Receptor for advanced glycation end-products (RAGE) is one of the alveolar type I cell-associated proteins in the lung.
To test the hypothesis that RAGE is a marker of alveolar epithelial type I cell ...injury.
Rats were instilled intratracheally with 10 mg/kg lipopolysaccharide or hydrochloric acid. RAGE levels were measured in the bronchoalveolar lavage (BAL) and serum in the rats and in the pulmonary edema fluid and plasma from patients with acute lung injury (ALI; n = 22) and hydrostatic pulmonary edema (n = 11).
In the rat lung injury studies, RAGE was released into the BAL and serum as a single soluble isoform sized approximately 48 kD. The elevated levels of RAGE in the BAL correlated well with the severity of experimentally induced lung injury. In the human studies, the RAGE level in the pulmonary edema fluid was significantly higher than the plasma level (p < 0.0001). The median edema fluid/plasma ratio of RAGE levels was 105 (interquartile range, 55-243). The RAGE levels in the pulmonary edema fluid from patients with ALI were higher than the levels from patients with hydrostatic pulmonary edema (p < 0.05), and the plasma RAGE level in patients with ALI were significantly higher than the healthy volunteers (p < 0.001) or patients with hydrostatic pulmonary edema (p < 0.05).
RAGE is a marker of type I alveolar epithelial cell injury based on experimental studies in rats and in patients with ALI.
To determine whether baseline plasma levels of the receptor for advanced glycation end products (RAGE), a novel marker of alveolar type I cell injury, are associated with the severity and outcomes of ...acute lung injury, and whether plasma RAGE levels are affected by lower tidal volume ventilation.
Measurement of plasma RAGE levels from 676 subjects enrolled in a large randomised controlled trial of lower tidal volume ventilation in acute lung injury.
Higher baseline plasma RAGE was associated with increased severity of lung injury. In addition, higher baseline RAGE was associated with increased mortality (OR for death 1.38 (95% CI 1.13 to 1.68) per 1 log increment in RAGE; p = 0.002) and fewer ventilator free and organ failure free days in patients randomised to higher tidal volumes. These associations persisted in multivariable models that adjusted for age, gender, severity of illness and the presence of sepsis or trauma. Plasma RAGE was not associated with outcomes in the lower tidal volume group (p = 0.09 for interaction in unadjusted analysis). In both tidal volume groups, plasma RAGE levels declined over the first 3 days; however, the decline was 15% greater in the lower tidal volume group (p = 0.02; 95% CI 2.4% to 25.0%).
Baseline plasma RAGE levels are strongly associated with clinical outcomes in patients with acute lung injury ventilated with higher tidal volumes. Lower tidal volume ventilation may be beneficial in part by decreasing injury to the alveolar epithelium.
Background: Because injury to the alveolar epithelial barrier is a characteristic feature of acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS), plasma surfactant protein ...levels may have prognostic value. To test this hypothesis plasma surfactant proteins A and D (SP-A and SP-D) levels were measured in patients with ALI or ARDS enrolled in the NHLBI sponsored multicentre ARDS Network randomised controlled trial of a 6 ml/kg v 12 ml/kg tidal volume strategy. Methods: Data from 565 participants in the clinical trial were used. Plasma levels of SP-A and SP-D were measured at baseline and on day 3 after the start of the mechanical ventilation protocol. The longitudinal impact of baseline plasma surfactant protein levels on clinical outcomes was examined by multivariate analysis, controlling for mechanical ventilation group, APACHE III score, and other clinical covariates. The effect of 6 ml/kg tidal volume ventilation on plasma SP-A and SP-D levels was evaluated using analysis of covariance. Results: Baseline plasma SP-A levels were not related to any clinical outcome. In contrast, higher baseline plasma SP-D levels were associated with a greater risk of death (OR 1.21 per 100 ng/ml increment; 95% CI 1.08 to 1.35), fewer ventilator-free days (mean decrease −0.88 days; p=0.001), and fewer organ failure-free days (mean decrease −1.06 days; p<0.0001). The 6 ml/kg tidal volume strategy had no effect on the rise in plasma SP-A levels (p=0.91) but attenuated the rise in plasma SP-D levels (p=0.0006). Conclusions: Early in the course of ALI/ARDS an increased level of plasma SP-D is associated with a worse clinical outcome. The 6 ml/kg tidal volume strategy attenuated the rise of SP-D early in the clinical course. Taken together, these observations indicate that plasma SP-D, a product of alveolar type II cells, is a valuable biomarker in ALI/ARDS.
The need to increase the donor pool for lung transplantation is a major public health issue. We previously found that administration of mesenchymal stem cells “rehabilitated” marginal donor lungs ...rejected for transplantation using ex vivo lung perfusion. However, the use of stem cells has some inherent limitation such as the potential for tumor formation. In the current study, we hypothesized that microvesicles, small anuclear membrane fragments constitutively released from mesenchymal stem cells, may be a good alternative to using stem cells. Using our well established ex vivo lung perfusion model, microvesicles derived from human mesenchymal stem cells increased alveolar fluid clearance (i.e. ability to absorb pulmonary edema fluid) in a dose‐dependent manner, decreased lung weight gain following perfusion and ventilation, and improved airway and hemodynamic parameters compared to perfusion alone. Microvesicles derived from normal human lung fibroblasts as a control had no effect. Co‐administration of microvesicles with anti‐CD44 antibody attenuated these effects, suggesting a key role of the CD44 receptor in the internalization of the microvesicles into the injured host cell and its effect. In summary, microvesicles derived from human mesenchymal stem cells were as effective as the parent mesenchymal stem cells in rehabilitating marginal donor human lungs.
Microvesicles, small anuclear membrane‐bound fragments derived from mesenchymal stem cells, are preliminarily studied as a stem cell–derived therapy for rehabilitating marginal donor human lungs during ex vivo lung perfusion.
Acute cor pulmonale in ARDS Vieillard-Baron, A.; Price, L. C.; Matthay, M. A.
Intensive care medicine,
10/2013, Letnik:
39, Številka:
10
Journal Article
The Acute Respiratory Distress Syndrome Ware, Lorraine B; Matthay, Michael A
The New England journal of medicine,
05/2000, Letnik:
342, Številka:
18
Journal Article
Recenzirano
The acute respiratory distress syndrome is a common, devastating clinical syndrome of acute lung injury that affects both medical and surgical patients. Since the last review of this syndrome ...appeared in the
Journal,
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more uniform definitions have been devised and important advances have occurred in the understanding of the epidemiology, natural history, and pathogenesis of the disease, leading to the design and testing of new treatment strategies. This article provides an overview of the definitions, clinical features, and epidemiology of the acute respiratory distress syndrome and discusses advances in the areas of pathogenesis, resolution, and treatment.
Historical Perspective and Definitions . . .
Because experimental studies have shown that intact alveolar epithelial fluid transport function is critical for resolution of pulmonary edema and acute lung injury, we measured net alveolar fluid ...clearance in 79 patients with acute lung injury or the acute respiratory distress syndrome. Pulmonary edema fluid and plasma were sampled serially in the first 4 hours after intubation. Net alveolar fluid clearance was calculated from sequential edema fluid protein measurements. Mean alveolar fluid clearance was 6%/h. Of the patients, 56% had impaired alveolar fluid clearance (< 3%/h), 32% had submaximal clearance (> or = 3%/h, < 14%/h), and 13% had maximal clearance (> or = 14%/h). These findings are contrasted to our recent report of 65 patients with hydrostatic pulmonary edema, in whom mean alveolar fluid clearance was 13%/h; only 25% had impaired clearance whereas 75% had submaximal or maximal clearance (J Appl Physiol 1999;87:1301-1312). Acute lung injury with maximal alveolar fluid clearance were more likely to be female (p = 0.03), and less likely to have sepsis (p = 0.01). Endogenous and exogenous catecholamines did not correlate with alveolar fluid clearance. Patients with maximal alveolar fluid clearance had significantly lower mortality and a shorter duration of mechanical ventilation. In summary, in contrast to hydrostatic pulmonary edema, alveolar fluid clearance in patients with acute lung injury and the acute respiratory distress syndrome is impaired in the majority of patients, and maximal alveolar fluid clearance is associated with better clinical outcomes.
Departments of Medicine and Anesthesia and the Cardiovascular
Research Institute, University of California, San Francisco,
California 94143-0130
To characterize the rate and regulation of
alveolar ...fluid clearance in the uninjured human lung, pulmonary edema
fluid and plasma were sampled within the first 4 h after tracheal
intubation in 65 mechanically ventilated patients with severe
hydrostatic pulmonary edema. Alveolar fluid clearance was calculated
from the change in pulmonary edema fluid protein concentration over time. Overall, 75% of patients had intact alveolar fluid clearance ( 3%/h). Maximal alveolar fluid clearance ( 14%/h) was present in
38% of patients, with a mean rate of 25 ± 12%/h. Hemodynamic factors (including pulmonary arterial wedge pressure and left ventricular ejection fraction) and plasma epinephrine levels did not
correlate with impaired or intact alveolar fluid clearance. Impaired
alveolar fluid clearance was associated with a lower arterial pH and a
higher Simplified Acute Physiology Score II. These factors may be
markers of systemic hypoperfusion, which has been reported to impair
alveolar fluid clearance by oxidant-mediated mechanisms. Finally,
intact alveolar fluid clearance was associated with a greater
improvement in oxygenation at 24 h along with a trend toward shorter
duration of mechanical ventilation and an 18% lower hospital
mortality. In summary, alveolar fluid clearance in humans may be rapid
in the absence of alveolar epithelial injury. Catecholamine-independent
factors are important in the regulation of alveolar fluid clearance in
patients with severe hydrostatic pulmonary edema.
-agonist; congestive heart failure; alveolar fluid clearance; mechanical ventilation; left atrial hypertension
More than 35 years have passed since it was discovered that the application of positive end-expiratory pressure (PEEP) improved arterial oxygenation in patients with certain forms of respiratory ...failure who were treated with mechanical ventilation. In this study, investigators from an NIH-sponsored consortium compared the effects of higher and lower levels of PEEP on survival after the institution of mechanical ventilation. The trial was terminated early after neither approach proved to have an advantage.
This study compared the effects of higher and lower levels of PEEP on survival.
Mechanical ventilation is critical for the survival of most patients with acute lung injury and the acute respiratory distress syndrome (ARDS). However, some approaches to mechanical ventilation may cause additional lung injury,
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which could delay or prevent resolution of respiratory failure. Ventilator-induced lung injury may be caused by overdistention of aerated lung regions, especially when large tidal volumes are used.
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Ventilator-induced lung injury may also occur if a substantial portion of the lung is not aerated at end-expiration because of atelectasis, flooding, and consolidation. This may cause excessive mechanical forces in aerated lung regions,
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between aerated and nonaerated . . .
Lung protective ventilation has been widely adopted for the management of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Consequently, ventilator associated lung injury and ...mortality have decreased. It is not known if this ventilation strategy changes the prognostic value of previously identified demographic and pulmonary predictors of mortality, such as respiratory compliance and the arterial oxygen tension to inspired oxygen fraction ratio (Pao(2)/Fio(2)).
Demographic, clinical, laboratory and pulmonary variables were recorded in 149 patients with ALI/ARDS. Significant predictors of mortality were identified in bivariate analysis and these were entered into multivariate analysis to identify independent predictors of mortality.
Hospital mortality was 41%. In the bivariate analysis, 17 variables were significantly correlated with mortality, including age, APACHE II score and the presence of cirrhosis. Pulmonary parameters associated with death included Pao(2)/Fio(2) and oxygenation index ((mean airway pressurexFio(2)x100)/Pao(2)). In unadjusted analysis, the odds ratio (OR) of death for Pao(2)/Fio(2) was 1.57 (CI 1.12 to 3.04) per standard deviation decrease. However, in adjusted analysis, Pao(2)/Fio(2) was not a statistically significant predictor of death, with an OR of 1.29 (CI 0.82 to 2.02). In contrast, oxygenation index (OI) was a statistically significant predictor of death in both unadjusted analysis (OR 1.89 (CI 1.28 to 2.78)) and in adjusted analysis (OR 1.84 (CI 1.13 to 2.99)).
In this cohort of patients with ALI/ARDS, OI was an independent predictor of mortality, whereas Pao(2)/Fio(2) was not. OI may be a superior predictor because it integrates both airway pressure and oxygenation into a single variable.
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