrier and consequently remains in the circulation. The observation that adrecizumab increases plasma concentrations of ADM indicates that ADM‐binding by adrecizumab is able to drain ADM from the interstitium into the circulation. We therefore hypothesize that administration of adrecizumab improves vascular integrity, leading to improvement of tissue congestion and thereby may improve clinical outcomes in patients with acute decompensated heart failure. A phase II study with adrecizumab in patients with sepsis is ongoing and a phase II study on the effects of adrecizumab in patients with acute decompensated heart failure with elevated ADM is currently in preparation.

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“…ADM is induced in response to bacterial exposure and hypoxia [14,15]. In COPD airway inflammation, ADM may act primarily to promote tissue repair and maintain microvascular function [16,17]. Arginine vasopressin (AVP) is a potent vasoconstrictor that promotes water retention and plays a role in the body's stress response by stimulating adrenocorticotrophic hormone secretion [18].…”

Section: Introductionmentioning

confidence: 99%

Mortality risk prediction in COPD by a prognostic biomarker panel

Stolz¹,

Meyer²,

Rakic³

et al. 2014

Eur Respir J

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Chronic obstructive pulmonary disease (COPD) is a complex disease with various phenotypes. The simultaneous determination of multiple biomarkers reflecting different pathobiological pathways could be useful in identifying individuals with an increased risk of death.We derived and validated a combination of three biomarkers (adrenomedullin, arginine vasopressin and atrial natriuretic peptide), assessed in plasma samples of 385 patients, to estimate mortality risk in stable COPD. Biomarkers were analysed in combination and defined as high or low.In the derivation cohort (n5142), there were 73 deaths during the 5-year follow-up. Crude hazard ratios for mortality were 3.0 (95% CI 1.8-5.1) for one high biomarker, 4.8 (95% CI 2.4-9.5) for two biomarkers and 9.6 (95% CI 3.3-28.3) for three high biomarkers compared with no elevated biomarkers. In the validation cohort (n5243), 87 individuals died. Corresponding hazard ratios were 1.9 (95% CI 1.1-3.3), 3.1 (95% CI 1.8-5.4) and 5.4 (95% CI 2.5-11.4). Multivariable adjustment for clinical variables as well as the BODE (body mass index, airflow obstruction, dyspnoea, exercise capacity) index and stratification by the Global Initiative for Chronic Obstructive Lung Disease stages provided consistent results. The addition of the panel of three biomarkers to the BODE index generated a net reclassification improvement of 57.9% (95% CI 21.7-92.4%) and 45.9% (95% CI 13.9-75.7%) at 3 and 5 years, respectively.Simultaneously elevated levels of adrenomedullin, arginine vasopressin and atrial natriuretic peptide are associated with increased risk of death in patients with stable COPD. @ERSpublications Simultaneously elevated levels of ADM, AVP and ANP are associated with increased risk of death in COPD

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Suppression of adrenomedullin contributes to vascular leakage and altered epithelial repair during asthma

Cited by 12 publications

References 38 publications

Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease

Identification of genes differentially regulated by vitamin D deficiency that alter lung pathophysiology and inflammation in allergic airways disease

Adrenomedullin in heart failure: pathophysiology and therapeutic application

Mortality risk prediction in COPD by a prognostic biomarker panel

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