Showing papers by "Michael A. Matthay published in 2009"

Higher versus Lower Positive End-Expiratory Pressures in Patients with the Acute Respiratory Distress Syndrome

Abstract: The members of the Writing Committee background Most patients requiring mechanical ventilation for acute lung injury and the acute res- piratory distress syndrome (ARDS) receive positive end-expiratory pressure (PEEP) of 5 to 12 cm of water. Higher PEEP levels may improve oxygenation and reduce ven- tilator-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 me- chanical 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 me- chanical 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 out- comes are similar whether lower or higher PEEP levels are used.

Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung.

Abstract: Recent studies have suggested that bone marrow-derived multipotent mesenchymal stem cells (MSCs) may have therapeutic applications in multiple clinical disorders including myocardial infarction, diabetes, sepsis, and hepatic and acute renal failure. Here, we tested the therapeutic capacity of human MSCs to restore alveolar epithelial fluid transport and lung fluid balance from acute lung injury (ALI) in an ex vivo perfused human lung preparation injured by E. coli endotoxin. Intra-bronchial instillation of endotoxin into the distal airspaces resulted in pulmonary edema with the loss of alveolar epithelial fluid transport measured as alveolar fluid clearance. Treatment with allogeneic human MSCs or its conditioned medium given 1 h following endotoxin-induced lung injury reduced extravascular lung water, improved lung endothelial barrier permeability and restored alveolar fluid clearance. Using siRNA knockdown of potential paracrine soluble factors, secretion of keratinocyte growth factor was essential for the beneficial effect of MSCs on alveolar epithelial fluid transport, in part by restoring amiloride-dependent sodium transport. In summary, treatment with allogeneic human MSCs or the conditioned medium restores normal fluid balance in an ex vivo perfused human lung injured by E. coli endotoxin.

Allogeneic human mesenchymal stem cells for treatment of E. Coli endotoxin-induced acute lung injury in an ex vivo perfused human lung

Abstract: Recent studies have suggested that bone marrow-derived multipotent mesenchymal stem cells (MSCs) may have therapeutic applications in multiple clinical disorders including myocardial infarction, diabetes, sepsis, and hepatic and acute renal failure. Here, we tested the therapeutic capacity of human MSCs to restore alveolar epithelial fluid transport and lung fluid balance from acute lung injury (ALI) in an ex vivo perfused human lung preparation injured by E. coli endotoxin. Intra-bronchial instillation of endotoxin into the distal airspaces resulted in pulmonary edema with the loss of alveolar epithelial fluid transport measured as alveolar fluid clearance. Treatment with allogeneic human MSCs or its conditioned medium given 1 h following endotoxin-induced lung injury reduced extravascular lung water, improved lung endothelial barrier permeability and restored alveolar fluid clearance. Using siRNA knockdown of potential paracrine soluble factors, secretion of keratinocyte growth factor was essential for the beneficial effect of MSCs on alveolar epithelial fluid transport, in part by restoring amiloride-dependent sodium transport. In summary, treatment with allogeneic human MSCs or the conditioned medium restores normal fluid balance in an ex vivo perfused human lung injured by E. coli endotoxin.

Platelet depletion and aspirin treatment protect mice in a two-event model of transfusion-related acute lung injury

Abstract: Transfusion-related acute lung injury (TRALI) is the leading cause of transfusion-associated mortality in the US. Previously, we established an immune-mediated TRALI mouse model, wherein mice with cognate antigen were challenged with MHC class I mAb. In this study, when mice housed in a rodent, specific pathogen-free barrier room were challenged with MHC I mAb, there was significant protection from TRALI compared with nonbarrier mice. Priming mice with LPS restored lung injury with mAb challenge. Using TLR4-deficient bone marrow chimeras, the priming phenotype was restricted to animals with WT hematopoietic cells, and depletion of either neutrophils or platelets was protective. Both neutrophils and platelets were sequestered in the lungs of mice with TRALI, and retention of platelets was neutrophil dependent. Interestingly, treatment with aspirin prevented lung injury and mortality, but blocking the P selectin or CD11b/CD18 pathways did not. These data suggest a 2-step mechanism of TRALI: priming of hematopoietic cells, followed by vascular deposition of activated neutrophils and platelets that then mediate the severe lung injury. Furthermore, our data offer an explanation for the increased incidence of TRALI in patients with immune priming conditions, and we suggest what we believe to be a novel therapeutic approach.

Recent trends in acute lung injury mortality: 1996-2005.

Abstract: OBJECTIVE:: Studies from single centers have suggested that mortality from acute lung injury (ALI) has declined over time. However, recent trends in ALI mortality from centers across the United States are unknown. Whether recent advances in the treatment of ALI or related critical illnesses have resulted in decreased mortality from ALI is not clear. METHODS:: In a study of 2,451 mechanically ventilated patients with ALI enrolled in the Acute Respiratory Distress Syndrome Network randomized controlled trials between 1996 and 2005, we evaluated whether there was a temporal improvement in 60-day mortality. We also investigated whether there were temporal improvements in mortality specific to individual causes of lung injury (pneumonia, sepsis, trauma, aspiration, and transfusion). RESULTS:: Crude mortality was 35% in 1996-1997 and declined during each subsequent time period to a low of 26% in 2004-2005 (test for trend p Language: en

Simvastatin Decreases Lipopolysaccharide-induced Pulmonary Inflammation in Healthy Volunteers

Abstract: Rationale: Simvastatin inhibits inflammatory responses in vitro and in murine models of lung inflammation in vivo. As simvastatin modulates a number of the underlying processes described in acute lung injury (ALI), it may be a potential therapeutic option.Objectives: To investigate in vivo if simvastatin modulates mechanisms important in the development of ALI in a model of acute lung inflammation induced by inhalation of lipopolysaccharide (LPS) in healthy human volunteers.Methods: Thirty healthy subjects were enrolled in a double-blind, placebo-controlled study. Subjects were randomized to receive 40 mg or 80 mg of simvastatin or placebo (n = 10/group) for 4 days before inhalation of 50 μg LPS. Measurements were performed in bronchoalveolar lavage fluid (BALF) obtained at 6 hours and plasma obtained at 24 hours after LPS challenge. Nuclear translocation of nuclear factor-κB (NF-κB) was measured in monocyte-derived macrophages.Measurements and Main Results: Pretreatment with simvastatin reduced LPS-induc...

Racial and ethnic disparities in mortality from acute lung injury

Abstract: Objective:Little is known about the influence of race and ethnicity on mortality from acute lung injury (ALI). We sought to determine whether black race or Hispanic ethnicity is independently associated with mortality among patients with ALI.Design:Retrospective cohort study of patients enrolled in

Potential application of mesenchymal stem cells in acute lung injury

Abstract: Despite extensive research into the pathogenesis of acute lung injury and the acute respiratory distress syndrome (ALI/ARDS), mortality remains high at approximately 40%. Current treatment is primarily supportive, with lung-protective ventilation and a fluid conservative strategy. Pharmacologic therapies that reduce the severity of lung injury in experimental studies have not yet been translated into effective clinical treatment options. Therefore, innovative therapies are needed. Recent studies have suggested that bone-marrow-derived multipotent mesenchymal stem cells (MSC) may have therapeutic applications in multiple clinical disorders including myocardial infarction, diabetes, sepsis, hepatic and acute renal failure. Recently, MSC have been studied in several in vivo models of lung disease. This review focuses on first describing the existing experimental literature that has tested the use of MSC in models of ALI/ARDS, and then the potential mechanisms underlying their therapeutic use with an emphasis on secreted paracrine soluble factors. The review concludes with a discussion of future research directions required for potential clinical trials.

NADPH Oxidase-1 Plays a Crucial Role in Hyperoxia-induced Acute Lung Injury in Mice

Abstract: Rationale: Hyperoxia-induced acute lung injury has been used for many years as a model of oxidative stress mimicking clinical acute lung injury and the acute respiratory distress syndrome. Excess quantities of reactive oxygen species (ROS) are responsible for oxidative stress–induced lung injury. ROS are produced by mitochondrial chain transport, but also by NADPH oxidase (NOX) family members. Although NOX1 and NOX2 are expressed in the lungs, their precise function has not been determined until now.Objectives: To determine whether NOX1 and NOX2 contribute in vivo to hyperoxia-induced acute lung injury.Methods: Wild-type and NOX1- and NOX2-deficient mice, as well as primary lung epithelial and endothelial cells, were exposed to room air or 100% O2 for 72 hours.Measurements and Main Results: Lung injury was significantly prevented in NOX1-deficient mice, but not in NOX2-deficient mice. Hyperoxia-dependent ROS production was strongly reduced in lung sections, in isolated epithelial type II cells, and lung e...

Soluble intercellular adhesion molecule-1 and clinical outcomes in patients with acute lung injury

Abstract: Objective To determine if levels of soluble intercellular adhesion molecule-1 (sICAM-1), a marker of alveolar epithelial and endothelial injury, differ in patients with hydrostatic pulmonary edema and acute lung injury (ALI) and are associated with clinical outcomes in patients with ALI.

Receptor for advanced glycation end-products (RAGE) is an indicator of direct lung injury in models of experimental lung injury

Abstract: Receptor for advanced glycation end-products (RAGE) is a marker of alveolar type I cells and is elevated in the pulmonary edema fluid of patients with acute lung injury (ALI). We tested the hypothesis that RAGE in the bronchoalveolar lavage (BAL) would be elevated in experimental models of direct ALI characterized by alveolar epithelial cell injury. We developed ELISA measurements for RAGE and studied ALI (direct and indirect) mouse models and collected BAL at specified endpoints to measure RAGE. We also tested whether levels of BAL RAGE correlated 1) with the severity of lung injury in acid and hyperoxia-induced ALI and 2) with the beneficial effect of a novel treatment, mesenchymal stem cells (MSC), in LPS-induced ALI. In ALI models of direct lung injury induced by intratracheal instillation of acid, LPS, or Escherichia coli, the BAL RAGE was 58-, 22-, and 13-fold elevated, respectively. In contrast, BAL RAGE was not detectable in indirect models of ALI induced by an intraperitoneal injection of thiourea or by an intravenous injection of MHC I monoclonal antibody that produces a mouse model of transfusion-related ALI. BAL RAGE did correlate with the severity of lung injury in acid and hyperoxia-induced ALI. In addition, with LPS-induced ALI, BAL RAGE was markedly reduced with MSC treatment. In summary, BAL RAGE is an indicator of ALI, and it may be useful in distinguishing direct from indirect models of ALI as well as assessing the response to specific therapies.

The pathogenetic and prognostic value of biologic markers in acute lung injury.

Abstract: Over the past 2 decades, measurement of biomarkers in both the airspaces and plasma early in the course of acute lung injury has provided new insights into the mechanisms of lung injury. In addition, biologic markers of cell-specific injury, acute inflammation, and altered coagulation correlate with mortality from acute lung injury in several single center studies as well as in multicenter clinical trials. To date, biomarkers have been measured largely for research purposes. However, with improved understanding of their role in the pathogenesis of acute lung injury, biomarkers may play an important role in early detection of lung injury, risk stratification for clinical trials, and, ultimately, tailoring specific therapies to individual patients. This article provides a review of biologic markers in acute lung injury, with an emphasis on recent analysis of results from multicenter clinical trials.

Measurement of extravascular lung water using the single indicator method in patients: research and potential clinical value.

Abstract: Extravascular lung water includes all of the fluid within the lung but outside of the vasculature. Lung water increases as a result of increased hydrostatic vascular pressure or from an increase in lung endothelial and epithelial permeability or both. Experimentally, extravascular lung water has been measured gravimetrically. Clinically, the chest radiograph is used to determine whether extravascular lung water is present but is an insensitive instrument for determining the quantity of lung water. Bedside measurement of extravascular lung water in patients is now possible using a single indicator thermodilution method. This review critically evaluates the experimental and clinical evidence supporting the potential value of measuring extravascular lung water in patients using the single indicator method.

Blood product transfusions and clinical outcomes in pediatric patients with acute lung injury

Abstract: Multiple transfusions are a known risk factor for the development of the acute respiratory distress syndrome (ARDS) in critically ill adult patients (1, 2). Several recent studies have investigated a possible association of red blood cell, platelet, and fresh-frozen plasma (FFP) transfusions with the development of acute lung injury (ALI) or with increased mortality in patients with ALI/ARDS. A large, randomized controlled trial of red blood cell transfusions in the intensive care unit suggested that adult patients who received a liberal strategy of red blood cell transfusions tended to have an increase in 30-day mortality, and an increased risk of developing ARDS (3). A prospective observational study of critically ill adults at risk for ARDS suggested that red blood cell transfusions were a risk factor for developing ARDS as well as for increased mortality in patients who did develop ARDS (4). A retrospective analysis of risk factors associated with the development of ALI/ARDS in critically ill adults identified that transfusions of FFP, platelets, or red blood cells were associated with an increased risk of developing ALI/ARDS, with the greatest risk being associated with FFP transfusions (5). In addition, FFP was implicated as a risk factor associated with the development of ALI in mechanically ventilated critical care adult patients (6). ALI is also an important problem in children, as recognized by the original description of ARDS in 1967 (7), as well as by a recent epidemiologic study of 328 children with ALI (8). Because red blood cell, platelet, and FFP transfusion may be associated with increased mortality in adult patients with ALI/ARDS, it is important to identify whether or not there is an association between outcomes and blood product transfusion in children with ALI/ARDS. To determine whether blood product transfusions were associated with adverse outcomes in pediatric patients with ALI/ARDS, we analyzed a large prospective database of children with ALI/ARDS (8). The epidemiology and clinical risk factors associated with death and prolonged mechanical ventilation in this cohort has been previously published (8). We tested the hypothesis that transfusions of packed red blood cells, platelets, and/or FFP within the first 72 hours after the diagnosis of ALI/ARDS were associated with increased mortality.

Protective mechanisms of activated protein C in severe inflammatory disorders

Abstract: The protein C system is an important natural anticoagulant mechanism mediated by activated protein C (APC) that regulates the activity of factors VIIIa and Va. Besides well-defined anticoagulant properties, APC also demonstrates anti-inflammatory, anti-apoptotic and endothelial barrier-stabilizing effects that are collectively referred to as the cytoprotective effects of APC. Many of these beneficial effects are mediated through its co-receptor endothelial protein C receptor, and the protease-activated receptor 1, although exact mechanisms remain unclear and are likely pleiotropic in nature. Increased insight into the structure–function relationships of APC facilitated design of APC variants that conserve cytoprotective effects and reduce anticoagulant features, thereby attenuating the risk of severe bleeding with APC therapy. Impairment of the protein C system plays an important role in acute lung injury/acute respiratory distress syndrome and severe sepsis. The pathophysiology of both diseases states involves uncontrolled inflammation, enhanced coagulation and compromised fibrinolysis. This leads to microvascular thrombosis and organ injury. Administration of recombinant human APC to correct the dysregulated protein C system reduced mortality in severe sepsis patients (PROWESS trial), which stimulated further research into its mechanisms of action. Several other clinical trials evaluating recombinant human APC have been completed, including studies in children and less severely ill adults with sepsis as well as a study in acute lung injury. On the whole, these studies have not supported the use of APC in these populations and challenge the field of APC research to search for additional answers. This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009

4G/5G Polymorphism of Plasminogen Activator Inhibitor -1 Gene Is Associated with Mortality in Intensive Care Unit Patients with Severe Pneumonia

Abstract: Background: Higher plasma and pulmonary edema fluid levels of plasminogen activator inhibitor-1 (PAI-1) are associated with increased mortality in patients with pneumonia and acute lung injury. The 4G allele of the 4G/5G polymorphism of the PAI-1 gene is associated with higher PAI-1 levels and an increased incidence of hospitalizations for pneumonia. The authors hypothesized that the 4G allele would be associated with worse clinical outcomes (mortality and ventilator-free days) in patients with severe pneumonia. Methods: The authors enrolled patients admitted with severe pneumonia in a prospective cohort. Patients were followed until hospital discharge. DNA was isolated from blood samples, and genotyping detection for the PAI-1 4G/5G polymorphism was carried out using Taqman-based allelic discrimination. Results: A total of 111 patients were available for analysis. Distribution of genotypes was 4G/4G 26 of 111 (23%), 4G/5G 59 of 111 (53%), and 5G/5G 26 of 111 (23%). Of 111 patients, 32 (29%) died before hospital discharge and 105 patients (94%) received mechanical ventilation. Patients with the 4G/4G and the 4G/5G genotypes had higher mortality (35% vs. 8%, P 0.007) and fewer ventilator-free days (median 4 vs. 13, P 0.04) compared to patients with the 5G/5G genotype. Conclusions: The 4G allele of the 4G/5G polymorphism in the PAI-1 gene is associated with fewer ventilator-free days and increased mortality in hospitalized patients with severe pneumonia. These findings suggest that PAI-1 may have a role in pathogenesis and that the 4G/5G polymorphism may be an important biomarker of risk in patients with severe pneumonia. PROCOAGULANT activity is increased and anticoagulant and fibrinolytic activities are decreased in the alveoli of patients with pneumonia. Intraalveolar fibrin deposition, which is the hallmark of many acute inflammatory lung diseases, including pneumonia, exerts beneficial effects by sealing leakage sites when the capillary endothelium and alveolar epithelial barrier are compromised. However, when this process of fibrin deposition is severe and persistent, it can have deleterious effects. Excessive fibrin deposition enhances inflammatory responses by activating endothelial cells to produce proinflammatory mediators and an increase in vascular permeability. Fibrin is degraded by plasmin, a proteolytic enzyme that is present in the tissues in the form of an inactive precursor, plasminogen. The decreased fibrinolysis in patients with pneumonia is mainly attributed to elevation in plasminogen activator inhibitor–1 (PAI-1) activity. 1– 8 PAI-1 is activated during infection and has been shown to be elevated in the air spaces of patients with ventilator-associated pneumonia, aspiration pneumonia, and acute lung injury. 2–5,8 –11 Higher plasma and bronchoalveolar lavage (BAL) fluid levels of PAI-1 levels are associated with severe disease and adverse clinical outcomes both in patients with pneumonia and in patients with the acute respiratory distress syndrome. In patients with pneumonia, PAI-1 concentration in BAL fluid is higher in patients requiring mechanical ventilation than in those who do not require

Higher pulmonary dead space may predict prolonged mechanical ventilation after cardiac surgery

Abstract: Children undergoing congenital heart surgery are at risk for prolonged mechanical ventilation and length of hospital stay. We investigated the prognostic value of pulmonary dead space fraction as a non-invasive, physiologic marker in this population. In a prospective, cross-sectional study, we measured pulmonary dead space fraction in 52 intubated, pediatric patients within 24 hr postoperative from congenital heart surgery. Measurements were obtained with a bedside, non-invasive cardiac output (NICO) monitor (Respironics Novametrix, Inc., Wallingford, CT). Median pulmonary dead space fraction was 0.46 (25-75% IQR 0.34-0.55). Pulmonary dead space fraction significantly correlated with duration of mechanical ventilation and length of hospital stay in the entire cohort (r(s) = 0.51, P = 0.0002; r(s) = 0.51, P = 0.0002) and in the subset of patients without residual intracardiac shunting (r(s) = 0.45, P = 0.008; r(s) = 0.49, P = 0.004). In a multivariable logistic regression model, pulmonary dead space fraction remained an independent predictor for prolonged mechanical ventilation in the presence of cardiopulmonary bypass time and ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen (OR 2.2; 95% CI 1.14-4.38; P = 0.02). The area under the receiver operator characteristic curve for this model was 0.91. Elevated pulmonary dead space fraction is associated with prolonged mechanical ventilation and hospital stay in pediatric patients who undergo surgery for congenital heart disease and has additive predictive value in identifying those at risk for longer duration of mechanical ventilation. Pulmonary dead space may be a useful prognostic tool for clinicians in patients who undergo congenital heart surgery.

Role of protease activated receptor 2 in experimental acute lung injury and lung fibrosis.

Abstract: Protease activated receptor 2 (PAR2) is widely-distributed (lung, liver, kidney, etc.) and expressed by variety of cells (i.e. leukocytes, epithelial cells, endothelial cells, and fibroblast). PAR2 may participate in many pathological processes, such as, inflammation, injury, as well as fibrosis. Therefore, in this study, we tested whether PAR2 would exert a role in acid-induced acute lung injury, E. coli pneumonia, bleomycin-induced acute lung injury and fibrosis. Acid, E. coli, or bleomycin were intratracheally instilled into the lungs of both wildtype and PAR2 knockout mice to detect differences in pulmonary edema, lung vascular permeability, lung fibrosis, and other parameters. Knockout of PAR2 did not affect the extent of pulmonary edema and lung vascular permeability in acid-induced acute lung injury. Also, both activation of PAR2 in the airspaces of the lung and deletion of PAR2 did not alter the magnitude of pulmonary edema and lung vascular permeability in E. coli pneumonia. Finally, PAR2 deficiency did not affect the severity of lung inflammation and lung fibrosis in bleomycin-induced acute lung injury and lung fibrosis models. Thus, PAR2 does not appear to play a critical role in the pathogeneses of experimental acid-induced acute lung injury, E. coli pneumonia, and bleomycin-induced acute lung injury and pulmonary fibrosis in mice.

Neutrophil sandwiches injure the microcirculation.

Abstract: Experiments in two mouse models of thromboinflammatory disease show how neutrophils stick to red blood cells and platelets—leading to reduced blood flow and damage to the microcirculation. Polarized expression of αMβ2 integrins on neutrophils helps set the process in motion (pages 384−391).

Role of coagulation pathways and treatment with activated protein C in hyperoxic lung injury

Abstract: Background: Activated protein C significantly decreases mortality in severe sepsis but its role in acute lung injury from non-infectious etiologies is unclear. We tested the role of activated protein C in hyperoxic acute lung injury by studying the physiology of lung injury development, measurement of key coagulation proteins, and treatment with murine activated protein C. Methods: Mice were continuously exposed to >95% oxygen and lung injury was assessed by extravascular lung water, lung vascular protein permeability, and alveolar fluid clearance. Coagulation proteins were measured in the plasma. Recombinant, murine activated protein C was administered in preventive and treatment strategies. Results: Hyperoxia produces dramatic increases in lung vascular permeability and extravascular lung water between 72 and 96 hours. Lung fluid balance is also adversely affected by progressive decreases in basal and cAMP-stimulated alveolar fluid clearance. Plasma activated protein C levels decrease beginning at 72 hours and are 90% depleted at 96 hours. There were no significant changes in plasma protein C, thrombomodulin, endothelial protein C receptor, plasminogen activator inhibitor-1, or thrombin-antithrombin complexes at later time points of hyperoxia. Lung thrombomodulin expression was severely decreased during late hyperoxia and activated protein C plasma levels were not restored by excess thrombin administration. Finally, administration of recombinant, murine activated protein C failed to improve indices of lung injury. Conclusions: Endogenous activated protein C plasma levels decrease with hyperoxic lung injury due to significant endothelial dysfunction, but replacement of murine activated protein C fails to improve lung injury.

A computational approach to understand in vitro alveolar morphogenesis.

Abstract: Primary human alveolar type II (AT II) epithelial cells maintained in Matrigel cultures form alveolar-like cysts (ALCs) using a cytogenesis mechanism that is different from that of other studied epithelial cell types: neither proliferation nor death is involved. During ALC formation, AT II cells engage simultaneously in fundamentally different, but not fully characterized activities. Mechanisms enabling these activities and the roles they play during different process stages are virtually unknown. Identifying, characterizing, and understanding the activities and mechanisms are essential to achieving deeper insight into this fundamental feature of morphogenesis. That deeper insight is needed to answer important questions. When and how does an AT cell choose to switch from one activity to another? Why does it choose one action rather than another? We report obtaining plausible answers using a rigorous, multi-attribute modeling and simulation approach that leveraged earlier efforts by using new, agent and object-oriented capabilities. We discovered a set of cell-level operating principles that enabled in silico cells to self-organize and generate systemic cystogenesis phenomena that are quantitatively indistinguishable from those observed in vitro. Success required that the cell components be quasi-autonomous. As simulation time advances, each in silico cell autonomously updates its environment information to reclassify its condition. It then uses the axiomatic operating principles to execute just one action for each possible condition. The quasi-autonomous actions of individual in silico cells were sufficient for developing stable cyst-like structures. The results strengthen in silico to in vitro mappings at three levels: mechanisms, behaviors, and operating principles, thereby achieving a degree of validation and enabling answering the questions posed. We suggest that the in silico operating principles presented may have a biological counterpart and that a semiquantitative mapping exists between in silico causal events and in vitro causal events.

Anti-chemokine autoantibody:chemokine immune complexes activate endothelial cells via IgG receptors.

Abstract: Our previous studies revealed that the presence in lung fluids of anti–IL-8 autoantibody:IL-8 immune complexes is an important prognostic indicator for the development and outcome of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). Anti–IL-8:IL-8 complexes purified from lung edema fluids trigger chemotaxis of neutrophils, induce activation of these cells, and regulate their apoptosis, all via IgG receptor, FcγRIIa. Importantly, increased levels of FcγRIIa are present in lungs of patients with ARDS, where FcγRIIa is partially associated with anti–IL-8:IL-8 complexes. In the current study, we demonstrate the ability of anti–IL-8:IL-8 complexes to promote an inflammatory phenotype of human umbilical vein endothelial cells via interaction with FcγRIIa. Human umbilical vein endothelial cells cultured in the presence of the complexes become activated, as shown by increased phosphorylation of ERK, JNK, and Akt, and augmented nuclear translocation of NF-κB. Anti–IL-8:IL-8 complexes also up-regu...

Early elevations in B-type natriuretic peptide levels are associated with poor clinical outcomes in pediatric acute lung injury.

Abstract: Objectives To determine B-type natriuretic peptide (BNP) levels in infants and children with acute lung injury (ALI), and to investigate associations between BNP levels and clinical outcome. Design Prospective observational study. Subjects After informed consent, plasma was collected from 48 pediatric patients on day 1 of ALI. Methodology Plasma BNP levels were measured by immunoassay on day 1 of ALI in 48 pediatric patients. Associations between BNP levels and outcome were determined. Results The mean PaO2/FiO2 at the onset of ALI was 155 (±74) and BNP values ranged from 5 to 2,060 pg/ml with a mean of 109 (±311). BNP levels were inversely correlated with ventilator-free days (Spearman rho −0.30, P = 0.04), and positively correlated with exhaled tidal volume (Spearman rho 0.44, P = 0.02). BNP levels were higher in patients receiving inotropic support (n = 12) than patients not receiving inotropic support (n = 33, P = 0.02). BNP levels were correlated with PRISM III scores (Spearman rho 0.55, P < 0.001) and PELOD scores (Spearman rho 0.4, P = 0.006). Mortality for the cohort was 15%. BNP levels were higher in non-survivors (n = 7) than survivors (n = 41, P = 0.055). Conclusions BNP levels are elevated in children with ALI/ARDS early in the disease course, and increased levels are associated with worse clinical outcome. Pediatr Pulmonol. 2009; 44:1118–1124. ©2009 Wiley-Liss, Inc.