adrenomedullin and Lung-Diseases

Intermedin/adrenomedullin-2 (IMD/AM2) belongs to the calcitonin gene-related peptide (CGRP) / adrenomedullin (AM) family. The biological actions of this family are attributed to their actions at three receptor subtypes comprising the calcitonin receptor-like receptor (CLR) complexed with one of three receptor activity modifying proteins. In contrast to AM and CGRP, IMD binds non-selectively to all three receptor subtypes: CGRP, AM1, AM2. The peptide displays an overlapping but differential and more restricted distribution across the healthy systemic and pulmonary vasculature, heart and kidney relative to CGRP and AM. This, combined with tissue, regional and cell-type specific receptor expression, underpins differences in regard to magnitude, potency and duration of haemodynamic, cardiac and renal effects of IMD relative to those of AM and CGRP, and receptor-subtype involvement. In common with other family members, IMD protects the mammalian vasculature, myocardium and kidney from acute ischaemia-reperfusion injury, chronic oxidative stress and pressure-loading; IMD inhibits apoptosis, attenuates maladaptive tissue remodelling and preserves cardiac and renal function. Robust upregulation of IMD expression in rodent models of cardiovascular and renal disease argues strongly for the pathophysiological relevance of this particular counter-regulatory peptide. Such findings are likely to translate well to the clinic: early reports indicate that IMD is expressed in and protects cultured human vascular and cardiac non-vascular cells from simulated ischaemia-reperfusion injury, primarily via the AM1 receptor, and may have utility as a plasma biomarker in cardiovascular disease. These observations should provide the rationale for short-term administration of the peptide in acute disease, including myocardial infarction, cerebrovascular insult, cardiac and renal failure.

Topics: Adrenomedullin; Animals; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Cardiovascular System; Humans; Inflammation; Kidney Diseases; Lung Diseases; Organ Specificity; Oxidative Stress; Peptide Hormones; Protective Agents; Receptors, Adrenomedullin; Receptors, Calcitonin Gene-Related Peptide; Reperfusion Injury

Although originally discovered because of their ability to affect hemodynamics, vasoactive peptides have been found to function in a variety of capacities including neurotransmission, endocrine functions, and the regulation of cell proliferation. A growing body of evidence describes the ability of vasoactive peptides to regulate cell death by apoptosis in either a positive or negative fashion depending on the peptide and the type of target cell. The available evidence to date is strongest for the peptides endothelin, angiotensin II, vasoactive intestinal peptide, atrial natriuretic peptide, and adrenomedullin. Each of these peptides is discussed, with specific regard to apoptosis, in terms of regulatory activity, target cell specificity, and potential role in pulmonary physiology.

Topics: Adrenomedullin; Angiotensin II; Animals; Apoptosis; Atrial Natriuretic Factor; Endothelin-1; Humans; Lung; Lung Diseases; Peptides; Vasoactive Intestinal Peptide

Hypoxia contributes to airway inflammation and remodeling in several lung diseases; however, exactly how hypoxic pulmonary epithelium regulates allergic inflammation remains to be fully characterized. Here, we report that conditional deletion of the E3 ubiquitin ligase VHL in lung epithelial cells resulted in exacerbated type 2 responses accompanied by selective increase of group 2 innate lymphoid cells (ILC2s) at steady state and following inflammation or helminth infection. Ablation of expression of the hypoxia-inducible factor 2α (HIF2α) significantly reversed VHL-mediated ILC2 activation. VHL deficiency in lung epithelial cells caused increased expression of the peptide hormone adrenomedullin (ADM), and our data suggest that HIF2α controls Adm expression. ADM directly promoted ILC2 activation both in vitro and in vivo. Our findings indicate that the hypoxic response mediated by the VHL-HIF2α axis is critical for control of pulmonary type 2 responses by increasing ADM expression in lung epithelia, causing ILC2 activation.

Topics: Adrenomedullin; Epithelium; Humans; Hypoxia; Immunity, Innate; Inflammation; Lung; Lung Diseases; Lymphocytes

The aim of the study was to assess the role of midregional proadrenomedullin (MR-proADM) in patients with COVID-19.. We included 110 patients hospitalized for COVID-19. Biochemical biomarkers, including MR-proADM, were measured at admission. The association of plasma MR-proADM levels with COVID-19 severity, defined as a requirement for mechanical ventilation or in-hospital mortality, was evaluated.. Patients showed increased levels of MR-proADM. In addition, MR-proADM was higher in patients who died during hospitalization than in patients who survived (median, 2.59 nmol/L; interquartile range, 2.3-2.95 vs median, 0.82 nmol/L; interquartile range, 0.57-1.03; P <.0001). Receiver operating characteristic curve analysis showed good accuracy of MR-proADM for predicting mortality. A MR-proADM value of 1.73 nmol/L was established as the best cutoff value, with 90% sensitivity and 95% specificity (P <.0001).. We found that MR-proADM could represent a prognostic biomarker of COVID-19.

Topics: Adrenomedullin; Aged; Alanine Transaminase; Aspartate Aminotransferases; Biomarkers; C-Reactive Protein; Comorbidity; COVID-19; Female; Humans; Hypertension; Interleukin-6; Lung Diseases; Male; Middle Aged; Patient Selection; Prognosis; Protein Precursors; Retrospective Studies; SARS-CoV-2; Severity of Illness Index; Survival Analysis; Triage

Primary graft dysfunction (PGD) after lung transplantation (LT) is a heterogeneous syndrome that comprises clinical presentations with diverse grades of severity. Proadrenomedullin (proADM) levels may be associated with PGD and may enhance its relationship with outcomes. We prospectively included 100 LT recipients. Plasma levels of proADM were measured at 24, 48 and 72 h after admission to the intensive care unit (ICU). We assessed their relationship with PGD grade and ICU mortality. Fifty patients (50%) presented grade 3 PGD at ICU admission. Twenty-two patients (22%) developed grade 3 PGD at 72 h, the only grade associated with higher mortality (odds ratio 6.84, 95% confidence interval [CI] 1.47-38.44). ProADM levels measured at 24 h (3.25 vs. 1.61 nmol/L; p = 0.016) and 72 h (2.17 vs. 1.35 nmol/L; p = 0.011) were higher in these patients than the rest of the population. When we added the individual predictive utility of grade 3 PGD at 72 h for ICU mortality (area under the curve [AUC] 0.72, 95% CI 0.53-0.90) to that of ProADM at 72 h, the predictive value of the model improved (AUC 0.81, 95% CI 0.65-0.97). Higher levels of proADM measured following LT are associated with grade 3 PGD at 72 h. ProADM enhances the association of this entity with mortality.

Topics: Adrenomedullin; Adult; Biomarkers; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Intensive Care Units; Lung Diseases; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Primary Graft Dysfunction; Prognosis; Prospective Studies; Protein Precursors; Risk Assessment; Risk Factors; Severity of Illness Index

Mid-regional pro-atrial natriuretic peptide (MR-proANP), procalcitonin (PCT), and mid-regional pro-adrenomedullin (MR-proADM) demonstrated usefulness for management of emergency department patients with dyspnea.. To evaluate in patients with dyspnea, the prognostic value for 30 and 90 days mortality and readmission of PCT, MR-proADM, and MR-proANP, a multicenter prospective study was performed evaluating biomarkers at admission, 24 and 72 hours after admission. Based on final diagnosis, patients were divided into acute heart failure (AHF), primary lung diseases, or both (AHF + NO AHF).. Five hundred one patients were enrolled. Procalcitonin and MR-proADM values at admission and at 72 hours were significantly (P < .001) predictive for 30-day mortality: baseline PCT with an area under the curve (AUC) of 0.70 and PCT at 72 hours with an AUC of 0.61; baseline MR-proADM with an AUC of 0.62 and MR-proADM at 72 hours with an AUC of 0.68. As for 90-day mortality, both PCT and MR-proADM baseline and 72 hours values showed a significant (P < .0001) predictive ability: baseline PCT with an AUC of 0.73 and 72 hours PCT with an AUC of 0.64; baseline MR-proADM with an AUC of 0.66 and 72 hours MR-proADM with an AUC of 0.71. In AHF, group biomarkers predicted rehospitalization and mortality at 90 days, whereas in AHF + NO AHF group, they predict mortality at 30 and 90 days.. In patients admitted for dyspnea, assessment of PCT plus MR-proADM improves risk stratification and management. Combined use of biomarkers is able to predict in the total cohort both rehospitalization and death at 30 and 90 days.

Topics: Adrenomedullin; Aged; Aged, 80 and over; Biomarkers; Calcitonin; Calcitonin Gene-Related Peptide; Dyspnea; Emergency Service, Hospital; Female; Heart Failure; Hospital Mortality; Humans; Italy; Lung Diseases; Male; Patient Admission; Predictive Value of Tests; Prognosis; Prospective Studies; Protein Precursors; Risk Assessment

Peak oxygen uptake (peak VO(2)) is a predictor of outcome in patients with lung disease. In these patients, peak VO(2) is typically determined by ventilation and gas exchange. However, it is not well known whether cardiac strain contributes to peak VO(2) in patients with chronic lung disease.. To assess the relationship between several novel biomarkers reflecting different aspects of cardiac function and peak VO(2) in patients with chronic lung disease.. Plasma concentrations of midregional pro-A-type natriuret- ic peptide (MR-proANP), midregional proadrenomedullin (MR-proADM), C-terminal proendothelin-1 (CT-proET-1), and C-terminal provasopressin (copeptin) were measured in 85 patients with a variety of chronic pulmonary diseases [age 57 ± 14 years, forced expiratory volume in the 1st second (FEV(1)) 76 ± 23% of the predicted value] undergoing maximal cardiopulmonary exercise testing (peak VO(2) 18.6 ± 6.6 ml/kg/min).. Raised MR-proANP (r = -0.54), MR- proADM (r = -0.54), and CT-proET-1 (r = -0.49; p < 0.001 for all) but not copeptin (r = -0.05; p = 0.68) concentrations were associated with lower peak VO(2), and these associations were independent of age, gender, medication, FEV(1) and oxygenation. The relationship between MR-proANP, MR-proADM, and CT-proET-1 and peak VO(2) was significant whether patients had an obstructive ventilatory disease or not.. In patients with chronic lung disease, several biomarkers known to reflect measures of cardiac function were associated with peak VO(2) independent of lung function, indicating that cardiac strain may contribute to exercise limitation in these patients due to concomitant cardiac disease or in the context of a pulmonary-cardiac interaction.

Topics: Adrenomedullin; Adult; Aged; Atrial Natriuretic Factor; Biomarkers; Endothelin-1; Female; Forced Expiratory Volume; Humans; Lung Diseases; Male; Middle Aged; Oxygen Consumption; Peptide Fragments; Protein Precursors; Vital Capacity

To study the role of endothelin (ET-1) and adrenomedullin (AM) on pulmonary vascular pressure/flow characteristic (pulmonary arterial pressure/cardiac output (Pap/CO)) during low-dose dobutamine infusion.. Case control study of 14 patients (12 men, 2 women) with severe lung disease (chronic obstructive pulmonary disease, COPD n=5; cystic fibrosis, CF n=9) and 5 control subjects (CTRL, 4 men, 1 woman). ET-1 and AM plasma levels in pulmonary artery (mixed venous blood, ven) and aorta or femoral artery (arterial, art), were measured at baseline and during dobutamine infusion (5-10-15 mcg kg(-1) min(-1)). The Ppa/CO coordinates obtained at baseline and during dobutamina infusion for each patients were used to calculate the Slope and Intercept by linear regression analysis.. Baseline hemodynamics measurements were similar in the three groups with a trend towards a mild elevation in Ppa in CF group (Ppa mm Hg: CTRL 19+/-3.5, COPD 19.4+/-5.5, CF 22.7+/-7.5). Baseline plasma ET-1(ET-1ven pg ml(-1): CTRL 13.9+/-6.7, COPD 20.1+/-14, CF 20.4+/-7.1; ET-1art pg ml(-1): CTRL 16.7+/-6.4, COPD 20.1+/-11.7, CF 18.1+/-3.9) and AM (AMven pg ml(-1): CTRL 15.8+/-5, COPD 31.8+/-17.6, CF 27.7+/-7.6; AMart pg ml(-1): CTRL 15.9+/-1.4, COPD 21.4+/-3.8, CF 27+/-7.6) showed a trend towards higher value among patients' groups compared to the controls. Baseline ET-1 pulmonary gradient did not show significant difference among the three groups as well AM pulmonary gradient. Dobutamine infusion caused a comparable increase of heart rate and CO in the three groups. Mean pulmonary pressure had a trend towards a greater increase in COPD and CF than in controls, consequently, pulmonary Pap/CO relationship showed a steeper slope in patients' groups (Slope mm Hg L(-1) min(-1): CTRL 0.9+/-0.3, COPD 2.1+/-0.8 p<0.02 vs. CTRL, CF 1.9+/-0.9 p<0.03 vs CTRL). During dobutamine plasma ET-1 and AM showed a great individual variability resulting in no significant difference among groups. ET-1 pulmonary gradient showed a trend towards pulmonary uptake in patients' groups (ET-1art-ven pg min(-1): CTRL 2.7+/-2.9, COPD-6.1+/-7.8, CF -4+/-4.8) while AM pulmonary gradient did not show any particular pattern. During dobutamine ET-1 was significantly correlated to Pap/CO characteristics (Slope and ET-1ven, r=-0.59, p<0.05; Slope and ET-1art-ven, r=-0.60, p<0.05; Intercept and ET-1art-ven, r=0.63, p<0.004), and ET-1art-ven was the only independent variable related to Slope and Intercept.. In patients with moderate pulmonary vascular impairment, ET-1 pulmonary gradient, but not AM pulmonary gradient, is inversely correlated with pulmonary incremental resistance, suggesting a role of ET-1 in the regulation of pulmonary vascular resistance.

Topics: Adrenergic beta-Agonists; Adrenomedullin; Adult; Aged; Blood Pressure; Dobutamine; Endothelin-1; Female; Humans; Lung; Lung Diseases; Male; Middle Aged; Multivariate Analysis; Peptides; Pulmonary Circulation; Respiratory Function Tests

To investigate the changes of pulmonary IMD and its receptor system-calcitonin receptor-like receptor (CL) and receptor activity modifying proteins (RAMPs) mRNA in acute lung injury(ALI) induced by oleic acid of rats.. Contents of IMD in plasma and lung homogenates were measured by radioimmunoassay(RIA). The lung mRNA of IMD, CL and RAMPs was determined by semi-quantitative RT-PCR.. Compared with control group, in ALI group, the contents of IMD1-53 in plasma and lung homogenates were decreased by 20.8% and 74.5% (all P < 0.05) , respectively. Furthermore , it was found that the levels of IMD, CL, RAMP1 and RAMP2 mRNA in lung were decreased by 30%, 38%, 26% and 37.9% (all P < 0. 05) , respectively. The levels of CL , RAMP1 or RAMP2 mRNA were positively correlated with down-regulations of IMD mRNA in ALI. However, compared with control group, the maximum binding capacity of IMD1-53 to plasma membranes was significantly increased in ALI group, and the affinity of IMD1-53 for its receptor almost had no change.. The amount of IMD 1-53 is down-regulated and IMD receptor system also down-regulated in Oliec acid induced ALI of rats. These changes suggest that IMD and its receptor system probably are involved in the development of ALI.

Topics: Acute Disease; Adrenomedullin; Animals; Bronchoalveolar Lavage Fluid; Calcitonin Receptor-Like Protein; Intracellular Signaling Peptides and Proteins; Lung; Lung Diseases; Male; Membrane Proteins; Neuropeptides; Oleic Acid; Oxygen; Rats; Rats, Wistar; Receptor Activity-Modifying Protein 1; Receptor Activity-Modifying Protein 2; Receptor Activity-Modifying Proteins; Receptors, Calcitonin; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

To study adrenomedullin (AM) plasma levels in patients with severe lung disease and to analyze the relationship between AM and heart changes, hemodynamics and blood gases.. Case control study of 56 patients (36 men, 20 women) with severe lung disease and 9 control subjects (7 men, 2 women). Patients with end-stage pulmonary disease, including chronic obstructive pulmonary disease (COPD, n=11), cystic fibrosis (CF, 26), idiopatic pulmonary fibrosis (ILD, n=9), and idiopatic pulmonary arterial hypertension (PAH, n=10), who were evaluated for lung trasplantation between January 1997 and September 2000, and nine patients who underwent lung surgery for a solitary benign nodule. AM plasma levels in pulmonary artery (mixed venous blood, vein) and aorta or femoral artery (arterial, art), art and vein blood gases, pulmonary hemodynamics, systemic hemodynamics, two-dimensional transthoracic echocardiography and echo-Doppler study.. Plasma AM (art and ven) levels were higher among patients' group compared to the controls (AMart p<0.02 and AMven p<0.04) for CF, ILD, PAH (AMart, pg ml(-1) Controls 13.7+/-3.6, COPD 22.8+/-6.2, CF 28.1+/-11.4, ILD 34.1+/-14.3, PAH 35.1+/-18.9; AMven, pg ml(-1) Controls 14.2+/-4.8, COPD 28.1+/-12.6, CF 31.7+/-14.1, ILD 38.7+/-16.5, PAH 40.1+/-4.4). We found with a trend towards higher concentration in ILD and PAH patients compared to COPD and CF but no statistical significant differences. Mixed-venous AM was higher than arterial AM in all groups resulting in AM uptake (AMPulmUp pg min(-1) Controls 4.8+/-22.6, COPD 21.1+/-44.9, CF 20.6+/-45.1, ILD 23.7+/-38.5, PAH 29.9+/-49.7). The univariate analysis showed a weak but significant correlation between AMart and mean systemic arterial pressure, heart rate, mean pulmonary arterial pressure and systemic vascular resistance. In the multivariate analysis, four variables emerged as independent factors of AMart including mean pulmonary arterial pressure, heart rate, mean systemic arterial pressure and left ventricular diastolic diameter (F=8.6, p<0.00001, r=0.60, r2=0.32). A similar weak correlation was apparent between AMven, systemic vascular resistance, and mean pulmonary arterial pressure. The results of multivariate analysis identify right atrial enlargement, mean right atrial pressure, heart rate and left ventricular dimensions as the only independent variables related to AMven (F=4.3, p<0.0004 r=0.56, r2=0.26). AM pulmonary uptake was significantly correlated with AMven (r=0.65), but not with hemodynamic, blood gas and echocardiographic variables.. AM plasma levels are elevated in patients with severe lung disease in face of a preserved pulmonary uptake. These results suggest that the high AM plasma levels in patients with severe lung disease are not caused by a reduced pulmonary clearance, instead suggesting a systemic production.

Topics: Adrenomedullin; Adult; Cystic Fibrosis; Echocardiography; Female; Humans; Lung Diseases; Male; Middle Aged; Peptides; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis

Adrenomedullin (ADM) is upregulated independently by hypoxia and LPS, two key factors in the pathogenesis of acute lung injury (ALI). This study evaluates the expression of ADM in ALI using experimental models combining both stimuli: an in vivo model of rats treated with LPS and acute normobaric hypoxia (9% O2) and an in vitro model of rat lung cell lines cultured with LPS and exposed to hypoxia (1% O2). ADM expression was analyzed by in situ hybridization, Northern blot, Western blot, and RIA analyses. In the rat lung, combination of hypoxia and LPS treatments overcomes ADM induction occurring after each treatment alone. With in situ techniques, the synergistic effect of both stimuli mainly correlates with ADM expression in inflammatory cells within blood vessels and, to a lesser extent, to cells in the lung parenchyma and bronchiolar epithelial cells. In the in vitro model, hypoxia and hypoxia + LPS treatments caused a similar strong induction of ADM expression and secretion in epithelial and endothelial cell lines. In alveolar macrophages, however, LPS-induced ADM expression and secretion were further increased by the concomitant exposure to hypoxia, thus paralleling the in vivo response. In conclusion, ADM expression is highly induced in a variety of key lung cell types in this rat model of ALI by combination of hypoxia and LPS, suggesting an essential role for this mediator in this syndrome.

Topics: Acute Disease; Adrenomedullin; Animals; Capillary Permeability; Cell Line; Endothelial Cells; Epithelial Cells; Female; Hypoxia; Lipopolysaccharides; Lung; Lung Diseases; Macrophages, Alveolar; Peptides; Pulmonary Circulation; Rats; Rats, Inbred F344; RNA, Messenger