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Results: 1 to 10 of 29

Publication Record


Endothelial-to-mesenchymal transition in lipopolysaccharide-induced acute lung injury drives a progenitor cell-like phenotype.
Suzuki T, Tada Y, Nishimura R, Kawasaki T, Sekine A, Urushibara T, Kato F, Kinoshita T, Ikari J, West J, Tatsumi K
(2016) Am J Physiol Lung Cell Mol Physiol 310: L1185-98
MeSH Terms: Acute Lung Injury, Animals, Apoptosis, Cell Proliferation, Cell Transdifferentiation, Cells, Cultured, Endothelial Progenitor Cells, Endothelium, Vascular, Female, Gene Expression, Lipopolysaccharides, Mice, Inbred C57BL, NADPH Oxidases, Phenotype, Reactive Oxygen Species, Transforming Growth Factor beta1, Transforming Growth Factor beta2
Show Abstract · Added April 2, 2019
Pulmonary vascular endothelial function may be impaired by oxidative stress in endotoxemia-derived acute lung injury. Growing evidence suggests that endothelial-to-mesenchymal transition (EndMT) could play a pivotal role in various respiratory diseases; however, it remains unclear whether EndMT participates in the injury/repair process of septic acute lung injury. Here, we analyzed lipopolysaccharide (LPS)-treated mice whose total number of pulmonary vascular endothelial cells (PVECs) transiently decreased after production of reactive oxygen species (ROS), while the population of EndMT-PVECs significantly increased. NAD(P)H oxidase inhibition suppressed EndMT of PVECs. Most EndMT-PVECs derived from tissue-resident cells, not from bone marrow, as assessed by mice with chimeric bone marrow. Bromodeoxyuridine-incorporation assays revealed higher proliferation of capillary EndMT-PVECs. In addition, EndMT-PVECs strongly expressed c-kit and CD133. LPS loading to human lung microvascular endothelial cells (HMVEC-Ls) induced reversible EndMT, as evidenced by phenotypic recovery observed after removal of LPS. LPS-induced EndMT-HMVEC-Ls had increased vasculogenic ability, aldehyde dehydrogenase activity, and expression of drug resistance genes, which are also fundamental properties of progenitor cells. Taken together, our results demonstrate that LPS induces EndMT of tissue-resident PVECs during the early phase of acute lung injury, partly mediated by ROS, contributing to increased proliferation of PVECs.
Copyright © 2016 the American Physiological Society.
0 Communities
1 Members
0 Resources
MeSH Terms
Cell-free hemoglobin: a novel mediator of acute lung injury.
Shaver CM, Upchurch CP, Janz DR, Grove BS, Putz ND, Wickersham NE, Dikalov SI, Ware LB, Bastarache JA
(2016) Am J Physiol Lung Cell Mol Physiol 310: L532-41
MeSH Terms: Acute Lung Injury, Alveolar Epithelial Cells, Animals, Biomarkers, Cell Line, Cell Membrane Permeability, Cytokines, Hemoglobins, Humans, Lipopolysaccharides, Lung, Mice, Inbred C57BL, Respiratory Distress Syndrome, Adult
Show Abstract · Added February 17, 2016
Patients with the acute respiratory distress syndrome (ARDS) have elevated levels of cell-free hemoglobin (CFH) in the air space, but the contribution of CFH to the pathogenesis of acute lung injury is unknown. In the present study, we demonstrate that levels of CFH in the air space correlate with measures of alveolar-capillary barrier dysfunction in humans with ARDS (r = 0.89, P < 0.001) and in mice with ventilator-induced acute lung injury (r = 0.89, P < 0.001). To investigate the specific contribution of CFH to ARDS, we studied the impact of purified CFH in the mouse lung and on cultured mouse lung epithelial (MLE-12) cells. Intratracheal delivery of CFH in mice causes acute lung injury with air space inflammation and alveolar-capillary barrier disruption. Similarly, in MLE-12 cells, CFH increases proinflammatory cytokine expression and increases paracellular permeability as measured by electrical cell-substrate impedance sensing. Next, to determine whether these effects are mediated by the iron-containing heme moiety of CFH, we treated mice with intratracheal hemin, the chloride salt of heme, and found that hemin was sufficient to increase alveolar permeability but failed to induce proinflammatory cytokine expression or epithelial cell injury. Together, these data identify CFH in the air space as a previously unrecognized driver of lung epithelial injury in human and experimental ARDS and suggest that CFH and hemin may contribute to ARDS through different mechanisms. Interventions targeting CFH and heme in the air space could provide a new therapeutic approach for ARDS.
Copyright © 2016 the American Physiological Society.
0 Communities
2 Members
0 Resources
13 MeSH Terms
Regulation of alveolar procoagulant activity and permeability in direct acute lung injury by lung epithelial tissue factor.
Shaver CM, Grove BS, Putz ND, Clune JK, Lawson WE, Carnahan RH, Mackman N, Ware LB, Bastarache JA
(2015) Am J Respir Cell Mol Biol 53: 719-27
MeSH Terms: Acute Lung Injury, Animals, Blood Coagulation, Capillary Permeability, Disease Models, Animal, Epithelial Cells, Gene Expression, Hemorrhage, Lipopolysaccharides, Mice, Mice, Knockout, Myeloid Cells, Pulmonary Alveoli, Respiratory Distress Syndrome, Adult, Respiratory Mucosa, Thromboplastin
Show Abstract · Added February 12, 2016
Tissue factor (TF) initiates the extrinsic coagulation cascade in response to tissue injury, leading to local fibrin deposition. Low levels of TF in mice are associated with increased severity of acute lung injury (ALI) after intratracheal LPS administration. However, the cellular sources of the TF required for protection from LPS-induced ALI remain unknown. In the current study, transgenic mice with cell-specific deletions of TF in the lung epithelium or myeloid cells were treated with intratracheal LPS to determine the cellular sources of TF important in direct ALI. Cell-specific deletion of TF in the lung epithelium reduced total lung TF expression to 39% of wild-type (WT) levels at baseline and to 29% of WT levels after intratracheal LPS. In contrast, there was no reduction of TF with myeloid cell TF deletion. Mice lacking myeloid cell TF did not differ from WT mice in coagulation, inflammation, permeability, or hemorrhage. However, mice lacking lung epithelial TF had increased tissue injury, impaired activation of coagulation in the airspace, disrupted alveolar permeability, and increased alveolar hemorrhage after intratracheal LPS. Deletion of epithelial TF did not affect alveolar permeability in an indirect model of ALI caused by systemic LPS infusion. These studies demonstrate that the lung epithelium is the primary source of TF in the lung, contributing 60-70% of total lung TF, and that lung epithelial, but not myeloid, TF may be protective in direct ALI.
0 Communities
2 Members
0 Resources
16 MeSH Terms
Clinical and biological heterogeneity in acute respiratory distress syndrome: direct versus indirect lung injury.
Shaver CM, Bastarache JA
(2014) Clin Chest Med 35: 639-53
MeSH Terms: Acute Lung Injury, Animals, Disease Models, Animal, Humans, Respiratory Distress Syndrome, Adult, Risk Factors
Show Abstract · Added January 28, 2015
The acute respiratory distress syndrome (ARDS) is a heterogeneous group of illnesses affecting the pulmonary parenchyma with acute onset bilateral inflammatory pulmonary infiltrates with associated hypoxemia. ARDS occurs after 2 major types of pulmonary injury: direct lung injury affecting the lung epithelium or indirect lung injury disrupting the vascular endothelium. Greater understanding of the differences between direct and indirect lung injury may refine the classification of patients with ARDS and lead to development of new therapeutics targeted at specific subpopulations of patients with ARDS.
Copyright © 2014 Elsevier Inc. All rights reserved.
0 Communities
1 Members
0 Resources
6 MeSH Terms
Differential role for p120-catenin in regulation of TLR4 signaling in macrophages.
Yang Z, Sun D, Yan Z, Reynolds AB, Christman JW, Minshall RD, Malik AB, Zhang Y, Hu G
(2014) J Immunol 193: 1931-41
MeSH Terms: Acute Lung Injury, Adaptor Proteins, Vesicular Transport, Animals, Bronchoalveolar Lavage Fluid, Catenins, Cells, Cultured, Endocytosis, Interferon Regulatory Factor-3, Interferon-beta, Interleukin-6, Leukocyte Count, Lipopolysaccharides, Macrophages, Alveolar, Male, Mice, Mice, Inbred C57BL, Myeloid Differentiation Factor 88, NF-kappa B, Neutrophils, Protein Transport, RNA Interference, Signal Transduction, Toll-Like Receptor 2, Toll-Like Receptor 3, Toll-Like Receptor 4, Tumor Necrosis Factor-alpha, rhoA GTP-Binding Protein
Show Abstract · Added May 2, 2016
Activation of TLR signaling through recognition of pathogen-associated molecular patterns is essential for the innate immune response against bacterial and viral infections. We have shown that p120-catenin (p120) suppresses TLR4-mediated NF-кB signaling in LPS-challenged endothelial cells. In this article, we report that p120 differentially regulates LPS/TLR4 signaling in mouse bone marrow-derived macrophages. We observed that p120 inhibited MyD88-dependent NF-κB activation and release of TNF-α and IL-6, but enhanced TIR domain-containing adapter-inducing IFN-β-dependent IFN regulatory factor 3 activation and release of IFN-β upon LPS exposure. p120 silencing diminished LPS-induced TLR4 internalization, whereas genetic and pharmacological inhibition of RhoA GTPase rescued the decrease in endocytosis of TLR4 and TLR4-MyD88 signaling, and reversed the increase in TLR4-TIR domain-containing adapter-inducing IFN-β signaling induced by p120 depletion. Furthermore, we demonstrated that altered p120 expression in macrophages regulates the inflammatory phenotype of LPS-induced acute lung injury. These results indicate that p120 functions as a differential regulator of TLR4 signaling pathways by facilitating TLR4 endocytic trafficking in macrophages, and support a novel role for p120 in influencing the macrophages in the lung inflammatory response to endotoxin.
Copyright © 2014 by The American Association of Immunologists, Inc.
1 Communities
1 Members
0 Resources
27 MeSH Terms
NF-κB inhibition after cecal ligation and puncture reduces sepsis-associated lung injury without altering bacterial host defense.
Li H, Han W, Polosukhin V, Yull FE, Segal BH, Xie CM, Blackwell TS
(2013) Mediators Inflamm 2013: 503213
MeSH Terms: Acute Lung Injury, Animals, Bacterial Infections, Cells, Cultured, I-kappa B Kinase, Imidazoles, Ligation, Macrophages, Mice, NF-kappa B, Neutrophils, Phagocytosis, Quinoxalines, Sepsis
Show Abstract · Added March 25, 2014
INTRODUCTION - Since the NF-κB pathway regulates both inflammation and host defense, it is uncertain whether interventions targeting NF-κB would be beneficial in sepsis. Based on the kinetics of the innate immune response, we postulated that selective NF-κB inhibition during a defined time period after the onset of sepsis would reduce acute lung injury without compromising bacterial host defense.
METHODS - Mice underwent cecal ligation and puncture (CLP). An NF-κB inhibitor, BMS-345541 (50 µg/g mice), was administered by peroral gavage beginning 2 hours after CLP and repeated at 6 hour intervals for 2 additional doses.
RESULTS - Mice treated with BMS-345541 after CLP showed reduced neutrophilic alveolitis and lower levels of KC in bronchoalveolar lavage fluid compared to mice treated with CLP+vehicle. In addition, mice treated with CLP+BMS had minimal histological evidence of lung injury and normal wet-dry ratios, indicating protection from acute lung injury. Treatment with the NF-κB inhibitor did not affect the ability of cultured macrophages to phagocytose bacteria and did not alter bacterial colony counts in blood, lung tissue, or peritoneal fluid at 24 hours after CLP. While BMS-345541 treatment did not alter mortality after CLP, our results showed a trend towards improved survival.
CONCLUSION - Transiently blocking NF-κB activity after the onset of CLP-induced sepsis can effectively reduce acute lung injury in mice without compromising bacterial host defense or survival after CLP.
1 Communities
2 Members
0 Resources
14 MeSH Terms
Lung ventilation strategies and regional lung inflammation.
Luan L, Hernandez A, Sherwood ER
(2013) Crit Care 17: 184
MeSH Terms: Acute Lung Injury, Animals, Respiration, Artificial
Show Abstract · Added October 18, 2015
Protective mechanical ventilation is currently accepted as a key strategy for the management of acute lung injury (ALI) and its most severe form, acute respiratory distress syndrome. The study by de Prost and colleagues in the current issue of Critical Care provides new insights into the impact of ventilation strategies on pulmonary function, gas exchange, and regional cellular metabolic activity during early ALI in sheep. The group reports that a protective ventilation strategy may attenuate neutrophil activation in dependent lung regions during early experimental ALI. This is an innovative report that provides the basis for further study.
0 Communities
1 Members
0 Resources
3 MeSH Terms
β-Catenin and CCNs in lung epithelial repair.
Lawson WE, Blackwell TS
(2013) Am J Physiol Lung Cell Mol Physiol 304: L579-81
MeSH Terms: Acute Lung Injury, Animals, CCN Intercellular Signaling Proteins, Cysteine-Rich Protein 61, Female, Humans, Proto-Oncogene Proteins, Respiratory Mucosa, Transendothelial and Transepithelial Migration, beta Catenin
Added March 7, 2014
1 Communities
2 Members
0 Resources
10 MeSH Terms
NADPH oxidase and Nrf2 regulate gastric aspiration-induced inflammation and acute lung injury.
Davidson BA, Vethanayagam RR, Grimm MJ, Mullan BA, Raghavendran K, Blackwell TS, Freeman ML, Ayyasamy V, Singh KK, Sporn MB, Itagaki K, Hauser CJ, Knight PR, Segal BH
(2013) J Immunol 190: 1714-24
MeSH Terms: Acute Lung Injury, Animals, Cell Line, Tumor, Disease Models, Animal, Human Umbilical Vein Endothelial Cells, Humans, Inflammation Mediators, Intubation, Intratracheal, Male, Mice, Mice, 129 Strain, Mice, Inbred C57BL, Mice, Knockout, NADPH Oxidases, NF-E2-Related Factor 2, Neutrophil Infiltration, Neutrophils
Show Abstract · Added March 13, 2014
Recruitment of neutrophils and release of reactive oxygen species are considered to be major pathogenic components driving acute lung injury (ALI). However, NADPH oxidase, the major source of reactive oxygen species in activated phagocytes, can paradoxically limit inflammation and injury. We hypothesized that NADPH oxidase protects against ALI by limiting neutrophilic inflammation and activating Nrf2, a transcriptional factor that induces antioxidative and cytoprotective pathways. Our objective was to delineate the roles of NADPH oxidase and Nrf2 in modulating acute lung inflammation and injury in clinically relevant models of acute gastric aspiration injury, a major cause of ALI. Acid aspiration caused increased ALI (as assessed by bronchoalveolar lavage fluid albumin concentration) in both NADPH oxidase-deficient mice and Nrf2(-/-) mice compared with wild-type mice. NADPH oxidase reduced airway neutrophil accumulation, but Nrf2 decreased ALI without affecting neutrophil recovery. Acid injury resulted in a 120-fold increase in mitochondrial DNA, a proinflammatory and injurious product of cellular necrosis, in cell-free bronchoalveolar lavage fluid. Pharmacologic activation of Nrf2 by the triterpenoid 1-[2-cyano-3-,12-dioxooleana-1,9 (11)-dien-28-oyl]imidazole limited aspiration-induced ALI in wild-type mice and reduced endothelial cell injury caused by mitochondrial extract-primed human neutrophils, leading to the conclusion that NADPH oxidase and Nrf2 have coordinated, but distinct, functions in modulating inflammation and injury. These results also point to Nrf2 as a therapeutic target to limit ALI by attenuating neutrophil-induced cellular injury.
0 Communities
1 Members
0 Resources
17 MeSH Terms
Cecal ligation model of sepsis in mice: new insights.
Bastarache JA, Matthay MA
(2013) Crit Care Med 41: 356-7
MeSH Terms: Acute Lung Injury, Animals, Cause of Death, Female, Mice, Respiratory Distress Syndrome, Adult, Sepsis
Added May 19, 2014
0 Communities
1 Members
0 Resources
7 MeSH Terms