Showing papers by "Michael A. Matthay published in 2004"
TL;DR: Data indicate that, during prolonged hypoxia, HIF-α proteins negatively regulate Hif-1α expression through an increase in aHIF and destabilization of HIF/2α mRNA, which likely conveys target gene specificity.
391 citations
TL;DR: 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.
Abstract: 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 ...
244 citations
TL;DR: Treatment is supportive, with a prognosis substantially better than most causes of clinical acute lung injury, and the pathogenesis of TRALI may be explained by a "two-hit" hypothesis.
207 citations
TL;DR: Because injury to distal lung epithelial cells, including alveolar type II cells, is important in the pathogenesis of ALI, the elevation of KL-6 concentrations in plasma and epithelial lining fluid could be valuable indicators for poor prognosis in clinical ALI.
Abstract: KL-6 is a pulmonary epithelial mucin more prominently expressed on the surface membrane of alveolar type II cells when these cells are proliferating, stimulated, and/or injured. We hypothesized that high levels of KL-6 in epithelial lining fluid and plasma would reflect the severity of lung injury in patients with acute lung injury (ALI). Epithelial lining fluid was obtained at onset (day 0) and day 1 of acute respiratory distress syndrome (ARDS)/ALI by bronchoscopic microsampling procedure in 35 patients. On day 0, KL-6 and albumin concentrations in epithelial lining fluid were significantly higher than in normal controls (P < 0.001), and the concentrations of KL-6 in epithelial lining fluid (P < 0.002) and in plasma (P < 0.0001) were higher in nonsurvivors than in survivors of ALI/ARDS. These observations were corroborated by the immunohistochemical localization of KL-6 protein expression in the lungs of nonsurvivors with ALI and KL-6 secretion from cultured human alveolar type II cells stimulated by proinflammatory cytokines. Because injury to distal lung epithelial cells, including alveolar type II cells, is important in the pathogenesis of ALI, the elevation of KL-6 concentrations in plasma and epithelial lining fluid could be valuable indicators for poor prognosis in clinical ALI.
164 citations
TL;DR: Clinically relevant airspace concentrations of β2-adrenergic agonists stimulate maximal cAMP-dependent airspace fluid clearance in normal lungs and reduce pulmonary edema in acid aspiration-induced lung injury by increasing alveolar fluid clearance and decreasing endothelial permeability.
Abstract: Objective:To determine whether clinically relevant airspace concentrations of β2-adrenergic agonists stimulated maximal alveolar fluid clearance rates and to determine whether β2 agonist therapy decreased pulmonary edema in experimental acute lung injury.Design:Prospective randomized laboratory inve
155 citations
TL;DR: Findings indicate that soluble IL-1β bioactivity and autocrine IL- 1β-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.
Abstract: 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.
133 citations
TL;DR: Alveolar albumin clearance occurs by receptor-mediated transcytosis at low protein concentrations but proceeds by passive paracellular mechanisms at higher concentrations, and Because protein concentrations in pulmonary edema fluid are high, albumin concentrations of 5 g/100 ml or more, clearance of alveolar protein occurs byParacellular pathways in the setting of pulmonary edEMA.
Abstract: Transport of protein across the alveolar epithelial barrier is a critical process in recovery from pulmonary edema and is also important in maintaining the alveolar milieu in the normal healthy lun...
115 citations
TL;DR: A brief review of the most promising proteomics methods and some of their applications to pulmonary research is provided.
Abstract: Proteomics aims to study the whole protein content of a biological sample in one set of experiments. Such an approach has the potential value to acquire an understanding of the complex responses of an organism to a stimulus. The large vascular and air space surface area of the lung expose it to a multitude of stimuli that can trigger a variety of responses by many different cell types. This complexity makes the lung a promising, but also challenging, target for proteomics. Important steps made in the last decade have increased the potential value of the results of proteomics studies for the clinical scientist. Advances in protein separation and staining techniques have improved protein identification to include the least abundant proteins. The evolution in mass spectrometry has led to the identification of a large part of the proteins of interest rather than just describing changes in patterns of protein spots. Protein profiling techniques allow the rapid comparison of complex samples and the direct investigation of tissue specimens. In addition, proteomics has been complemented by the analysis of posttranslational modifications and techniques for the quantitative comparison of different proteomes. These methodologies have made the application of proteomics on the study of specific diseases or biological processes under clinically relevant conditions possible. The quantity of data that is acquired with these new techniques places new challenges on data processing and analysis. This article provides a brief review of the most promising proteomics methods and some of their applications to pulmonary research.
112 citations
Journal Article•
TL;DR: In ARDS a sustained VD/VT elevation is characteristic of nonsurvivors, so dead-space measurements made beyond the first 24 hours may have prognostic value.
Abstract: BACKGROUND: The ratio of pulmonary dead space to tidal volume (VD/VT) in acute respiratory distress syndrome (ARDS) is reported to be between 0.35 and 0.55. However, VD/VT has seldom been measured with consideration to the evolving pathophysiology of ARDS.
METHODS: We made serial VD/VT measurements with 59 patients who required mechanical ventilation for ≥ 6 days. We measured VD/VT within 24 h of the point at which the patient met the American-European Consensus Conference criteria for ARDS, and we repeated the VD/VT measurement on ARDS days 2, 3, and 6 with a bedside metabolic monitor during volume-regulated ventilation. We analyzed the changes in VD/VT over the 6-day period to determine whether VD/VT has a significant association with mortality.
RESULTS: VD/VT was significantly higher in nonsurvivors on day 1 (0.61 ± 0.09 vs 0.54 ± 0.08, p < 0.05), day 2 (0.63 ± 0.09 vs 0.53 ± 0.09, p < 0.001), day 3 (0.64 ± 0.09 vs 0.53 ± 0.09, p < 0.001), and day 6 (0.66 ± 0.09 vs 0.51 ± 0.08, p < 0.001).
CONCLUSION: In ARDS a sustained VD/VT elevation is characteristic of nonsurvivors, so dead-space measurements made beyond the first 24 hours may have prognostic value.
106 citations
TL;DR: Development of mouse models in which the function of regulatory proteins can be systematically analyzed will provide a better and more integrated picture of lung fluid balance.
Abstract: This review summarizes the highlights of the EB2004 symposium that dealt with the integrated aspects of the lung fluid balance. It is apparent that maintenance of lung fluid balance requires the pr...
98 citations
TL;DR: This study details protein profiles in plasma and pulmonary edema fluid from 16 ALI patients and plasma and bronchoalveolar lavage fluid from 12 normal subjects to identify novel changes that could serve as new biomarkers of lung injury.
Abstract: 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.
TL;DR: It is proposed that soluble MD-2 is an important mediator of organ inflammation during sepsis and leaking into the extravascular space supports LPS activation of TLR4-expressing epithelial cells.
TL;DR: Data demonstrate that the ADPRT domain of ExoT is active in vivo and contributes to the pathogenesis of P. aeruginosa infections.
Abstract: ExoT is a type III secreted effector protein found in almost all strains of Pseudomonas aeruginosa and is required for full virulence in an animal model of acute pneumonia. It is comprised of an N-terminal domain with GTPase activating protein (GAP) activity towards Rho family GTPases and a C-terminal ADP ribosyltransferase (ADPRT) domain with minimal activity towards a synthetic substrate in vitro. Consistent with its activity as a Rho family GTPase, ExoT has been shown to inhibit P. aeruginosa internalization into epithelial cells and macrophages, disrupt the actin cytoskeleton through a Rho-dependent pathway, and inhibit wound repair in a scrape model of injured epithelium. We have previously shown that mutation of the invariant arginine of the GAP domain to lysine (R149K) results in complete loss of GAP activity in vitro but only partially inhibits ExoT anti-internalization and cell rounding activity. We have constructed in-frame deletions and point mutations within the ADPRT domain in order to test whether this domain might account for the residual activity observed in ExoT GAP mutants. Deletion of a majority of the ADPRT domain (residues 234 to 438) or point mutations of the ADPRT catalytic site (residues 383 to 385) led to distinct changes in host cell morphology and substantially reduced the ability of ExoT to inhibit in vitro epithelial wound healing over a 24-h period. In contrast, only subtle effects on the efficiency of ExoT-induced bacterial internalization were observed in the ADPRT mutant forms. Expression of each domain individually in Saccharomyces cerevisiae was toxic, whereas expression of each of the catalytically inactive mutant domains was not. Collectively, these data demonstrate that the ADPRT domain of ExoT is active in vivo and contributes to the pathogenesis of P. aeruginosa infections.
TL;DR: 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.
TL;DR: Since relevant clinical outcomes correlate with rates of edema clearance in ALI, therapies based on the understanding of the mechanisms and regulation of fluid transport may be developed.
Abstract: 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.
TL;DR: H( 2)O(2) inhibits alveolar epithelial wound repair in large part by induction of apoptosis, which may be a promising new approach to improve repair of the alveolars epithelium in patients with acute lung injury.
Abstract: 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.
TL;DR: It is 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, and it was demonstrated that IgG receptor, FcgammaRIIa, is the receptor involved in cellular activation mediated by these complexes.
Abstract: 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...
TL;DR: DVI is more efficient than nasal inhalation and invasive intratracheal instillation for delivering experimental fluids into the distal airspaces of anesthetized mice and should be valuable for experimental lung studies in mice.
Abstract: 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 techniq...
TL;DR: The protein C system is markedly disrupted in patients with ALI/ARDS from both septic and nonseptic causes, and may be a therapeutic target in patientsWith this study, plasma protein C levels were lower in ALi/ARDS compared with normal controls, and lower levels were associated with worse clinical outcomes.
Abstract: 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.
TL;DR: The acetylcholine receptor modulates interactions between the nervous system and the immune system, and is now harnessed to dampen inflammation and reduce mortality in a mouse model of sepsis.
Abstract: The acetylcholine receptor modulates interactions between the nervous system and the immune system. An acetylcholine receptor agonist, nicotine, is now harnessed to dampen inflammation and reduce mortality in a mouse model of sepsis (
pages 1216–1221
).
TL;DR: New evidence generated from a mouse model of allergic airway hyperreactivity suggests that disordered coagulation and fibrinolysis may contribute to the pathogenesis of asthma.
Abstract: In several clinical disorders, there are interactions between inflammation-dependent tissue injury and thrombin formation, fibrin deposition, and impaired fibrinolysis. New evidence generated from a mouse model of allergic airway hyperreactivity suggests that disordered coagulation and fibrinolysis may contribute to the pathogenesis of asthma . The inflammatory mechanisms that lead to airway smooth muscle contraction and airway hyperresponsiveness may be associated with accumulation of extravascular fibrin, plasma exudates, and inflammatory cells that can lead to airway closure.
TL;DR: It is indicated 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.
Abstract: 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...
TL;DR: This study provides the first direct evidence that hydrostatic forces may contribute to the development of re-expansion pulmonary edema.
Abstract: 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.
TL;DR: A novel in vitro system can be used to measure net vectorial fluid transport across cultured, polarized alveolar epithelial cells using an air-liquid interface.
Abstract: 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 dif...
TL;DR: 4 practices that carry the potential to reduce the incidence of ventilator-associated pneumonia in patients receiving mechanical ventilation are reviewed, including variation in patient positioning, continuous aspiration of subglottic secretions, selective digestive tract decontamination, and the use of sucralfate.
Abstract: Ventilator-associated pneumonia (VAP) is a leading cause of morbidity and mortality in the intensive care unit (ICU). The incidence of VAP varies greatly, ranging from 6 to 52% of intubated patients depending on patient risk factors. The cumulative incidence is approximately 1-3% per day of intubation. Overall, VAP is associated with an attributable mortality of up to 30%. Attributable mortality approaches 50% when VAP is caused by the more virulent organisms that typify late-onset VAP (occurring 4 or more days into mechanical ventilation). The cost per episode of VAP is substantial, although specific data are lacking. The average cost per episode of nosocomial pneumonia is estimated at $3000 to $6000, and the additional length of stay for patients who develop VAP is estimated at 13 days. VAP is typically categorized as either early-onset VAP (occurring in the first 3-4 days of mechanical ventilation) or late-onset VAP. This distinction is important microbiologically. Early-onset VAP is commonly caused by antibiotic-sensitive community-acquired organisms (eg, Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus). Lateonset VAP is commonly caused by antibiotic-resistant nosocomial organisms (eg, Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, Acinetobacter species, and Enterobacter species). Most episodes of ventilator-associated pneumonia (VAP) are thought to develop from the aspiration of oropharyngeal secretions containing potentially pathogenic organisms. Aspiration of gastric secretions may also contribute, though likely to a lesser degree. Tracheal intubation interrupts the body’s anatomic and physiologic defenses against aspiration, making mechanical ventilation a major risk factor for VAP. This chapter reviews 4 practices that carry the potential to reduce the incidence of VAP in patients receiving mechanical ventilation. They are: variation in patient positioning, continuous aspiration of subglottic secretions, selective digestive tract decontamination, and the use of sucralfate.
TL;DR: Results indicate that the dual–ET receptor antagonist, Tezosentan, can attenuate the pulmonary hypertension induced by OA, and may be useful in the management of acute pulmonary arterial hypertension, complicating the course of OA-induced lung injury.
Abstract: The objective of this study was to evaluate the cardiopulmonary effects of a dual–endothelin (ET) receptor antagonist, Tezosentan, on oleic acid (OA)-induced acute lung injury with pulmonary arterial hypertension in dogs. Twelve pentobarbital-anesthetized dogs with intravenous OA-induced acute lung injury (ALI) were divided into 2 groups. The control group (n = 6) received saline treatment, whereas the treatment group (n = 6) received the ET receptor antagonist, Tezosentan (1 mg/kg intravenous [IV] + 1 mg/kg/h IV infusion). Cardiopulmonary parameters were monitored continuously for 1 hour. OA administration resulted in a significant increase in mean pulmonary arterial pressure (MPAP) and pulmonary vascular resistance (PVR) and a decrease in mean systemic arterial pressure (MSAP), systemic vascular resistance (SVR), and cardiac output (CO) in all dogs. Tezosentan treatment markedly attenuated the pulmonary hypertension, with a 32% decrease in MPAP (from 23±2 mm Hg to 15±2 mm Hg; P < .01) and a 22% decrease...
TL;DR: It is clear that trauma patients with ALI/ARDS have a low mortality rate compared with other clinical conditions that lead to ALi/ARDS, and the need for modification of standardized scores such as Acute Physiology and Chronic Health Evaluation III and Injury Severity Score may have affected the results.
Abstract: Major trauma has been recognized for many years as a significant clinical risk factor for the development of acute respiratory failure from acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS). However, the attributable mortality of ALI/ARDS in victims of major trauma has not been well studied. In this issue of Critical Care Medicine, Treggiari and co-investigators (1) from the University of Seattle examine the contribution of ALI/ARDS to mortality in the setting of major trauma. The results from this study were both interesting and somewhat unexpected. No increase in mortality could be ascribed to ALI/ARDS alone. Mortality was predicted by the Acute Physiology Score, the Injury Severity Score, and the patient’s age, but not by the presence of ALI/ARDS. This finding contrasts with an earlier study of patients enrolled from 1983 to 1985 by the same group at the University of Washington in Seattle (2). In the earlier study, trauma patients who developed ARDS had a higher mortality rate (58%) than those who did not develop ARDS (13%) (2). The authors of the current study refer to this previous work and identify both improvements in patient care and declining mortality rates in ALI/ARDS patients (3, 4) over the intervening 20 yrs to explain the results (1). Because the earlier study also included patients with other risk factors for ALI, such as sepsis, it may not have assessed the impact of ALI/ARDS exclusively from major trauma. As an interesting additional analysis, the current study divided the trauma patients with ALI/ARDS into subgroups based on the presence or absence of traumatic brain injury. The adjusted risks for mortality in the patients with brain injury and either ALI or ARDS were 0.6 and 0.62, respectively, although the confidence intervals were wide in both cases. The authors conclude that no additional risk for mortality was explained by brain injury alone. In contrast, a recent study from San Francisco General Hospital by Holland et al. (5) prospectively evaluated patients with severe brain injury alone and reported a significantly higher mortality rate in patients who ultimately developed ALI/ARDS, a finding that was independent of the Injury Severity Score as determined by multivariate analysis. The mortality rate was significantly higher in the San Francisco study, and ALI/ARDS was only directly responsible for 3/16 deaths (19%), suggesting that the patients in the San Francisco study were more severely ill (5). Further work is needed to help clarify the differences between the two studies regarding the relationship of traumatic brain injury and acute lung injury. Why is the development of ALI/ARDS in trauma patients not associated with an increase in mortality in the current study from Seattle (1)? Previous studies may not have adequately controlled for the severity of injury or the contribution of multiple comorbidities. Better management of critically ill patients may have also reduced mortality (3, 4). Alternatively, the need for modification of standardized scores such as Acute Physiology and Chronic Health Evaluation III and Injury Severity Score may have affected the results. Patients with ALI/ARDS often have worse chest physiology scores, which would be expected to contribute to excess mortality. Therefore, by eliminating the chest physiology scores in the current study, the results may have been biased toward the null value. Despite these issues, it is clear that trauma patients with ALI/ARDS have a low mortality rate compared with other clinical conditions that lead to ALI/ARDS. In a study examining the ARDS Network study population by clinical conditions that predisposed to ALI/ARDS, patients with trauma had the lowest mortality rate (11%) (6), similar to the current study in which ALI patients had a 9% mortality and ARDS patients had a 16% mortality (1). In prior work, higher mortality rates were reported for other predisposing conditions such as sepsis (43%), pneumonia (36%), and aspiration (37%) (6). Moreover, mortality for trauma patients with ALI/ARDS was similar, regardless of the ventilation strategy (11% vs. 12%), unlike other groups where low tidal volume ventilation was associated with lower mortality rates (6). Several experimental and clinical studies have identified an important role for both endothelial and epithelial injury in the pathophysiology of ALI/ARDS (7– 10). Interestingly, the severity of lung endothelial and alveolar epithelial injury in ALI/ARDS from major trauma appears to be less than that of other clinical disorders associated with lung injury. For example, Moss et al. (9) found that in patients with acute lung injury, plasma levels of von Willebrand factor and Eselectin, both markers of endothelial injury, were significantly elevated in patients with sepsis vs. patients with trauma. These investigators also measured soluble intercellular adhesion molecule-1, a biological marker of both endothelial and epithelial injury. Remarkably, the soluble intercellular adhesion molecule-1 levels in the trauma patients were not elevated above control patients (9). In an earlier study of ARDS patients, the majority of whom were trauma patients (65%), there was no significant difference in plasma E-selectin levels between patients who ultimately developed ARDS and those who did not (11). In addition to lung endothelial injury, several studies have provided morphologic, biochemical, and physiologic evidence for alveolar epithelial injury in ALI/ARDS (12). Recent work by Eisner et al. (13) examined plasma levels of a product of alveolar epithelial type II cells, surfactant protein D, in the patients who *See also p. 327.
TL;DR: In a multivariate analysis, BNP levels and these four radiographic findings provided additional diagnostic accuracy beyond all other clinical and radiographic variables combined.
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TL;DR: This issue of AJP–Lung Cellular and Molecular Physiology features a focus on articles that were submitted as a part of a call for papers on acute lung injury.
Abstract: this issue of AJP–Lung Cellular and Molecular Physiology features a focus on articles that were submitted as a part of a call for papers on acute lung injury. Considerable progress has been made in the last two decades to understand potential treatment modalities for acute lung injury. However,
TL;DR: Since the differentially expressed proteins play important roles in innate immunity and in pulmonary edema fluid clearance, the attenuated response of ATII after HTV ventilation might indicate a clinically relevant impediment.
Abstract: A proteomics approach to ventilator-induced lung injury might identify protein patterns that contribute to epithelial injury. To identify changes in alveolar type II cells (ATII), rats were mechanically ventilated for 5 hours with a high tidal volume (HTV; 20 ml/kg, no positive end expiratory pressure) or a low tidal volume (LTV; 6 ml/kg, positive end expiratory pressure 4 cmH2O) and compared with pooled controls without mechanical ventilation (SV). ATII were isolated and lysed. Protein expression was compared using the recently introduced cleavable isotope coded affinity tag (ICAT) methodology. After tryptic digestion, cysteine containing peptides were tagged with biotin, extracted using an avidin-coated column and identified by HPLC and mass spectrometry with collision-induced dissociation. Spectra were interrogated against the Swissprot database and quantified using the ProteinProspector software. HTV ventilation resulted in morphologic changes, pulmonary edema and neutrophil influx in the lung. Quantization showed differential expression of several hundred proteins following both HTV and LTV ventilation. Most proteins were upregulated by LTV ventilation compared with SV. For some proteins, upregulation was markedly attenuated after HTV compared with LTV. This was not true for ICAM-1, which correlated with the increased number of neutrophils in these samples. After HTV, surfactant proteins B and D followed different patterns. Since the differentially expressed proteins play important roles in innate immunity and in pulmonary edema fluid clearance, the attenuated response of ATII after HTV ventilation might indicate a clinically relevant impediment.
Figure 1
Table 1