endothelin-1 and Pneumonia

Biomarkers have been intensively studied in community-acquired pneumonia (CAP) in recent years. In the context of the CAPNETZ study we had the unique opportunity to evaluate old and new biomarkers in a multicentre study with a high number of patients.. In several substudies we found the following results: procalcitonin, CRP and leukocytes show highest values in patients with typical bacterial etiology of CAP, but do not allow individual prediction of etiology. Patients without antibiotic pre-treatment show higher values of biomarkers compared to patients with antibiotic pre-treatment. New cardiovascular biomarkers are good predictors for short- and long-term mortality in CAP, superior to the inflammatory markers procalcitonin, CRP and leukocytes and at least comparable to the clinical CRB-65 score. Pro-Adrenomedullin is among the new biomarkers the one with the best prognostic value.. Biomarkers correlate with the severity of CAP but do not allow individual prediction of etiology. New cardiovascular biomarkers are suitable for the evaluation of short- and long-term prognosis in CAP. The combination of several biomarkers reflecting different pathophysiological pathways has the potential to improve management of CAP in the future.

Topics: Adolescent; Adrenomedullin; Adult; Age Distribution; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Community-Acquired Infections; Comorbidity; Endothelin-1; Female; Germany; Humans; Inflammation; Leukocyte Count; Male; Middle Aged; Pneumonia; Predictive Value of Tests; Protein Precursors; Respiratory Rate; Survival Analysis; Vasopressins; Young Adult

We assessed the ability of mid-regional proadrenomedullin (MR-proADM) and C-terminal proendothelin-1 (CT-proET-1) to predict 28-day mortality in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia.. Biomarkers were collected during the first seven days in this prospective observational cohort study. We investigated the relationship between biomarkers and mortality in a multivariable Cox regression model adjusted for age and SOFA score.. In 105 critically ill patients with confirmed SARS-CoV-2 pneumonia 28-day mortality was 28.6%. MR-proADM and CT-proET-1 were significantly higher in 28-day non-survivors at baseline and over time. ROC curves revealed high accuracy to identify non-survivors for baseline MR-proADM and CT-proET-1, AUC 0.84, (95% CI 0.76-0.92), p < 0.001 and 0.79, (95% CI 0.69-0.89), p < 0.001, respectively. The AUC for prediction of 28-day mortality for MR-proADM and CT-proET-1 remained high over time. MR-proADM ≥1.57 nmol/L and CT-proET-1 ≥ 111 pmol/L at baseline were significant predictors for 28-day mortality (HR 6.80, 95% CI 3.12-14.84, p < 0.001 and HR 3.72, 95% CI 1.71-8.08, p 0.01).. Baseline and serial MR-proADM and CT-proET-1 had good ability to predict 28-day mortality in critically ill patients with SARS-CoV-2 pneumonia.. NEDERLANDS TRIAL REGISTER, NL8460.

Topics: Adrenomedullin; Biomarkers; COVID-19; Critical Illness; Endothelin-1; Endothelium; Humans; Peptide Fragments; Pneumonia; Prognosis; Prospective Studies; Protein Precursors; SARS-CoV-2

Airborne particulate matter (PM) is associated with an increased risk for cardiovascular diseases. Although the goal of thermal remediation is to eliminate organic wastes through combustion, when incomplete combustion occurs, organics chemisorb to transition metals to generate PM-containing environmentally persistent free radicals (EPFRs). Similar EPFR species have been detected in PM found in diesel and gasoline exhaust, woodsmoke, and urban air. Prior in vivo studies demonstrated that EPFRs reduce cardiac function secondary to elevations in pulmonary arterial pressures. In vitro studies showed that EPFRs increase ROS and cytokines in pulmonary epithelial cells. We thus hypothesized that EPFR inhalation would promote lung inflammation and oxidative stress, leading to systemic inflammation, vascular endothelial injury, and a decline in vascular function. Mice were exposed to EPFRs for either 4 h or for 4 h/day for 10 days and lung and vascular function were assessed. After a 4-h exposure, plasma nitric oxide (NO) was reduced while endothelin-1 (ET-1) was increased, however lung function was not altered. After 10 day, plasma NO and ET-1 levels were again altered and lung tidal volume was reduced. These time course studies suggested the vasculature may be an early target of injury. To test this hypothesis, an intermediate time point of 3 days was selected. Though the mice exhibited no marked inflammation in either the lung or the blood, we did note significantly reduced endothelial function concurrent with a reduction in lung tidal volume and an elevation in annexin V protein levels in the lung. Although vascular dysfunction was not dependent upon inflammation, it may be associated with an injury at the air-blood interface. Gene expression analysis suggested roles for oxidative stress and aryl hydrocarbon receptor (Ahr) signaling. Studies probing the relationship between pulmonary oxidative stress and AhR signaling at the air-blood interface with vascular dysfunction seem warranted.

Topics: Animals; Aorta; Basic Helix-Loop-Helix Transcription Factors; Cardiovascular Diseases; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Environmental Pollutants; Free Radicals; Gene Expression Regulation; Inhalation Exposure; Lung; Male; Mice, Inbred C57BL; Nitric Oxide; Oxidative Stress; Particulate Matter; Pneumonia; Receptors, Aryl Hydrocarbon; Tidal Volume; Time Factors

Breathlessness is the most common symptom in people with pulmonary arterial hypertension and congenital heart disease (CHD-APAH), previously thought to be caused by worsening PAH, but perhaps also by inflammation and abnormalities of lung function. We studied lung function and airway inflammation in patients with CHD-APAH and compared the results with controls.. Raised biomarkers for inflammation were found in CHD-APAH. Significant abnormalities in airway physiology may contribute to the dyspnea but are not driven by inflammation as assessed by circulating and sputum cytokines. A relationship between increased serum endothelin-1 and airway dysfunction may relate to its bronchoconstrictive properties.

Topics: Adult; Biomarkers; Bronchoconstriction; Case-Control Studies; Databases, Factual; Dyspnea; Endothelin-1; Exercise Tolerance; Female; Heart Defects, Congenital; Hemodynamics; Humans; Hypertension, Pulmonary; Inflammation Mediators; Lung; Male; Middle Aged; Plethysmography, Whole Body; Pneumonia; Risk Factors; Spirometry; Sputum; Up-Regulation; Walk Test

Pulmonary exposure to the plant toxin ricin leads to respiratory insufficiency and death. To date, in-depth study of acute respiratory distress syndrome (ARDS) following pulmonary exposure to toxins is hampered by the lack of an appropriate animal model. To this end, we established the pig as a large animal model for the comprehensive study of the multifarious clinical manifestations of pulmonary ricinosis. Here, we report for the first time, the monitoring of barometric whole body plethysmography for pulmonary function tests in non-anesthetized ricin-treated pigs. Up to 30 h post-exposure, as a result of progressing hypoxemia and to prevent carbon dioxide retention, animals exhibited a compensatory response of elevation in minute volume, attributed mainly to a large elevation in respiratory rate with minimal response in tidal volume. This response was followed by decompensation, manifested by a decrease in minute volume and severe hypoxemia, refractory to oxygen treatment. Radiological evaluation revealed evidence of early diffuse bilateral pulmonary infiltrates while hemodynamic parameters remained unchanged, excluding cardiac failure as an explanation for respiratory insufficiency. Ricin-intoxicated pigs suffered from increased lung permeability accompanied by cytokine storming. Histological studies revealed lung tissue insults that accumulated over time and led to diffuse alveolar damage. Charting the decline in PaO2/FiO2 ratio in a mechanically ventilated pig confirmed that ricin-induced respiratory damage complies with the accepted diagnostic criteria for ARDS. The establishment of this animal model of pulmonary ricinosis should help in the pursuit of efficient medical countermeasures specifically tailored to deal with the respiratory deficiencies stemming from ricin-induced ARDS.

Topics: Animals; Blood Cell Count; Body Temperature; Bronchoalveolar Lavage Fluid; Cytokines; Disease Models, Animal; Endothelin-1; Female; Hydrogen-Ion Concentration; Inflammation Mediators; Lung; Lung Injury; Oxygen; Partial Pressure; Permeability; Pneumonia; Pulmonary Gas Exchange; Respiratory Distress Syndrome; Respiratory Function Tests; Ricin; Swine

High mobility group box-1 (HMGB1), a proinflammatory cytokine, plays a pivotal role in tissue remodeling and angiogenesis, both of which are crucial for the pathogenesis of pulmonary arterial hypertension. In this study, we explored the relationship between HMGB1 and pulmonary hypertension and whether glycyrrhizin, an inhibitor of HMGB1, attenuates disease progression in an animal model of pulmonary hypertension induced by monocrotaline sodium (MCT).. After inducing pulmonary hypertension through a single subcutaneous injection of MCT (60 mg/kg) to Sprague-Dawley rats, we administered daily intraperitoneal injections of either glycyrrhizin (GLY, 50 mg/kg), an inhibitor of HMGB1, or saline (control) for either 4 or 6 weeks.. Expression levels of HMGB1 in serum increased from the second week after MCT injection and remained elevated throughout the experiment periods. Lung tissue levels of HMGB1 assessed by immunohistochemical staining at 4 weeks after MCT injection also increased. Chronic inhibition of HMGB1 by GLY treatment reduced the MCT-induced increase in right ventricular (RV) systolic pressure, RV hypertrophy (ratio of RV to [left ventricle + septum]), and pulmonary inflammation. MCT-induced muscularization of the pulmonary artery was also attenuated in the GLY-treated group. As assessed 6 weeks after MCT injection, the GLY-treated group exhibited increased survival (90% [18 of 20]) when compared with the control group (60% [12 of 20]; p =0.0027).. Glycyrrhizin, an inhibitor of HMGB1, attenuates pulmonary hypertension progression and pulmonary vascular remodeling in the MCT-induced pulmonary hypertension rat model. Further studies are needed to confirm the potential of HMGB1 as a novel therapeutic target for pulmonary hypertension.

Topics: Animals; Antihypertensive Agents; Arterial Pressure; Cell Proliferation; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin-1; Glycyrrhizic Acid; HMGB1 Protein; Humans; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Male; Monocrotaline; Muscle, Smooth, Vascular; Pneumonia; Pulmonary Artery; Rats, Sprague-Dawley; Time Factors; Vascular Remodeling; Ventricular Dysfunction, Right; Ventricular Function, Right

As a novel kind of nanomaterial with wide potential applications, the adverse effects of carbon nanotubes (CNTs) have recently received significant attention after respiratory exposure. In this study, single-wall carbon nanotubes (SWCNTs) containing different metal contents were intratracheally instilled into lungs of spontaneously hypertensive rats. Pulmonary and cardiovascular system alterations were evaluated at 24 and 72 h post-instillation. Biomarkers of inflammation, oxidative stress and cell damage in the bronchoalveolar lavage fluid (BALF) were increased significantly 24 h post-exposure of SWCNTs. The increased endothelin-1 levels in BALF and plasma and angiotensin I-converting enzyme in plasma suggested endothelial dysfunction in the pulmonary circulation and peripheral vascular thrombosis. These findings suggest that respiratory exposure to SWCNTs can induce acute pulmonary and cardiovascular responses and individuals with existing cardiovascular diseases are very susceptible to SWCNTs exposure. The co-existence of metal residues in SWCNTs can aggravate the adverse effects.

Topics: Administration, Inhalation; Analysis of Variance; Animals; Biomarkers; Bronchoalveolar Lavage Fluid; Cytokines; Endothelin-1; Heart; Histocytochemistry; Iron; Leukocytes; Lung; Male; Myocardium; Nanotubes, Carbon; Oxidative Stress; Peptidyl-Dipeptidase A; Pneumonia; Rats; Rats, Inbred SHR

Excessive activation of the endothelium is associated with adverse outcomes in patients with systemic infections. Endothelium-associated peptides, such as endothelin-1 (ET-1), correlate closely with endothelial activation, and therefore serve as surrogate biomarkers. Our aim was to investigate precursor peptides of endothelin-1 (proET1) on admission and during follow-up on days 3, 5 and 7 in a prospective cohort of 925 patients with community-acquired pneumonia.. We investigated the association of initial and follow-up proET1 and other prohormone levels with 30-day mortality and ICU admission in proportional Cox regression models with time-varying covariates adjusted for the pneumonia-severity-index (PSI), and calculated reclassification statistics.. The mortality rate and ICU admission rate were 5.4% (95% CI 3.9-6.8%) and 9.0% (95% CI 7.1-10.8%). ProET1 levels on admission and changes from baseline to day 3 were significant mortality predictors with adjusted hazard ratios of 10.5 (95% CI 2.9-38.6) and 28.4 (95% CI 7.0-115.1). Initial proET1 levels improved the PSI in reclassification statistics (net reclassification improvement of 0.29, p<0.0001) and in c-statistics (from 0.79 to 0.83, p<0.01). Changes of proET1 on day 3 improved the c-statistic of the combined model of PSI and initial proET1 from 0.80 to 0.85 (p<0.01) and reclassification tables demonstrated a significant improvement (net reclassification improvement 0.44, p<0.0001). Similar significant results were found for the risk for ICU admission.. In community-acquired pneumonia, ET-1 precursor peptides on admission and changes from baseline to day 3 were independent predictors for mortality and ICU admission, and significantly improved the PSI. If verified in intervention studies, monitoring of proET1 may be helpful for endothelium targeting therapies and for risk stratification complementary to other prohormones.

Topics: Aged; Aged, 80 and over; Cohort Studies; Community-Acquired Infections; Endothelin-1; Female; Hospital Mortality; Humans; Intensive Care Units; Male; Middle Aged; Pneumonia; Predictive Value of Tests; Proportional Hazards Models; Prospective Studies; Risk Assessment; Severity of Illness Index; Switzerland; Treatment Outcome

Several new biomarkers are related to mortality in community-acquired pneumonia (CAP).. Aim of this study was to compare new biomarkers for the prediction of short- and long-term all-cause mortality in CAP.. We enrolled 728 patients (59.0 ± 18.2 yr) with CAP. Midregional proadrenomedullin (MR-proADM), midregional proatrial natriuretic peptide (MR-proANP), proarginin-vasopressin (copeptin), proendothelin-1 (CT-proET-1), procalcitonin (PCT), C-reactive protein, white blood cell (WBC) count, and clinical confusion, respiratory rate, blood pressure, and age over 65 years (CRB-65) score were determined on admission. Patients were followed up for 180 days.. In patients who died of any cause within 28 and 180 days (2.5 and 5.1%, respectively), MR-proADM, MR-proANP, copeptin, CT-proET-1 and PCT as well as CRB-65 were significantly higher compared with survivors. MR-proADM had the best performance for 28 days (HR 3.67) and 180 days (HR 2.84) survival. The C index of MR-proADM for 28-day survival (0.85) was superior to MR-proANP (0.81), copeptin (0.78), CT-proET-1 (0.79), and CRB-65 (0.72) for the prediction of mortality. For prediction of mortality at 180 days, the C index of MR-proADM (0.78) was higher than that for MR-proANP (0.74), copeptin (0.73), CT-proET-1 (0.76), PCT, C-reactive protein, and white blood cells. MR-proADM was independent of CRB-65, and added prognostic information for short- and long-term mortality. MR-proADM was an independent and strong predictor of short- and long-term mortality.. All new biomarkers were good predictors of short- and long-term all-cause mortality, superior to inflammatory markers, and at least comparable to CRB-65 score. MR-proADM showed the best performance. A combination of CRB-65 with MR-proADM might be the best predictor for mortality.

Topics: Adolescent; Adrenomedullin; Adult; Age Distribution; Aged; Aged, 80 and over; Atrial Natriuretic Factor; Biomarkers; Blood Pressure; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Cardiovascular Diseases; Community-Acquired Infections; Comorbidity; Endothelin-1; Female; Germany; Humans; Inflammation; Leukocyte Count; Male; Middle Aged; Pneumonia; Predictive Value of Tests; Protein Precursors; Respiratory Rate; Survival Analysis; Vasopressins; Young Adult

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Coronary Circulation; Diabetes Mellitus; Endothelin-1; Humans; Hyperalgesia; Hypertension, Pulmonary; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Myocardial Infarction; Pneumonia; Receptors, Tumor Necrosis Factor; Syndrome

We recently demonstrated that inhalation of the endothelin receptor A (ETA) antagonist LU 135252 improved arterial oxygenation and reduced pulmonary artery pressure in experimental acute lung injury (ALI). In this study we analyzed potential immune modulatory effects of inhaled LU 135252 in experimental ALI. ALI was induced by repeated lung lavage in intubated (100% O2) and anesthetized piglets. Animals were randomly assigned to inhale either nebulized LU 135252 (0.3 mg.kg(-1), ALI + LU group, n = 8) or saline buffer (ALI control group, n = 16), both for 30 min. Surviving animals were sacrificed 6 h after induction of ALI, and lung tissue specimens were obtained from all animals for histology and immunhistochemistry. Induction of ALI significantly decreased arterial oxygenation in all animals. Inhalation of LU 135252 significantly reduced mortality and induced significant and sustained increase in PaO2 (316 +/- 47 mm Hg vs. control 53 +/- 3 mm Hg, p < 0.001). We measured a significant reduction in the number of pulmonary leukocyte L1 antigen-positive cells in ALI + LU animals (8% +/- 1% positive cells vs. control 12% +/- 2% positive cells, p < 0.05). The number of CD3-positive cells was not altered by treatment with LU 135252. Pulmonary tissue concentration of IL-6 was significantly suppressed by LU 135252 inhalation (4 +/- 1 pg.100 mg-1 wet weight vs. control 7 +/- 1 pg.100 mg(-1) wet weight, p < 0.05). Concentrations of TNF-alpha, IL-1beta, and ET-1 in pulmonary tissue were not influenced by inhalation of LU 135252. In conclusion, we demonstrated that inhalation of LU 135252 not only improves mortality and gas exchange, but also blunts the local immune response in experimental ALI.

Topics: Administration, Inhalation; Animals; Blood Pressure; Cytokines; Data Interpretation, Statistical; Endothelin A Receptor Antagonists; Endothelin-1; Heart Rate; Immunoenzyme Techniques; Immunologic Factors; Interleukin-1; Lung; Oxygen; Phenylpropionates; Pneumonia; Pulmonary Circulation; Pulmonary Gas Exchange; Pyrimidines; Swine; Tumor Necrosis Factor-alpha

To explore a novel nonspecific immunomodulation for the treatment of allergic airway inflammation by RNA interference for endothelin converting enzyme (ECE) using 12-alkylated chitosans/plasmid-encoding antisense ECE complex nanoparticles.. Forty BALB/c mice were randomly divided into Group N (normal control), Group NM (OVA + 12-ACSs/antisense-ECE plasmid), Group As (OVA) and Group DNA (OVA + antisense-ECE plasmid), and sensitized by intraperitoneal injection of OVA at day 1 and day 14, followed by challenge with aerosol of 1% OVA at day 24, 25 and 26, but with saline as a control (N). Supernatants from cultured splenocytes and lung homogenates were subjected to detection of the levels of interleukin-4, 5, 10, 13 (IL-4, 5, 10, 13), interferon-gamma (IFN-gamma) and endothelin-1 (ET-1) by using ELISA. Lung tissues were embedded, sliced and HE stained for histopathologic examination. The cultured splenocytes were subjected to flow cytometry detection (IL-4, IL-10 and IFN-gamma).. Mice in group NM showed a lower level of cell count than that in either group AS or group DNA. Compared with N group, the lung tissues taken from the mice in As and DNA groups displayed allergic inflammation with eosinophil infiltration, while the pulmonary inflammation was decreased significantly in group NM. The levels of ET-1, IL-4, IL-13 and IL-5 were down regulated in group NM compared to As and DNA groups (P < 0.05 or P < 0.01). After stimulation by OVA, the splenocytes from the mice in NM group produced a higher level of IL-10 than that from As and DNA groups (P < 0.05 or P < 0.01). The number of Th2 lymphocytes (CD(4)(+) T cells with IL-4 expression) was significantly elevated in the mice of As, DNA and NM groups respectively, while the number of Th2 lymphocytes was lower in the mice of group NM than in the mice of group As or group DNA. The number of CD(4)(+)CD(25)(+) cells with IL-10 expression was up-regulated in the mice of As, DNA and NM groups respectively compared to the control. The percentage of T regulating cells was higher in the mice of group NM compared with that in the mice of group As or group DNA. No detectable difference in the level of Th1 cells (CD(4)(+) T cells with IFN-gamma expression) was found among the 4 groups.. 12-ACSs can encapsulate and deliver antisense-ECE expression plasmid into bronchial epithelial cells in vitro and 12-ACSs/antisense ECE plasmid complex nanoparticles have the capability to down regulate the synthesis of ET-1 and thus decrease the allergic airway inflammation in OVA-sensitized mice.

Topics: Animals; Aspartic Acid Endopeptidases; Chitosan; Endothelin-1; Endothelin-Converting Enzymes; Female; Inflammation; Metalloendopeptidases; Mice; Mice, Inbred BALB C; Nanoparticles; Plasmids; Pneumonia; Respiratory Hypersensitivity

The current study examined the role of endothelin-1 (ET-1) in mediating acute lung inflammation induced by short-term cigarette smoke exposure. Hamsters received intraperitoneal injections of ET-1, followed by a 2-hour period of smoke exposure, for 3 consecutive days. The lungs were then evaluated for inflammatory changes, using the following parameters: (1) lung histopathology, (2) neutrophil content of bronchoalveolar lavage fluid (BALF), (3) percent tumor necrosis factor receptor 1 (TNFR1)-labeled BALF macrophages, and (4) alveolar septal cell apoptosis. Results indicate that ET-1 significantly amplified the effect of smoke on each of these inflammatory markers and that these responses could be blocked by pretreatment with a novel endothelin receptor A antagonist, HJP272. In particular, exogenous ET-1 induced a marked increase in BALF neutrophils, consistent with a role for this mediator as an inflammatory cell "gatekeeper."

Topics: Acute Disease; Animals; Apoptosis; Cricetinae; Endothelin-1; Hydroxyquinolines; Lung; Mesocricetus; Pneumonia; Receptors, Tumor Necrosis Factor, Type I; Tobacco Smoke Pollution

Circulating levels of endothelin-1 are increased in sepsis and correlate with severity of disease. A rapid and easy immunoassay has been developed to measure the more stable ET-1 precursor peptides proET-1. The objective of this study was to assess the diagnostic and prognostic value of proET-1 in a prospective cohort of mainly septic patients with community-acquired pneumonia.. We evaluated 281 consecutive patients with community acquired pneumonia. Serum proET-1 plasma levels were measured using a new sandwich immunoassay.. ProET-1 levels exhibited a gradual increase depending on the clinical severity of pneumonia as assessed by the pneumonia severity index (PSI) and the CURB65 scores (p < 0.001 and p < 0.01). The diagnostic accuracy to predict bacteraemia of procalcitonin (AUC 0.84 [95% 0.74-0.93]) was superior than C-reactive protein (AUC 0.67 [95%CI 0.56-0.78]) and leukocyte count (AUC 0.66 [95%CI 0.55-0.78]) and in the range of proET-1(AUC of 0.77 [95%CI 0.67-0.86]). ProET-1 levels on admission were increased in patients with adverse medical outcomes including death and need for ICU admission. ROC curve analysis to predict the risk for mortality showed a prognostic accuracy of proET-1 (AUC 0.64 [95%CI 0.53-0.74]), which was higher than C-reactive protein (AUC 0.51 [95%CI 0.41-0.61]) and leukocyte count (AUC 0.55 [95%CI 0.44-0.65]) and within the range of the clinical severity scores (PSI AUC 0.69 [95%CI 0.61-0.76] and CURB65 0.67 [95%CI 0.57-0.77]) and procalcitonin (AUC 0.59 [95% 0.51-0.67]). ProET-1 determination improved significantly the prognostic accuracy of the CURB65 score (AUC of the combined model 0.69 [95%CI 0.59-0.79]). In a multivariate logistic regression model, only proET1 and the clinical severity scores were independent predictors for death and for the need for ICU admission.. In community-acquired pneumonia, ET-1 precursor peptides correlate with disease severity and are independent predictors for mortality and ICU admission. If confirmed in future studies, proET-1 levels may become another helpful tool for risk stratification and management of patients with community-acquired pneumonia.. ISRCTN04176397.

Topics: Aged; Aged, 80 and over; Bacteremia; Community-Acquired Infections; Endothelin-1; Female; Humans; Immunoassay; Logistic Models; Male; Middle Aged; Multivariate Analysis; Pneumonia; Prognosis; Protein Precursors; Randomized Controlled Trials as Topic; ROC Curve; Severity of Illness Index; Switzerland; Treatment Outcome

Fresh vehicular emissions potentially represent a ubiquitous environmental concern for cardiovascular health. We compared electrocardiographic effects of fresh gasoline engine emissions with resuspended paved road dust in a mouse model of coronary insufficiency. Apolipoprotein E (ApoE)-/- mice on a high fat diet were exposed by whole-body inhalation to either gasoline emissions at 60 microg/m3 particulate matter (PM), an equivalent atmosphere with particles filtered out of the whole exhaust, or paved road dust at 0.5 and 3.5 mg /m3 for 6 h/d for 3 d. Radiotelemetry recordings of electrocardiogram (ECG) were analyzed for changes in T-wave morphology (QT interval, T-wave amplitude, and T-wave Area). Following exposures, lung lavage and blood samples were obtained to assay for markers of pulmonary and systemic inflammation. No exposure induced significant changes in heart rate and only the high concentration of road dust induced signs of pulmonary inflammation. T-wave area exhibited significant deviation from baseline values during exposure to gasoline exhaust particulates, but not to either concentration of road dust or gasoline emissions sans particulates. Gasoline-exposed mice demonstrated elevated plasma endothelin-1, but did not cause systemic inflammation. These data support the hypothesis that freshly-generated engine emissions, as opposed to resuspended paved road dust, may drive cardiac effects that have been observed at road-sides in the environment. The absence of ECG effects for both very high concentrations of road dust PM and equivalent concentrations of the vapor/gas phase of gasoline engine exhaust further indicate the specific risk conferred by fresh vehicular PM.

Topics: Animals; Apolipoproteins E; Biomarkers; Bronchoalveolar Lavage Fluid; Coronary Disease; Dust; Electrocardiography; Electrophysiology; Endothelin-1; Gasoline; Heart; Inflammation; Male; Mice; Mice, Knockout; Particulate Matter; Pneumonia; Vehicle Emissions

Topics: Cell Hypoxia; Culture Techniques; Endothelin-1; Endothelium, Vascular; Humans; Hypertension, Pulmonary; Nitric Oxide; Nitric Oxide Synthase; Organ Culture Techniques; Pneumonia; Pseudomonas Infections; Pulmonary Heart Disease

The intratracheal (i.t.) instillation of Sephadex beads into rat induced inflammation and a 30-fold increase in the endothelin-1-like immunoreactivity (ET-1-LI) of broncho-alveolar lavage fluid. The levels were highest 24 h after the instillation and had declined significantly after 48 h. At a dose of 1 mg kg-1 i.t., the glucocorticosteroid budesonide almost abolished this response. Phosphoramidon, which inhibits neutral endopeptidase, an enzyme reported to degrade ET-1 and also to inhibit the endothelin-converting enzyme, potentiated the Sephadex-induced rise in ET-1-LI. Chymostatin and heparin, which are reported to reduce the formation of ET-1, did not affect the increase in ET-1-LI. The present model represents a very reactive system for analyzing the changes in ET-1 levels during inflammation.

Topics: Animals; Bronchoalveolar Lavage Fluid; Budesonide; Chromatography, High Pressure Liquid; Dextrans; Endothelin-1; Enzyme Inhibitors; Glycopeptides; Heparin; Hydrogen Peroxide; Male; Oligopeptides; Pneumonia; Pregnenediones; Rats; Rats, Sprague-Dawley