adrenomedullin and Respiratory-Distress-Syndrome

Accurate biomarkers of the acute respiratory distress syndrome (ARDS) may help risk stratification and management. We assessed the relation between several biomarkers and the severity, course and outcome of late onset ARDS in 101 consecutive critically ill patients with new onset fever.. On study days 0, 1, 2 and 7 we measured angiopoietin-2 (ANG2), pentraxin-3 (PTX3), interleukin-6 (IL-6), procalcitonin (PCT) and midregional proadrenomedullin (proADM). ARDS was defined by the Berlin definition and by the lung injury score (LIS).. At baseline, 48% had ARDS according to the Berlin definition and 86% according to the LIS. Baseline markers poorly predicted maximum Berlin categories attained within 7 days, whereas ANG2 best predicted maximum LIS. Depending on the ARDS definition, the day-by-day area under the receiver operating characteristic curves suggested greatest monitoring value for IL-6 and PCT, followed by ANG2. ANG2 and proADM predicted outcome, independently of disease severity.. Whereas IL-6 and PCT had some disease monitoring value, ANG2 was the only biomarker capable of both predicting the severity, monitoring the course and predicting the outcome of late onset ARDS in febrile critically ill patients, irrespective of underlying risk factor, thereby yielding the most specific ARDS biomarker among those studied.

Topics: Adrenomedullin; Adult; Aged; Angiopoietin-2; Biomarkers; C-Reactive Protein; Calcitonin; Calcitonin Gene-Related Peptide; Critical Illness; Female; Fever; Humans; Interleukin-6; Lung Injury; Male; Middle Aged; Protein Precursors; Respiratory Distress Syndrome; Serum Amyloid P-Component; Severity of Illness Index

Adrenomedullin (AM), an endogenous peptide, has been shown to have a variety of protective effects on the cardiovascular system. However, the effect of AM on acute lung injury remains unknown. Accordingly, we investigated whether AM infusion ameliorates lipopolysaccharide (LPS)-induced acute lung injury in rats. Rats were randomized to receive continuous intravenous infusion of AM (0.1 microg x kg(-1) x min(-1)) or vehicle through a microosmotic pump. The animals were intratracheally injected with either LPS (1 mg/kg) or saline. At 6 and 18 h after intratracheal instillation, we performed histological examination and bronchoalveolar lavage and assessed the lung wet/dry weight ratio as an index of acute lung injury. Then we measured the numbers of total cells and neutrophils and the levels of tumor necrosis factor (TNF)-alpha and cytokine-induced neutrophil chemoattractant (CINC) in bronchoalveolar lavage fluid (BALF). In addition, we evaluated BALF total protein and albumin levels as indexes of lung permeability. LPS instillation caused severe acute lung injury, as indicated by the histological findings and the lung wet/dry weight ratio. However, AM infusion attenuated these LPS-induced abnormalities. AM decreased the numbers of total cells and neutrophils and the levels of TNF-alpha and CINC in BALF. AM also reduced BALF total protein and albumin levels. In addition, AM significantly suppressed apoptosis of alveolar wall cells as indicated by cleaved caspase-3 staining. In conclusion, continuous infusion of AM ameliorated LPS-induced acute lung injury in rats. This beneficial effect of AM on acute lung injury may be mediated by inhibition of inflammation, hyperpermeability, and alveolar wall cell apoptosis.

Topics: Adrenomedullin; Animals; Apoptosis; Bronchoalveolar Lavage Fluid; Bronchodilator Agents; Extravascular Lung Water; Lipopolysaccharides; Male; Pneumonia; Pulmonary Alveoli; Rats; Rats, Sprague-Dawley; Respiratory Distress Syndrome; Trachea

Ischemic bowel remains a critical problem, resulting in up to 80% mortality. Acute lung injury, a common complication after intestinal ischemia/reperfusion (I/R), might be responsible for such a high mortality rate. Our previous studies have shown that administration of a novel vasoactive peptide adrenomedullin (AM) and its binding protein (AMBP-1) reduces the systemic inflammatory response in rat models of both hemorrhage and sepsis. It remains unknown whether administration of AM/AMBP-1 has any protective effects on intestinal I/R-induced acute lung injury. We hypothesized that administration of AM/AMBP-1 after intestinal I/R prevents acute lung injury through downregulation of proinflammatory cytokines.. Intestinal I/R was induced by placing a microvascular clip across superior mesenteric artery (SMA) for 90 minutes in adult male Sprague-Dawley rats (275 to 325 g). On release of the SMA clamp, the animals were treated with either AM (12 mug/kg body weight) in combination with AMBP-1 (40 microg/kg body weight) or vehicle (1 mL normal saline) during a period of 30 minutes through a femoral vein catheter. Lung samples were collected at 4 hours after treatment or sham operation. Lung injury was assessed by examining lung water content, morphologic changes, and granulocyte myeloperoxidase activity. Tumor necrosis factor-alpha and interleukin-6 gene expression and their protein levels in the lungs were measured by reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. In additional groups of animals, AM/AMBP-1 or vehicle was administered at 1 hour after onset of reperfusion. Lung histology was examined at 3 hours after treatment.. Intestinal I/R induced considerable lung injury, as characterized by lung edema, histopathologic changes, increased myeloperoxidase activity, and proinflammatory cytokines (tumor necrosis factor-alpha and interleukin-6) levels in the lungs. Administration of AM/AMBP-1 after ischemia mitigated lung injury and dramatically downregulated proinflammatory cytokines. Lung injury was also ameliorated by delayed AM/AMBP-1 treatment as evidenced by improvement in lung histology.. AM/AMBP-1 can be developed as a novel treatment to attenuate acute lung injury after an episode of gut ischemia. The protective effect of AM/AMBP-1 appears to be mediated through downregulation of proinflammatory cytokines.

Topics: Adrenomedullin; Animals; Complement Factor H; Intestines; Male; Rats; Rats, Sprague-Dawley; Reperfusion Injury; Respiratory Distress Syndrome; Vasodilator Agents

Our aim was to evaluate if the combined inhalation of both nitric oxide (iNO) and aerosolized prostacyclin or iNO and adrenomedullin (ADM) is more effective in lowering pulmonary arterial pressure (PAP) and improving oxygenation than nitric oxide alone in an animal model with pulmonary hypertension (PH). Moreover, we studied the effect on pulmonary mechanics, surfactant activity, and pulmonary oxidative stress of the different treatments. Twenty-eight piglets with acute lung injury induced by lung lavages with saline were randomized to receive nitric oxide, nitric oxide plus prostacyclin, nitric oxide plus ADM or saline, after. Dynamic compliance, tidal volume, and airway resistance were measured. Lung tissue oxidation was evaluated by measuring total hydroperoxide and advanced oxidation protein products in bronchial aspirate samples. Surface surfactant activity was studied using Capillary Surfactometer. Inhaled nitric oxide combined with prostacyclin or ADM was more effective than nitric oxide alone in lowering PAP and improving oxygenation. Nitric oxide alone or combined increased lung compliance and tidal volume, and decreased airway resistance. No effects on surfactant surface activity and lung tissue oxidation were observed. The treatment with nitric oxide alone or combined with prostacyclin or ADM were effective in decreasing mean PAP and improving oxygenation in a piglet model of PH. However, nitric oxide plus prostacyclin and nitric oxide plus ADM were more effective than nitric oxide alone. The combination of aerosolized prostacyclin and ADM with nitric oxide might have a role in the treatment of infants with PH refractory to nitric oxide alone.

Topics: Administration, Inhalation; Adrenomedullin; Animals; Disease Models, Animal; Drug Therapy, Combination; Epoprostenol; Female; Hypertension, Pulmonary; Male; Nitric Oxide; Pulmonary Artery; Pulmonary Surfactants; Respiratory Distress Syndrome; Respiratory Function Tests; Sus scrofa; Vasodilator Agents

To investigate the changes in adrenomedullin release in bronchial alveolar lavage fluid (BALF) from different lung areas in acute respiratory distress syndrome (ARDS) of produced dogs, by pulmonary and extra-pulmonary causes, with low tidal volume and positive end expiratory pressure (PEEP) treatment under supine and prone position.. Twenty-four male mongrel dogs were randomly divided into ARDSp (ARDS caused by pulmonary causes) supine group, ARDSp prone group, ARDSexp (ARDS caused by extra-pulmonary causes) supine group, and ARDSexp prone group. A detergent to cause lung injury in ARDSp dogs, and intravenous oleic acid was given in ARDSexp dogs. The results of adrenomedullin in different areas of dog's lung (upper lobe, middle lobe, and lower lobe) and arterial blood gas under lung protective ventilation treatment were measured.. After lung injury, the arterial oxygenation index was lowered, and the levels of adrenomedullin in the upper lobe and middle lobe of ARDSp dogs were higher than that of ARDSexp dogs. After receiving low tidal volume and PEEP ventilation, the conditions of all the dogs were gradually getting ameliorated, and prone position ventilation gave better effects on lung injury dogs by inhibiting adrenomedullin release.. There are statistical differences in adrenomedullin release in different lung areas between ARDSp dogs and ARDSexp dogs, and in both ARDSexp dogs and ARDSp dogs low tidal volume and PEEP treatment under prone position ventilation give better results compared to supine position.

Topics: Adrenomedullin; Animals; Bronchoalveolar Lavage Fluid; Disease Models, Animal; Dogs; Lung; Male; Positive-Pressure Respiration; Posture; Random Allocation; Respiratory Distress Syndrome; Tidal Volume

We recently showed that pulmonary endothelins may affect coronary circulation under various experimental and clinical conditions. Here, we investigated the effect of pulmonary mediators on coronary tone in experimental acute respiratory distress syndrome. We focused particularly on pulmonary endothelin-1, a major vasoconstrictor in acute respiratory distress syndrome, and on adrenomedullin, a potent vasodilator that is up-regulated by inflammatory stimuli.. Controlled experiment that used isolated organs.. Experimental laboratory.. Wistar rats.. The saline effluent from an isolated lung was used to serially perfuse the coronary vessels of an isolated heart. We compared serial perfusion after 2-hr pretreatment of lungs with vehicle or endotoxin (50 microg/mL), and we used the following drugs to elucidate the coronary response observed: the endothelin type A receptor antagonist BQ-123 (2 microM), the endothelin type B antagonist A-192621 (500 nM), the endothelin-converting enzyme inhibitor phosphoramidon (50 microM), the calcitonin gene-related peptide type-1 receptor antagonist hCGRP(8-37) (2 microM), and the adrenomedullin receptor antagonist hAM(22-52) (200 nM) (n = 6 each).. In controls, serial perfusion decreased coronary flow to 87 +/- 3% of baseline (p < .05). BQ-123 and phosphoramidon prevented this effect, whereas blockade of endothelin type B and adrenomedullin-binding receptors had no effect. After endotoxin challenge, coronary flow significantly increased to 110 +/- 2%. This response was augmented by BQ-123 (124 +/- 2%) and phosphoramidon (123 +/- 3%); A-192621 had no effect. Application of hCGRP(8-37) and hAM(22-52) significantly decreased coronary flow to 81 +/- 3% and 88 +/- 2%, respectively. Flow decrease after blockade of both adrenomedullin-binding receptors (73 +/- 2%) significantly deteriorated peak left ventricular pressure, to 82 +/- 6% of baseline; rate of pressure increase, to 81 +/- 5%; and rate of pressure decline, to 77 +/- 6%. Endotoxin pretreatment elevated pulmonary venous big endothelin-1 (three-fold), endothelin-1 (two-fold), and adrenomedullin (five-fold).. In experimental acute respiratory distress syndrome, pulmonary adrenomedullin--via calcitonin gene-related peptide type-1 receptor and adrenomedullin receptor--outweighs the coronary vasoconstrictor impact of pulmonary big endothelin-1 exerted via endothelin type A receptors after conversion to mature endothelin-1. The consequence is prevention of flow-related deterioration of myocardial performance.

Topics: Adrenomedullin; Analysis of Variance; Animals; Antihypertensive Agents; Coronary Circulation; Endothelin Receptor Antagonists; Endothelin-1; Myocardial Contraction; Peptides; Peptides, Cyclic; Radioimmunoassay; Rats; Rats, Wistar; Receptors, Calcitonin Gene-Related Peptide; Respiratory Distress Syndrome