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Biomedical subjects

Michael A Matthay

Publications and source records attributed to Michael A Matthay.

At least 73 records · Page 4Linked to original sources
PubMed2004

Higher versus lower positive end-expiratory pressures in patients with the acute respiratory distress syndrome.

BACKGROUND: Most patients requiring mechanical ventilation for acute lung injury and the acute respiratory distress syndrome (ARDS) receive positive end-expiratory pressure (PEEP) of 5 to 12 cm of water. Higher PEEP levels may improve oxygenation and reduce ventilator-induced lung injury but may also cause circulatory depression and lung injury from overdistention. We conducted this trial to compare the effects of higher and lower PEEP levels on clinical outcomes in these patients. METHODS: We randomly assigned 549 patients with acute lung injury and ARDS to receive mechanical ventilation with either lower or higher PEEP levels, which were set according to different tables of predetermined combinations of PEEP and fraction of inspired oxygen. RESULTS: Mean (+/-SD) PEEP values on days 1 through 4 were 8.3+/-3.2 cm of water in the lower-PEEP group and 13.2+/-3.5 cm of water in the higher-PEEP group (P<0.001). The rates of death before hospital discharge were 24.9 percent and 27.5 percent, respectively (P=0.48; 95 percent confidence interval for the difference between groups, -10.0 to 4.7 percent). From day 1 to day 28, breathing was unassisted for a mean of 14.5+/-10.4 days in the lower-PEEP group and 13.8+/-10.6 days in the higher-PEEP group (P=0.50). CONCLUSIONS: These results suggest that in patients with acute lung injury and ARDS who receive mechanical ventilation with a tidal-volume goal of 6 ml per kilogram of predicted body weight and an end-inspiratory plateau-pressure limit of 30 cm of water, clinical outcomes are similar whether lower or higher PEEP levels are used.

Adult↗
PubMed2004

Hydrostatic mechanisms may contribute to the pathogenesis of human re-expansion pulmonary edema.

OBJECTIVE: The primary objective was to test the hypothesis that clinical re-expansion pulmonary edema is predominantly due to increased permeability of the alveolar-capillary barrier. A secondary objective was to determine if the alveolar epithelium was functionally intact in patients with re-expansion pulmonary edema by measuring net alveolar epithelial fluid transport in a subset of patients. DESIGN: Retrospective study of mechanically ventilated patients with re-expansion pulmonary edema. SETTING: Two academic tertiary care hospitals. PATIENTS: Seven patients with acute onset of re-expansion pulmonary edema after tube thoracostomy or thoracentesis. INTERVENTIONS: Pulmonary edema fluid and plasma were collected at the time of onset of re-expansion edema. MEASUREMENTS AND RESULTS: Contrary to our hypothesis, the mean initial edema fluid to plasma protein ratio was 0.58+/-0.21, supporting a hydrostatic mechanism of edema formation. Four of the patients had an initial edema fluid to plasma protein ratio of less than 0.65, consistent with pure hydrostatic pulmonary edema, while the others had a slight increase in permeability (edema fluid to plasma ratios of 0.67, 0.71 and 0.77), perhaps due to capillary stress failure from hydrostatic stress. Alveolar fluid clearance (mean 9.8+/-8.0%/h) was intact in the subset of three patients in whom it was measured. CONCLUSIONS: This study provides the first direct evidence that hydrostatic forces may contribute to the development of re-expansion pulmonary edema.

Acute Disease↗
PubMed2004

Bench-to-bedside review: the role of the alveolar epithelium in the resolution of pulmonary edema in acute lung injury.

Clearance of pulmonary edema fluid is accomplished by active ion transport, predominantly by the alveolar epithelium. Various ion pumps and channels on the surface of the alveolar epithelial cell generate an osmotic gradient across the epithelium, which in turn drives the movement of water out of the airspaces. Here, the mechanisms of alveolar ion and fluid clearance are reviewed. In addition, many factors that regulate the rate of edema clearance, such as catecholamines, steroids, cytokines, and growth factors, are discussed. Finally, we address the changes to the alveolar epithelium and its transport processes during acute lung injury (ALI). Since relevant clinical outcomes correlate with rates of edema clearance in ALI, therapies based on our understanding of the mechanisms and regulation of fluid transport may be developed.

Animals↗
PubMed2004

Significance of von Willebrand factor in septic and nonseptic patients with acute lung injury.

Systemic endothelial activation and injury are important causes of multiorgan system failure. We hypothesized that plasma levels of von Willebrand factor (VWF), a marker of endothelial activation and injury, would be associated with clinical outcomes in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). In 559 patients with ALI/ARDS enrolled in the National Heart, Lung, and Blood Institute ARDS Network trial of two VT strategies, plasma VWF levels were measured at randomization (mean 350 +/- 265% of normal control plasma) and Day 3 (344 +/- 207%). Baseline VWF levels were similar in patients with and without sepsis, and were significantly higher in nonsurvivors (435 +/- 333%) versus survivors (306 +/- 209%) even when controlling for severity of illness, sepsis, and ventilator strategy (increased odds ratio of death of 1.6 per SD size increase in VWF; 95% confidence interval, 1.4-2.1). Higher VWF levels were also significantly associated with fewer organ failure-free days. Ventilator strategy had no effect on VWF levels. In conclusion, the degree of endothelial activation and injury is strongly associated with outcomes in ALI/ARDS, regardless of the presence or absence of sepsis, and is not modulated by a protective ventilatory strategy. To improve outcomes further, new treatment strategies targeted at the endothelium should be investigated.

APACHE↗
PubMed2004

H(2)O(2) inhibits alveolar epithelial wound repair in vitro by induction of apoptosis.

Reactive oxygen species (ROS) are released into the alveolar space and contribute to alveolar epithelial damage in patients with acute lung injury. However, the role of ROS in alveolar repair is not known. We studied the effect of ROS in our in vitro wound healing model using either human A549 alveolar epithelial cells or primary distal lung epithelial cells. We found that H(2)O(2) inhibited alveolar epithelial repair in a concentration-dependent manner. At similar concentrations, H(2)O(2) also induced apoptosis, an effect seen particularly at the edge of the wound, leading us to hypothesize that apoptosis contributes to H(2)O(2)-induced inhibition of wound repair. To learn the role of apoptosis, we blocked caspases with the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-Asp (zVAD). In the presence of H(2)O(2), zVAD inhibited apoptosis, particularly at the wound edge and, most importantly, maintained alveolar epithelial wound repair. In H(2)O(2)-exposed cells, zVAD also maintained cell viability as judged by improved cell spreading and/or migration at the wound edge and by a more normal mitochondrial potential difference compared with cells not treated with zVAD. In conclusion, H(2)O(2) inhibits alveolar epithelial wound repair in large part by induction of apoptosis. Inhibition of apoptosis can maintain wound repair and cell viability in the face of ROS. Inhibiting apoptosis may be a promising new approach to improve repair of the alveolar epithelium in patients with acute lung injury.

Amino Acid Chloromethyl Ketones↗
PubMed2004

Fluid transport across cultured rat alveolar epithelial cells: a novel in vitro system.

Previous studies have used fluid-instilled lungs to measure net alveolar fluid transport in intact animal and human lungs. However, intact lung studies have two limitations: the contribution of different distal lung epithelial cells cannot be studied separately, and the surface area for fluid absorption can only be approximated. Therefore, we developed a method to measure net vectorial fluid transport in cultured rat alveolar type II cells using an air-liquid interface. The cells were seeded on 0.4-microm microporous inserts in a Transwell system. At 96 h, the transmembrane electrical resistance reached a peak level (1,530 +/- 115 Omega.cm(2)) with morphological evidence of tight junctions. We measured net fluid transport by placing 150 microl of culture medium containing 0.5 microCi of (131)I-albumin on the apical side of the polarized cells. Protein permeability across the cell monolayer, as measured by labeled albumin, was 1.17 +/- 0.34% over 24 h. The change in concentration of (131)I-albumin in the apical fluid was used to determine the net fluid transported across the monolayer over 12 and 24 h. The net basal fluid transport was 0.84 microl.cm(-2).h(-1). cAMP stimulation with forskolin and IBMX increased fluid transport by 96%. Amiloride inhibited both the basal and stimulated fluid transport. Ouabain inhibited basal fluid transport by 93%. The cultured cells retained alveolar type II-like features based on morphologic studies, including ultrastructural imaging. In conclusion, this novel in vitro system can be used to measure net vectorial fluid transport across cultured, polarized alveolar epithelial cells.

Albumins↗
PubMed2004

Malnutrition impairs alveolar fluid clearance in rat lungs.

Inadequate nutrition complicates the clinical course of critically ill patients, and many of these patients develop pulmonary edema. However, little is known about the effect of malnutrition on the mechanisms that resolve alveolar edema. Therefore, we studied the mechanisms responsible for the decrease in alveolar fluid clearance in rats exposed to malnutrition. Rats were allowed access to water, but not to food, for 120 h. Then, the left and right lungs were isolated for the measurement of lung water volume and alveolar fluid clearance, respectively. The rate of alveolar fluid clearance was measured by the progressive increase in the concentration of Evans blue dye that was instilled into the distal air spaces with an isosmolar 5% albumin solution over 1 h. Malnutrition decreased alveolar fluid clearance by 38% compared with controls. Amiloride (10(-3) M) abolished alveolar fluid clearance in malnourished rats. Either refeeding for 120 h following nutritional deprivation for 120 h or an oral supply of sodium glutamate during nutritional deprivation for 120 h restored alveolar fluid clearance to 91 and 86% of normal, respectively. Dibutyryl-cGMP, a cyclic nucleotide-gated cation channel agonist, increased alveolar fluid clearance in malnourished rats supplied with sodium glutamate. Terbutaline, a beta(2)-adrenergic agonist, increased alveolar fluid clearance in rats under all conditions (control, malnutrition, refeeding, and glutamate-treated). These results indicate that malnutrition impairs primarily amiloride-insensitive and dibutyryl-cGMP-sensitive alveolar fluid clearance, but this effect is partially reversible by refeeding, treatment with sodium glutamate, or beta-adrenergic agonist therapy.

Adenosine Triphosphate↗
PubMed2004

Pulmonary edema fluid from patients with early lung injury stimulates fibroblast proliferation through IL-1 beta-induced IL-6 expression.

Although the fibroproliferative response to lung injury occurs with a high frequency in patients with clinical acute lung injury, the mechanisms that initiate this response are largely unknown. This study was undertaken first to identify fibroblast mitogenic factors in pulmonary edema fluid, and second to examine the human lung fibroblast's gene expression profile in response to pulmonary edema fluid. The edema fluid obtained from patients with early lung injury has an eightfold higher concentration of IL-1beta and a twofold greater IL-1beta-dependent mitogenic effect than does fluid obtained from control patients with hydrostatic pulmonary edema. Furthermore, fibroblasts responded to acute lung injury patient-derived edema fluid through production of soluble mediators that possess an autocrine mitogenic effect. Gene array analysis reveals that acute lung injury edema fluid induces several inflammation-modulating and proliferation-related genes in fibroblasts, whose inductions are similarly dependent on bioactive IL-1beta. Most notably, the 20-fold induction of IL-6 mRNA and protein was completely blocked by IL-1 receptor antagonist. The combined addition of IL-1beta and IL-6 was mitogenic, and the proliferative response to conditioned medium from IL-1beta-exposed cells was blocked by antagonistically acting Abs to IL-6 or to gp130. These novel findings indicate that soluble IL-1beta bioactivity and autocrine IL-1beta-dependent IL-6 up-regulation are critical initiators of fibroblast activation and proliferation and that they likely play a role in the fibroproliferative response seen in human acute lung injury.

Adult↗
PubMed2004

Prolonged hypoxia differentially regulates hypoxia-inducible factor (HIF)-1alpha and HIF-2alpha expression in lung epithelial cells: implication of natural antisense HIF-1alpha.

Transcriptional adaptations to hypoxia are mediated by hypoxia-inducible factor (HIF)-1, a heterodimer of HIF-alpha and aryl hydrocarbon receptor nuclear translocator subunits. The HIF-1alpha and HIF-2alpha subunits both undergo rapid hypoxia-induced protein stabilization and bind identical target DNA sequences. When coexpressed in similar cell types, discriminating control mechanisms may exist for their regulation, explaining why HIF-1alpha and HIF-2alpha do not substitute during embryogenesis. We report that, in a human lung epithelial cell line (A549), HIF-1alpha and HIF-2alpha proteins were similarly induced by acute hypoxia (4 h, 0.5% O(2)) at the translational or posttranslational level. However, HIF-1alpha and HIF-2alpha were differentially regulated by prolonged hypoxia (12 h, 0.5% O(2)) since HIF-1alpha protein stimulation disappeared because of a reduction in its mRNA stability, whereas HIF-2alpha protein stimulation remained high and stable. Prolonged hypoxia also induced an increase in the quantity of natural antisense HIF-1alpha (aHIF), whose gene promoter contains several putative hypoxia response elements to which (as we confirm here) the HIF-1alpha or HIF-2alpha protein can bind. Finally, transient transfection of A549 cells by dominant-negative HIF-2alpha, also acting as a dominant-negative for HIF-1alpha, prevented both the decrease in the HIF-1alpha protein and the increase in the aHIF transcript. Taken together, these data indicate that, during prolonged hypoxia, HIF-alpha proteins negatively regulate HIF-1alpha expression through an increase in aHIF and destabilization of HIF-1alpha mRNA. This trans-regulation between HIF-1alpha and HIF-2alpha during hypoxia likely conveys target gene specificity.

Basic Helix-Loop-Helix Proteins↗
PubMed2004

Proteomic analysis of pulmonary edema fluid and plasma in patients with acute lung injury.

Proteomics is the large-scale analysis of protein profiles. This approach has not yet been reported in the study of acute lung injury (ALI). This study details protein profiles in plasma and pulmonary edema fluid (EF) from 16 ALI patients and plasma and bronchoalveolar lavage fluid (BALF) from 12 normal subjects. More than 300 distinct protein spots were evident in the EF and BALF of both normal subjects and ALI patients. Of these, 158 were identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. In the plasma and EF protein profile of ALI patients, there were multiple qualitative changes. For instance, in all normal subjects, but in only one of the ALI patients, seven distinct surfactant protein A isoforms were evident. Nearly all ALI patients also had protein spots that indicate truncation or other posttranslational modifications. Several of these novel changes could serve as new biomarkers of lung injury.

Adult↗
PubMed2004

Proinflammatory activity of anti-IL-8 autoantibody:IL-8 complexes in alveolar edema fluid from patients with acute lung injury.

A significant fraction of IL-8 in lung fluids from patients with the acute lung injury (ALI) is associated with anti-IL-8 autoantibodies (anti-IL-8:IL-8 complexes), and lung fluid concentrations of these complexes correlate with development and outcome of ALI. In this study, we examined whether anti-IL-8:IL-8 complexes exhibit proinflammatory activity in vitro. These complexes were purified from pulmonary edema fluid samples obtained from patients with ALI. First, we found that IL-8 bound to the autoantibody retained its ability to trigger chemotaxis of neutrophils, whereas control antibody did not have significant chemotactic activity. Next, we examined the ability of anti-IL-8:IL-8 complexes to induce neutrophil activation, i.e., neutrophil respiratory burst and degranulation. Anti-IL-8:IL-8 complexes triggered superoxide and myeloperoxidase release from human neutrophils, and in contrast, the control antibody had no effect. We also demonstrated that IgG receptor, FcgammaRIIa, is the receptor involved in cellular activation mediated by these complexes. Blockade of FcgammaRIIa completely reverses activity of the complexes with the exception of chemotaxis. Both FcgammaRIIa and IL-8 receptors mediate chemotactic activity of anti-IL-8:IL-8 complexes, with FcgammaRIIa being, however, a predominant receptor. Furthermore, activity of the complexes is partially dependent on the activation of the mitogen-activated protein kinases, i.e., ERK and p38, important components of the FcgammaRIIa signaling cascade. Anti-IL-8:IL-8 complexes may therefore be involved in the pathogenesis of lung inflammation in clinical acute lung injury.

Antigen-Antibody Complex↗
PubMed2004

Acute lung injury and acute respiratory distress syndrome in pregnancy.

Acute respiratory failure can be the result of a variety of clinical conditions, such as congestive heart failure, pneumonia, pulmonary embolism, exacerbation of obstructive lung diseases, and acute respiratory distress syndrome (ARDS). This article focuses on developments related to acute lung injury and ARDS and reviews epidemiology, pathogenesis and therapeutic advances with an emphasis on the obstetric population. A brief discussion of tocolytic-induced pulmonary edema, preeclampsia, venous air embolism, and aspiration-related ARDS is included. Management of pregnant women with ARDS is outlined.

Female↗
PubMed2004

Direct visual instillation as a method for efficient delivery of fluid into the distal airspaces of anesthetized mice.

Although several methods have been used to deliver fluid into the distal airspaces of the lung, the efficiency of these methods has been variable. Therefore, the authors have modified prior techniques to design a better method for direct visual instillation (DVI) of fluid into the trachea and compared its efficiency with two commonly used methods: nasal inhalation and invasive intratracheal instillation (delivery of the instillate by needle puncture of the trachea). The results showed that this method (DVI) can deliver fluid efficiently into either both lungs or into a single lung. Using an 131I-albumin labeling technique, DVI resulted in 92 +/- 1% retention of the labeled albumin in the lungs 1 hour after instillation, significantly greater than nasal inhalation (48 +/- 3%, P < .01) and invasive intratracheal instillation (77 +/- 3%, P < .05). Also, when bacteria (Escherichia coli) were instilled with the DVI method, the severity of gram-negative pneumonia was greater (6.5 +/- 0.5 g water/g dry weight) compared to delivery by nasal inhalation (5.5 +/- 0.4 g water/g dry weight, P < .05) or by invasive intratracheal instillation (5.9 +/- 0.4g water/g dry weight, P < .05). The authors conclude that DVI is more efficient than nasal inhalation and invasive intratracheal instillation for delivering experimental fluids into the distal airspaces of anesthetized mice. This method should be valuable for experimental lung studies in mice.

Administration, Inhalation↗
PubMed2004

Plasma protein C levels in patients with acute lung injury: prognostic significance.

Decreased circulating protein C is a marker of a prothrombotic state that has been associated with poor clinical outcomes in sepsis. However, protein C has not been measured in patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS). In this study, we measured circulating and intra-alveolar concentrations of protein C in 45 patients with ALI/ARDS from septic and nonseptic causes. Plasma protein C levels were lower in ALI/ARDS compared with normal controls. Lower levels of plasma protein C were associated with worse clinical outcomes, including death, fewer ventilator-free days, and more nonpulmonary organ failures, even when only patients without sepsis were analyzed. In summary, the protein C system is markedly disrupted in patients with ALI/ARDS from both septic and nonseptic causes. The protein C system may be a therapeutic target in patients with ALI/ARDS.

Adult↗