PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-12 (12)
 

Clipboard (0)
None
Journals
Year of Publication
Document Types
1.  Therapeutic Effects of Human Mesenchymal Stem Cells in Ex Vivo Human Lungs Injured with Live Bacteria 
Rationale: Mesenchymal stem cells secrete paracrine factors that can regulate lung permeability and decrease inflammation, making it a potentially attractive therapy for acute lung injury. However, concerns exist whether mesenchymal stem cells’ immunomodulatory properties may have detrimental effects if targeted toward infectious causes of lung injury.
Objectives: Therefore, we tested the effect of mesenchymal stem cells on lung fluid balance, acute inflammation, and bacterial clearance.
Methods: We developed an Escherichia coli pneumonia model in our ex vivo perfused human lung to test the therapeutic effects of mesenchymal stem cells on bacterial-induced acute lung injury.
Measurements and Main Results: Clinical-grade human mesenchymal stem cells restored alveolar fluid clearance to a normal level, decreased inflammation, and were associated with increased bacterial killing and reduced bacteremia, in part through increased alveolar macrophage phagocytosis and secretion of antimicrobial factors. Keratinocyte growth factor, a soluble factor secreted by mesenchymal stem cells, duplicated most of the antimicrobial effects. In subsequent in vitro studies, we discovered that human monocytes expressed the keratinocyte growth factor receptor, and that keratinocyte growth factor decreased apoptosis of human monocytes through AKT phosphorylation, an effect that increased bacterial clearance. Inhibition of keratinocyte growth factor by a neutralizing antibody reduced the antimicrobial effects of mesenchymal stem cells in the ex vivo perfused human lung and monocytes grown in vitro injured with E. coli bacteria.
Conclusions: In E. coli–injured human lungs, mesenchymal stem cells restored alveolar fluid clearance, reduced inflammation, and exerted antimicrobial activity, in part through keratinocyte growth factor secretion.
doi:10.1164/rccm.201206-0990OC
PMCID: PMC3678109  PMID: 23292883
acute lung injury; bacterial pneumonia; cell-based therapy; keratinocyte growth factor
2.  Plasma Angiopoietin-2 Predicts the Onset of Acute Lung Injury in Critically Ill Patients 
Rationale: Current clinical prediction scores for acute lung injury (ALI) have limited positive predictive value. No studies have evaluated predictive plasma biomarkers in a broad population of critically ill patients or as an adjunct to clinical prediction scores.
Objectives: To determine whether plasma angiopoietin-2 (Ang-2), von Willebrand factor (vWF), interleukin-8 (IL-8), and/or receptor for advanced glycation end products (sRAGE) predict ALI in critically ill patients.
Methods: Plasma samples were drawn from critically ill patients (n = 230) identified in the emergency department. Patients who had ALI at baseline or in the subsequent 6 hours were excluded, and the remaining patients were followed for development of ALI.
Measurements and Main Results: Nineteen patients developed ALI at least 6 hours after the sample draw. Higher levels of Ang-2 and IL-8 were significantly associated with increased development of ALI (P = 0.0008, 0.004, respectively). The association between Ang-2 and subsequent development of ALI was robust to adjustment for sepsis and vasopressor use. Ang-2 and the Lung Injury Prediction Score each independently discriminated well between those who developed ALI and those who did not (area under the receiver operating characteristic curve, 0.74 for each), and using the two together improved the area under the curve to 0.84 (vs. 0.74, P = 0.05). In contrast, plasma levels of sRAGE and vWF were not predictive of ALI.
Conclusions: Plasma biomarkers such as Ang-2 can improve clinical prediction scores and identify patients at high risk for ALI. In addition, the early rise of Ang-2 emphasizes the importance of endothelial injury in the early pathogenesis of ALI.
doi:10.1164/rccm.201208-1460OC
PMCID: PMC3678110  PMID: 23328529
acute respiratory distress syndrome; acute lung injury; receptor for advanced glycation end products; angiopoietin-2; Lung Injury Prediction Score
3.  Active and Passive Cigarette Smoking and Acute Lung Injury after Severe Blunt Trauma 
Rationale: Cigarette smoking has been demonstrated in laboratory studies to have effects on lung epithelial and endothelial function similar to those observed in acute lung injury (ALI). However, the association between active and passive cigarette smoke exposure and susceptibility to ALI has not been prospectively studied.
Objectives: We hypothesized that both active and passive cigarette smoke exposure would be associated with increased susceptibility to ALI after severe blunt trauma.
Methods: We measured levels of cotinine, a metabolite of nicotine and validated biomarker of tobacco use, in plasma samples obtained immediately on arrival at the emergency department from 144 adult subjects after severe blunt trauma. Patients were then followed for the development of ALI.
Measurements and Main Results: Increasing quartiles of plasma cotinine were associated with the development of ALI (odds ratio [OR] for developing ALI in highest cotinine quartile, 3.25; 95% confidence interval [CI], 1.22–8.68; P = 0.017 for trend across quartiles). Moderate to heavy passive smoke exposure was associated with nearly the same odds of developing ALI as active smoking (OR for moderate to heavy passive smoking compared with no exposure or low level exposure, 3.03; 95% CI, 1.15–8.04; OR for active smoking, 2.77; 95% CI, 1.28–5.99). This association persisted after adjusting for other predictors of ALI, including Injury Severity Score and alcohol abuse.
Conclusions: Both moderate to heavy passive smoking and active smoking are independently associated with the development of ALI after severe blunt trauma. This finding has important implications both for public health and for understanding the pathogenesis of ALI.
doi:10.1164/rccm.201011-1802OC
PMCID: PMC3136993  PMID: 21471091
cigarette smoking; acute lung injury; acute respiratory distress syndrome; cotinine; secondhand smoke exposure
6.  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. 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 endothelial cells from NOX1-deficient mice. Concomitantly, lung cell death in situ and in primary cells was markedly decreased in NOX1-deficient mice. In wild-type mice, hyperoxia led to phosphorylation of c-Jun N-terminal kinase (JNK) and extracellular signal–regulated kinase (ERK), two mitogen-activated protein kinases involved in cell death signaling, and to caspase-3 activation. In NOX1-deficient mice, JNK phosphorylation was blunted, and ERK phosphorylation and caspase-3 activation were decreased.
Conclusions: NOX1 is an important contributor to ROS production and cell death of the alveolocapillary barrier during hyperoxia and is an upstream actor in oxidative stress–induced acute lung injury involving JNK and ERK pathways in mice.
doi:10.1164/rccm.200902-0296OC
PMCID: PMC2778156  PMID: 19661248
NADPH oxidase; reactive oxygen species; hyperoxia; apoptosis; mitogen-activated protein kinases
7.  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.
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-induced BALF neutrophilia, myeloperoxidase, tumor necrosis factor-α, matrix metalloproteinases 7, 8, and 9, and C-reactive protein (CRP) as well as plasma CRP (all P < 0.05 vs. placebo). There was no significant difference between simvastatin 40 mg and 80 mg. BALF from subjects post-LPS inhalation induced a threefold up-regulation in nuclear NF-κB in monocyte-derived macrophages (P < 0.001); pretreatment with simvastatin reduced this by 35% (P < 0.001).
Conclusions: Simvastatin has antiinflammatory effects in the pulmonary and systemic compartment in humans exposed to inhaled LPS.
Clinical trial registered with www.controlled-trials.com (ISRCTN21056528).
doi:10.1164/rccm.200810-1584OC
PMCID: PMC2695496  PMID: 19324974
cytokines; matrix metalloproteinases; endotoxin; nuclear factor-κB; simvastatin; acute lung injury
8.  Randomized Clinical Trial of Activated Protein C for the Treatment of Acute Lung Injury 
Rationale: Microvascular injury, inflammation, and coagulation play critical roles in the pathogenesis of acute lung injury (ALI). Plasma protein C levels are decreased in patients with acute lung injury and are associated with higher mortality and fewer ventilator-free days.
Objectives: To test the efficacy of activated protein C (APC) as a therapy for patients with ALI.
Methods: Eligible subjects were critically ill patients who met the American/European consensus criteria for ALI. Patients with severe sepsis and an APACHE II score of 25 or more were excluded. Participants were randomized to receive APC (24 μg/kg/h for 96 h) or placebo in a double-blind fashion within 72 hours of the onset of ALI. The primary endpoint was ventilator-free days.
Measurements and Main Results: APC increased plasma protein C levels (P = 0.002) and decreased pulmonary dead space fraction (P = 0.02). However, there was no statistically significant difference between patients receiving placebo (n = 38) or APC (n = 37) in the number of ventilator-free days (median [25–75% interquartile range]: 19 [0–24] vs. 19 [14–22], respectively; P = 0.78) or in 60-day mortality (5/38 vs. 5/37 patients, respectively; P = 1.0). There were no differences in the number of bleeding events between the two groups.
Conclusions: APC did not improve outcomes from ALI. The results of this trial do not support a large clinical trial of APC for ALI in the absence of severe sepsis and high disease severity.
Clinical trial registered with www.clinicaltrials.gov (NCT 00112164).
doi:10.1164/rccm.200803-419OC
PMCID: PMC2542435  PMID: 18565951
acute respiratory distress syndrome; acute lung injury; activated protein C; ventilator-free days; mortality
9.  Impact of Low and High Tidal Volumes on the Rat Alveolar Epithelial Type II Cell Proteome 
Rationale: Mechanical ventilation with high tidal volumes leads to increased permeability, generation of inflammatory mediators, and damage to alveolar epithelial cells (ATII).
Objectives: To identify changes in the ATII proteome after two different ventilation strategies in rats.
Methods: Rats (n = 6) were ventilated for 5 hours with high- and low tidal volumes (Vts) (high Vt: 20 ml/kg; low Vt: 6 ml/kg). Pooled nonventilated rats served as control animals. ATII cells were isolated and lysed, and proteins were tryptically cleaved into peptides. Cellular protein content was evaluated by peptide labeling of the ventilated groups with 18O. Samples were fractionated by cation exchange chromatography and identified using electrospray tandem mass spectrometry. Proteins identified by 15 or more peptides were statistically compared using t tests corrected for the false discovery rate.
Measurements and Main Results: High Vt resulted in a significant increase in airspace neutrophils without an increase in extravascular lung water. Compared with low-Vt samples, high-Vt samples showed a 32% decrease in the inositol 1,4,5-trisphosphate 3 receptor (p < 0.01), a 34% decrease in Na+, K+-ATPase (p < 0.01), and a significantly decreased content in ATP synthase chains. Even low-Vt samples displayed significant changes, including a 66% decrease in heat shock protein 90-β (p < 0.01) and a 67% increase in mitochondrial pyruvate carboxylase (p < 0.01). Significant differences were found in membrane, acute phase, structural, and mitochondrial proteins.
Conclusions: After short-term exposure to high-Vt ventilation, significant reductions in membrane receptors, ion channel proteins, enzymes of the mitochondrial energy system, and structural proteins in ATII cells were present. The data supports the two-hit concept that an unfavorable ventilatory strategy may make the lung more vulnerable to an additional insult.
doi:10.1164/rccm.200605-621OC
PMCID: PMC1899270  PMID: 17363773
acute lung injury; alveolar epithelium; corticosterone
10.  Higher Urine Nitric Oxide Is Associated with Improved Outcomes in Patients with Acute Lung Injury 
Rationale: Nitrogen oxide (NO) species are markers for oxidative stress that may be pathogenic in acute lung injury (ALI).
Objectives: We tested two hypotheses in patients with ALI: (1) higher levels of urine NO would be associated with worse clinical outcomes, and (2) ventilation with lower Vt would reduce urine NO as a result of less stretch injury.
Methods: Urine NO levels were measured by chemiluminescence in 566 patients enrolled in the National Heart Lung and Blood Institute Acute Respiratory Distress Syndrome Network trial of 6 ml/kg versus 12 ml/kg Vt ventilation. The data were expressed corrected and uncorrected for urine creatinine (Cr).
Results: Higher baseline levels of urine NO to Cr were associated with lower mortality (odds ratio, 0.43 per log(10) increase in the ratio), more ventilator-free days (mean increase, 1.9 d), and more organ-failure–free days (mean increase, 2.3 d) on multivariate analysis (p < 0.05 for all analyses). Similar results were obtained using urine NO alone. NO to Cr levels were higher on Day 3 in the 6 ml/kg than in the 12 ml/kg Vt group (p = 0.04).
Conclusions: Contrary to our hypothesis, higher urine NO was associated with improved outcomes in ALI at baseline and after treatment with the 6 ml/kg Vt strategy. Higher endogenous NO may reflect less severe lung injury and better preservation of the pulmonary and systemic endothelium or may serve a protective function in patients with ALI.
doi:10.1164/rccm.200607-947OC
PMCID: PMC1899263  PMID: 17082495
acute respiratory distress syndrome; nitrogen oxide species; pulmonary endothelium; tidal volume; pulmonary edema
11.  Receptor for Advanced Glycation End-Products Is a Marker of Type I Cell Injury in Acute Lung Injury 
Rationale: Receptor for advanced glycation end-products (RAGE) is one of the alveolar type I cell–associated proteins in the lung.
Objectives: To test the hypothesis that RAGE is a marker of alveolar epithelial type I cell injury.
Methods: Rats were instilled intratracheally with 10 mg/kg lipopolysaccharide or hydrochloric acid. RAGE levels were measured in the bronchoalveolar lavage (BAL) and serum in the rats and in the pulmonary edema fluid and plasma from patients with acute lung injury (ALI; n = 22) and hydrostatic pulmonary edema (n = 11).
Main Results: In the rat lung injury studies, RAGE was released into the BAL and serum as a single soluble isoform sized ∼ 48 kD. The elevated levels of RAGE in the BAL correlated well with the severity of experimentally induced lung injury. In the human studies, the RAGE level in the pulmonary edema fluid was significantly higher than the plasma level (p < 0.0001). The median edema fluid/plasma ratio of RAGE levels was 105 (interquartile range, 55–243). The RAGE levels in the pulmonary edema fluid from patients with ALI were higher than the levels from patients with hydrostatic pulmonary edema (p < 0.05), and the plasma RAGE level in patients with ALI were significantly higher than the healthy volunteers (p < 0.001) or patients with hydrostatic pulmonary edema (p < 0.05).
Conclusion: RAGE is a marker of type I alveolar epithelial cell injury based on experimental studies in rats and in patients with ALI.
doi:10.1164/rccm.200509-1477OC
PMCID: PMC2662912  PMID: 16456142
acute respiratory distress syndrome; alveolar epithelium; biological markers; pulmonary edema
12.  Leukotrienes in Acute Lung Injury 
doi:10.1164/rccm.2505008
PMCID: PMC2718469  PMID: 16040787

Results 1-12 (12)