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

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.

Serotonin decreases alveolar epithelial fluid transport via a direct inhibition of the epithelial sodium channel.

Hypoxia and epithelial stretch that are commonly observed in patients with acute lung injury have been shown to promote the release of serotonin (5-hydroxytryptamine, 5-HT) in vitro. However, whether 5-HT contributes to the decrease of alveolar epithelial fluid transport, which is a hallmark of lung injury, is unknown. Thus, we investigated the effect of 5-HT on ion and fluid transport across the alveolar epithelium.

Potential application of mesenchymal stem cells in acute lung injury.

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.

Comparison of two non-bronchoscopic methods for evaluating inflammation in patients with acute hypoxaemic respiratory failure.

Introduction: The simple bedside method for sampling undiluted distal pulmonary edema fluid through a normal suction catheter (s-Cath) has been experimentally and clinically validated. However, there are no data comparing non-bronchoscopic bronchoalveolar lavage (mini-BAL) and s-Cath for assessing lung inflammation in acute hypoxaemic respiratory failure. We designed a prospective study in two groups of patients, those with acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and those with acute cardiogenic lung edema (ACLE), designed to investigate the clinical feasibility of these techniques and to evaluate inflammation in both groups using undiluted sampling obtained by s-Cath.

NADPH oxidase-1 plays a crucial role in hyperoxia-induced acute lung injury in mice.

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.

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

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.

Inhaled activated protein C: a novel therapy for acute lung injury?

Acute lung injury (ALI) is characterized by the presence of dysregulated coagulation and inflammation. Therefore, Waerhaug and colleagues hypothesized that administration of activated protein C (APC) via the inhaled route would be a novel and effective treatment for ALI. They demonstrated that inhaled APC improved oxygenation and lung aeration in a sheep model of lipopolysaccharide-induced ALI, but did not alter lung water or hemodynamics.

Protective mechanisms of activated protein C in severe inflammatory disorders.

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.

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

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.

Mesenchymally "stemming" angiogenesis.

In this issue of , Otsu and colleagues provide evidence that high concentrations of bone marrow–derived MSCs have the capacity to induce endothelial cell apoptosis in culture and inhibit angiogenesis and tumor growth in murine melanomas.

4G/5G polymorphism of plasminogen activator inhibitor-1 gene is associated with mortality in intensive care unit patients with severe pneumonia.

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.

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

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.

Neutrophil sandwiches injure the microcirculation.

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 αβ integrins on neutrophils helps set the process in motion (pages 384−391).

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

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. We sought to determine whether recent advances in the treatment of ALI and related critical illnesses have resulted in decreased mortality from ALI.

Simvastatin decreases lipopolysaccharide-induced pulmonary inflammation in healthy volunteers.

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.

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

Objective: There are data suggesting that blood product transfusions increase the risk of developing acute lung injury (ALI) in adults, and may be associated with increased mortality in adults with ALI. A possible association between transfusions and adverse outcomes of pediatric patients with ALI has not been studied previously. We tested the hypothesis that blood product transfusions to pediatric patients with ALI within the first 72 hours of the diagnosis would be associated with increased mortality and prolonged mechanical ventilation.

A computational approach to understand in vitro alveolar morphogenesis.

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.

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

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.

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

Protease activated receptor 2 (PAR2) is widely-distributed (lung, liver, kidney, etc.) and expressed by variety of cells (i.e.

Identification of early acute lung injury at initial evaluation in an acute care setting prior to the onset of respiratory failure.

Background: Despite being a focus of intensive investigation, acute lung injury (ALI) remains a major cause of morbidity and mortality. However, the current consensus definition impedes identification of patients with ALI before they require mechanical ventilation. To establish a definition of early ALI (EALI), we carried out a prospective cohort study to identify clinical predictors of progression to ALI.

Fatty acid transduction of nitric oxide signaling: nitrolinoleic acid mediates protective effects through regulation of the ERK pathway.

In vivo and in vitro studies revealed that nitroalkenes serve as protective mediators in the lung by inducing the cytoprotective enzyme heme oxygenase-1 (HO-1). Nitrolinoleic acid (LNO2) increased HO-1 mRNA, protein, and activity in cultured pulmonary epithelial cells treated with 5 to 50 microM LNO2 and in lungs of rats injected intraperitoneally with 2.6 mg/kg LNO2 twice daily for 20 days.

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

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, FcgammaRIIa. Importantly, increased levels of FcgammaRIIa are present in lungs of patients with ARDS, where FcgammaRIIa is partially associated with anti-IL-8:IL-8 complexes.

Racial and ethnic disparities in mortality from acute lung injury.

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 the Acute Respiratory Distress Syndrome Network randomized controlled trials.