William E Lawson

Vanderbilt University, Нашвилл, Michigan, United States

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Publications (69)367.71 Total impact

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    ABSTRACT: Secretory immunoglobulin A (SIgA) reaches the airway lumen by local transcytosis across airway epithelial cells or with tracheobronchial submucosal gland secretions. In chronic obstructive pulmonary disease (COPD), deficiency of SIgA on the airway surface has been reported. However, reduction of SIgA levels in sputum and bronchoalveolar lavage (BAL) fluid has not been consistently observed. To explain this discrepancy, we analyzed BAL fluid and lung tissue from patients with COPD and control subjects. Immunohistochemical analysis of large and small airways of COPD patients showed that MUC5AC is the predominant mucin expressed by airway epithelial cells, whereas MUC5B is expressed in submucosal glands of large airways. Dual immunostaining with anti-IgA and anti-MUC5B antibodies showed reduction of IgA on the airway surface as well as accumulation of IgA within MUC5B-positive luminal mucus plugs, suggesting that luminal SIgA originates from submucosal glands in COPD patients. We found that the concentration of SIgA in BAL is inversely correlated with forced expiratory volume in 1 s (FEV1) in COPD, but that the ratio of SIgA/MUC5B is a better predictor of FEV1, particularly in patients with moderate COPD. Together, these findings suggest that SIgA production by submucosal glands, which are expanded in COPD, is insufficient to compensate for reduced SIgA transcytosis by airway epithelial cells. Localized SIgA deficiency on the surface of small airways is associated with COPD progression and represents a potential new therapeutic target in COPD.
    Archiv für Pathologische Anatomie und Physiologie und für Klinische Medicin 10/2015; DOI:10.1007/s00428-015-1854-0 · 2.65 Impact Factor
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    ABSTRACT: 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) following intra-tracheal (IT) lipopolysaccharide (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 IT 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 levels at baseline and to 29% of wild-type levels after IT LPS. In contrast, there was no reduction of TF with myeloid cell TF deletion. Mice lacking myeloid cell TF (TF(Δmye)) did not differ from wild-type mice in coagulation, inflammation, permeability, or hemorrhage. However, mice lacking lung epithelial TF (TF(ΔLEpi)) had increased tissue injury, impaired activation of coagulation in the airspace, disrupted alveolar permeability, and increased alveolar hemorrhage after IT 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.
    American Journal of Respiratory Cell and Molecular Biology 04/2015; DOI:10.1165/rcmb.2014-0179OC · 3.99 Impact Factor
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    ABSTRACT: The aged population suffers increased morbidity and higher mortality in response to episodes of acute kidney injury (AKI). Aging is associated with telomere shortening, and both telomerase reverse transcriptase (TerT) and RNA (TerC) are essential to maintain telomere length. To define a role of telomerase deficiency in susceptibility to AKI, we used ischemia/reperfusion injury in wild-type mice or mice with either TerC or TerT deletion. Injury induced similar renal impairment at day 1 in each genotype, as assessed by azotemia, proteinuria, acute tubular injury score, and apoptotic tubular epithelial cell index. However, either TerC or TerT knockout significantly delayed recovery compared with wild-type mice. Electron microscopy showed increased autophagosome formation in renal tubular epithelial cells in wild-type mice but a significant delay of their development in TerC and TerT knockout mice. There were also impeded increases in the expression of the autophagosome marker LC3 II, prolonged accumulation of the autophagosome protein P62, an increase of the cell cycle regulator p16, and greater activation of the mammalian target of rapamycin (mTOR) pathway. The mTORC1 inhibitor, rapamycin, partially restored the ischemia/reperfusion-induced autophagy response, without a significant effect on either p16 induction or tubule epithelial cell proliferation. Thus, muting the maintenance of normal telomere length in mice impaired recovery from AKI, owing to an increase in tubule cell senescence and impairment of mTOR-mediated autophagy.Kidney International advance online publication, 11 March 2015; doi:10.1038/ki.2015.69.
    Kidney International 03/2015; 88(1). DOI:10.1038/ki.2015.69 · 8.56 Impact Factor

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    ABSTRACT: Background: Up to 20% of cases of idiopathic interstitial pneumonia (IIP) cluster in families, comprising the syndrome of Familial Interstitial Pneumonia (FIP); however, the genetic basis of FIP remains uncertain in a majority of families. We hypothesized that new disease-causing rare genetic variants could be identified using whole-exome sequencing of affected members from FIP families, providing additional insights into disease pathogenesis. Methods: Affected subjects from 25 kindreds were selected from an ongoing FIP registry for whole-exome sequencing (WES) from genomic DNA. Candidate rare variants were confirmed by Sanger sequencing and co-segregation analysis was performed in families, followed by additional sequencing of affected individuals from another163 kindreds. Results: We identified a potentially damaging rare variant in the gene encoding for regulator of telomere elongation helicase 1 (RTEL1) that segregated with disease and was associated with very short telomeres in peripheral blood mononuclear cells in one of 25 families in our original WES cohort. Evaluation of affected individuals in 163 additional kindreds revealed another 8 families (5%) with heterozygous rare variants in RTEL1 that segregated with clinical FIP. Probands and unaffected carriers of these rare variants had short telomeres (<10% for age) in peripheral blood mononuclear cells and increased T-circle formation, suggesting impaired RTEL1 function. Conclusions: Rare loss-of-function variants in RTEL1 represent a newly defined genetic predisposition for FIP, supporting the importance of telomere-related pathways in pulmonary fibrosis.
    American Journal of Respiratory and Critical Care Medicine 02/2015; 21(6). DOI:10.1164/rccm.201408-1510OC · 13.00 Impact Factor
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    ABSTRACT: Introduction: Asymptomatic relatives of patients with Familial Interstitial Pneumonia (FIP), the inherited form of Idiopathic Interstitial Pneumonia (IIP), carry increased risk for developing interstitial lung disease. Studying these at-risk individuals provides a unique opportunity to investigate early stages of FIP pathogenesis and develop predictive models of disease onset. Methods: Seventy-five asymptomatic first-degree relatives of FIP patients (mean age 50.8 years) underwent blood sampling and high-resolution chest CT (HRCT) scan in an ongoing cohort study; 72 consented to bronchoscopy with bronchoalveolar lavage (BAL) and transbronchial biopsies. Twenty-seven healthy individuals were used as controls. Results: Eleven of 75 at-risk subjects (14%) had evidence of interstitial changes by HRCT while 35.2% had abnormalities on transbronchial biopsies. No differences were noted in inflammatory cells in BAL between at-risk individuals and controls. At-risk subjects had increased herpesvirus DNA in cell-free BAL and evidence of herpesvirus antigen expression in alveolar epithelial cells (AECs), which correlated with expression of endoplasmic reticulum stress markers in AECs. Peripheral blood mononuclear cell and AEC telomere length were shorter in at-risk individuals than healthy controls. The minor allele frequency of the Muc5B rs35705950 promoter polymorphism was increased in at-risk subjects. Levels of several plasma biomarkers differed between at-risk subjects and controls, and correlated with abnormal HRCT scans. Conclusions: Evidence of lung parenchymal remodeling and epithelial dysfunction were identified in asymptomatic individuals at-risk for FIP. Together, these findings offer new insights into the early pathogenesis of IIP and provide an ongoing opportunity to characterize presymptomatic abnormalities that predict progression to clinical disease.
    American Journal of Respiratory and Critical Care Medicine 11/2014; 191(4). DOI:10.1164/rccm.201406-1162OC · 13.00 Impact Factor
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    American Journal of Respiratory and Critical Care Medicine 11/2014; · 13.00 Impact Factor
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    ABSTRACT: Short telomeres are frequently identified in patients with idiopathic pulmonary fibrosis (IPF) and its inherited form, familial interstitial pneumonia (FIP). We identified an FIP kindred with short telomeres who did not carry a mutation in known FIP genes TERT or hTR. We performed targeted sequencing of other telomere-related genes to identify the genetic basis of FIP in this kindred. DNA was isolated from peripheral blood mononuclear cells or paraffin-embedded lung block and PCR-based sequencing of DKC1, NOP10, TINF2 and NHP2 was performed. Peripheral blood mononuclear cell telomere length was measured by southern blot. Alveolar epithelial cell (AEC) telomere length was measured by fluorescence-in-situ-hydridization. Dyskerin and hTR expression in lymphoblastoid cell lines were measured by qPCR. The proband was a 69 year-old man with dyspnea, restrictive pulmonary function tests and reticular changes on high-resolution CT. An older male sibling had died from IPF. The proband had markedly shortened telomeres in peripheral blood and undetectably short telomeres in alveolar epithelial cells. Sequencing of dyskerin (DKC1) revealed that both affected siblings shared a novel A to G 1213 transition near the hTR binding domain that is predicted to encode a Thr405Ala amino acid substitution. hTR levels were decreased out of proportion to DKC1 expression in the T405A DKC1 proband, suggesting this mutation destabilizes hTR and impairs telomerase function. This DKC1 variant represents the third telomere-related gene identified as a genetic cause of FIP. Further investigation into mechanism by which dyskerin contributes to the development of lung fibrosis is warranted.
    Chest 02/2014; 146(1). DOI:10.1378/chest.13-2224 · 7.48 Impact Factor
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    ABSTRACT: Although in some cases clinical and radiographic features may be sufficient to establish a diagnosis of diffuse parenchymal lung disease (DPLD), surgical lung biopsy is frequently required. Recently a new technique for bronchoscopic lung biopsy has been developed using flexible cryo-probes. In this study we describe our clinical experience using bronchoscopic cryobiopsy for diagnosis of diffuse lung disease. A retrospective study of subjects who had undergone bronchoscopic cryobiopsy for evaluation of DPLD at an academic tertiary care center from January 1, 2012 through January 15, 2013 was performed. The procedure was performed using a flexible bronchoscope to acquire biopsies of lung parenchyma. H&E stained biopsies were reviewed by an expert lung pathologist. Twenty-five eligible subjects were identified. With a mean area of 64.2 mm(2), cryobiopsies were larger than that typically encountered with traditional transbronchial forceps biopsy. In 19 of the 25 subjects, a specific diagnosis was obtained. In one additional subject, biopsies demonstrating normal parenchyma were felt sufficient to exclude diffuse lung disease as a cause of dyspnea. The overall diagnostic yield of bronchoscopic cryobiopsy was 80% (20/25). The most frequent diagnosis was usual interstitial pneumonia (UIP) (n = 7). Three of the 25 subjects ultimately required surgical lung biopsy. There were no significant complications. In patients with suspected diffuse parenchymal lung disease, bronchoscopic cryobiopsy is a promising and minimally invasive approach to obtain lung tissue with high diagnostic yield.
    PLoS ONE 11/2013; 8(11):e78674. DOI:10.1371/journal.pone.0078674 · 3.23 Impact Factor
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    ABSTRACT: The median survival of patients with idiopathic pulmonary fibrosis continues to be approximately 3 years from the time of diagnosis, underscoring the lack of effective medical therapies for this disease. In the United States alone, approximately 40,000 patients die of this disease annually. In November 2012, the National Heart, Lung and Blood Institute held a workshop aimed at coordinating research efforts and accelerating the development of idiopathic pulmonary fibrosis therapies. Basic, translational and clinical researchers gathered with representatives from the National Heart Lung and Blood Institute, patient advocacy groups, pharmaceutical companies and the Food and Drug Administration to review the current state of idiopathic pulmonary fibrosis research and identify priority areas, opportunities for collaborations and directions for future research. The workshop was organized into groups that were tasked with assessing and making recommendations to promote progress in one of the following six critical areas of research: 1) biology of alveolar epithelial injury and aberrant repair, 2) role of extracellular matrix, 3) preclinical modeling, 4) the role of inflammation and immunity, 5) genetic, epigenetic and environmental determinants, 6) translation of discoveries into diagnostics and therapeutics. The workshop recommendations provide a basis for directing future research and strategic planning by scientific, professional and patient communities and the National Heart Lung and Blood Institute.
    American Journal of Respiratory and Critical Care Medicine 10/2013; 189(2). DOI:10.1164/rccm.201306-1141WS · 13.00 Impact Factor
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    ABSTRACT: PGI2 signaling through IP inhibits allergen-induced inflammatory responses in mice. We reported previously that PGI2 analogs decreased proinflammatory cytokine and chemokine production by mature BMDCs. However, whether PGI2 modulates the function of immature DCs has not been investigated. We hypothesized that PGI2 negatively regulates immature DC function and investigated the effect of PGI2 analogs on immature BMDC antigen uptake and migration in vitro and in vivo. Immature BMDCs were obtained from WT and IPKO mice, both on a C57BL/6 background. The PGI2 analog cicaprost decreased FITC-OVA uptake by immature BMDCs. In addition, cicaprost increased immature BMDC podosome dissolution, pro-MMP-9 production, cell surface CCR7 expression, and chemotactic migration toward CCL19 and CCL21, as well as chemokinesis, in an IP-specific fashion. These in vitro results suggested that cicaprost promotes migration of immature DCs from mucosal surface to draining LNs. This concept was supported by the finding that migration of immature GFP(+) BMDCs to draining LNs was enhanced by pretreatment with cicaprost. Further, migration of immature lung DCs labeled with PKH26 was enhanced by intranasal cicaprost administration. Our results suggest PGI2-IP signaling increases immature DC migration to the draining LNs and may represent a novel mechanism by which this eicosanoid inhibits immune responses.
    Journal of leukocyte biology 04/2013; 94(1). DOI:10.1189/jlb.1112559 · 4.29 Impact Factor
  • William E Lawson · Timothy S Blackwell ·
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    ABSTRACT: Not needed.
    AJP Lung Cellular and Molecular Physiology 03/2013; 304(9). DOI:10.1152/ajplung.00073.2013 · 4.08 Impact Factor
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    ABSTRACT: Interstitial lung fibrosis can develop as a consequence of occupational or medical exposures, as a result of genetic defects, following trauma or acute lung injury leading to fibroproliferative acute respiratory distress syndrome (ARDS) or can develop in an idiopathic manner. The pathogenesis of each of these forms of lung fibrosis is poorly understood. They each result in progressive loss of lung function with increasing dyspnea and ultimately, most forms result in mortality. To better understand the pathogenesis of lung fibrotic disorders, multiple animal models have been developed. This review summarizes common and emerging models of lung fibrosis to highlight their usefulness for understanding cell-cell and soluble mediator interactions which drive fibrotic responses. Recent advances have allowed for development of models to study targeted injury of type II alveolar epithelial cells, fibroblast autonomous effects and targeted genetic defects. Repetitive dosing in some models has more closely mimicked the pathology of human fibrotic lung disease. We also have a much better understanding of the fact that the aged lung increases susceptibility to fibrosis. Each of these models reviewed in this report offer a powerful tool to study some aspect of fibrotic lung disease.
    American Journal of Respiratory Cell and Molecular Biology 03/2013; 49(2). DOI:10.1165/rcmb.2013-0094TR · 3.99 Impact Factor
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    ABSTRACT: Aquaporin 11 (Aqp11) is a newly described member of the protein family of transport channels. Aqp11 associates with the endoplasmic reticulum (ER) and is highly expressed in proximal tubular epithelial cells in the kidney. Previously, we identified and characterized a recessive mutation of the highly conserved Cys227 to Ser227 in mouse Aqp11 that caused proximal tubule (PT) injury and kidney failure in mutant mice. The current study revealed induction of ER stress, unfolded protein response, and apoptosis as molecular mechanisms of this PT injury. Cys227Ser mutation interfered with maintenance of Aqp11oligomeric structure. Aqp11 is abundantly expressed in the S1 PT segment, a site of major renal glucose flux, and Aqp11 mutant mice developed PT-specific mitochondrial injury. Glucose increased Aqp11 protein expression in wild type kidney and up-regulation of Aqp11 expression by glucose in vitro was prevented by phlorizin, an inhibitor of sodium-dependent glucose transport across PT. Total Aqp11 levels in heterozygotes were higher than in wild type mice but were not further increased in response to glucose. In Aqp11 insufficient PT cells, glucose potentiated increases in reactive oxygen species (ROS) production. ROS production was also elevated in Aqp11 mutation carriers. Phenotypically normal mice heterozygous for the Aqp11 mutation repeatedly treated with glucose showed increased blood urea nitrogen levels that was prevented by the antioxidant sulforaphane or by phlorizin. Our results indicate an important role for Aqp11 to prevent glucose-induced oxidative stress in proximal tubules.
    AJP Renal Physiology 03/2013; 304(10). DOI:10.1152/ajprenal.00344.2012 · 3.25 Impact Factor
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    ABSTRACT: RATIONALE: Alveolar epithelial cells (AECs) play central roles in the response to lung injury and the pathogenesis of pulmonary fibrosis. OBJECTIVES: We aimed to determine the role of β-catenin in alveolar epithelium during bleomycin induced lung fibrosis. METHODS: Genetically modified mice were developed to selectively delete β-catenin in AECs and were crossed to cell fate reporter mice that express β-galactosidase (βgal) in cells of AEC lineage. Mice were given intratracheal bleomycin (0.04 units) and assessed for AEC death, inflammation, lung injury, and fibrotic remodeling. Mouse lung epithelial cells (MLE12) with siRNA knockdown of β-catenin underwent evaluation for wound closure, proliferation, and bleomycin induced cytotoxicity. MEASUREMENTS AND MAIN RESULTS: Increased β-catenin expression was noted in lung parenchyma following bleomycin. Mice with selective deletion of β-catenin in AECS had greater AEC death at 1 week following bleomycin, followed by increased numbers of fibroblasts and enhanced lung fibrosis as determined by semiquantitative histological scoring and total collagen content. However, no differences in lung inflammation or protein levels in bronchoalveolar lavage were noted. In vitro, β-catenin deficient AECs showed increased bleomycin induced cytotoxicity, as well as reduced proliferation and impaired wound closure. Consistent with these findings, mice with AEC β-catenin deficiency showed delayed recovery after bleomycin. CONCLUSIONS: β-catenin in the alveolar epithelium protects against bleomycin induced fibrosis. Our studies suggest that AEC survival and wound healing are enhanced through β-catenin dependent mechanisms. Activation of the developmentally important β-catenin pathway in AECs appears to contribute to epithelial repair following epithelial injury.
    American Journal of Respiratory and Critical Care Medicine 01/2013; 187(6). DOI:10.1164/rccm.201205-0972OC · 13.00 Impact Factor
  • Jonathan A Kropski · William E Lawson · Lisa R Young · Timothy S Blackwell ·
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    ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal lung disease for which there is no known treatment. Although the traditional paradigm of IPF pathogenesis emphasized chronic inflammation as the primary driver of fibrotic remodeling, more recent insights have challenged this view. Linkage analysis and candidate gene approaches have identified four genes that cause the inherited form of IPF, familial interstitial pneumonia (FIP). These four genes encode two surfactant proteins, surfactant protein C (encoded by SFTPC) and surfactant protein A2 (SFTPA2), and two components of the telomerase complex, telomerase reverse transcriptase (TERT) and the RNA component of telomerase (TERC). In this review, we discuss how investigating these mutations, as well as genetic variants identified in other inherited disorders associated with pulmonary fibrosis, are providing new insights into the pathogenesis of common idiopathic interstitial lung diseases, particularly IPF. Studies in this area have highlighted key roles for epithelial cell injury and dysfunction in the development of lung fibrosis. In addition, genetic approaches have uncovered the importance of several processes - including endoplasmic reticulum stress and the unfolded protein response, DNA-damage and -repair pathways, and cellular senescence - that might provide new therapeutic targets in fibrotic lung diseases.
    Disease Models and Mechanisms 01/2013; 6(1):9-17. DOI:10.1242/dmm.010736 · 4.97 Impact Factor
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    Harikrishna Tanjore · William E Lawson · Timothy S Blackwell ·
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    ABSTRACT: Current evidence suggests a prominent role for endoplasmic reticulum (ER) stress and activation of the unfolded protein response (UPR) in fibrotic conditions affecting a number of internal organs, including the lungs, liver, GI tract, kidney, and heart. ER stress enhances the susceptibility of structural cells, in most cases the epithelium, to pro-fibrotic stimuli. Studies suggest that ER stress facilitates fibrotic remodeling through activation of pro-apoptotic pathways, induction of epithelial-mesenchymal transition, and promotion of inflammatory responses. While genetic mutations that lead to ER stress underlie some cases of fibrosis, including lung fibrosis secondary to mutations in surfactant protein C (SFTPC), a variety of other factors can cause ER stress. These ER stress inducing factors include metabolic abnormalities, oxidative stress, viruses, and environmental exposures. Interestingly, the ability of the ER to maintain homeostasis under stress diminishes with age, potentially contributing to the fact that fibrotic disorders increase in incidence with aging. Taken together, underlying ER stress and UPR pathways are emerging as important determinants of fibrotic remodeling in different forms of tissue fibrosis. Further work is needed to better define the mechanisms by which ER stress facilitates progressive tissue fibrosis. In addition, it remains to be seen whether targeting ER stress and the UPR could have therapeutic benefit. This article is part of a Special Issue entitled: Fibrosis: Translation of basic research to human disease.
    Biochimica et Biophysica Acta 11/2012; 1832(7). DOI:10.1016/j.bbadis.2012.11.011 · 4.66 Impact Factor
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    ABSTRACT: Background: Systemic blockade of tissue factor (TF) attenuates acute lung injury (ALI) in animal models of sepsis but the effects of global TF deficiency are unknown. We used mice with complete knockout of mouse TF and low levels (∼1%) of human TF (LTF mice) to test the hypothesis that global TF deficiency attenuates lung inflammation in direct lung injury. Methods: LTF mice were treated with 10 μg of lipopolysaccharide (LPS) or vehicle administered by direct intratracheal injection and studied at 24 h. Results: Contrary to our hypothesis, LTF mice had increased lung inflammation and injury as measured by bronchoalveolar lavage cell count (3.4×10(5) wild-type (WT) LPS vs 3.3×10(5) LTF LPS, p=0.947) and protein (493 μg/ml WT LPS vs 1014 μg/ml LTF LPS, p=0.006), proinflammatory cytokines (TNF-α, IL-10, IL-12, p<0.035 WT LPS vs LTF LPS) and histology compared with WT mice. LTF mice also had increased haemorrhage and free haemoglobin in the airspace accompanied by increased oxidant stress as measured by lipid peroxidation products (F(2) isoprostanes and isofurans). Conclusions: These findings indicate that global TF deficiency does not confer protection in a direct lung injury model. Rather, TF deficiency causes increased intra-alveolar haemorrhage following LPS leading to increased lipid peroxidation. Strategies to globally inhibit TF may be deleterious in patients with ALI.
    Thorax 10/2012; 67(12). DOI:10.1136/thoraxjnl-2012-201781 · 8.29 Impact Factor

  • American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012

Publication Stats

2k Citations
367.71 Total Impact Points


  • 2004-2015
    • Vanderbilt University
      • • Department of Medicine
      • • Division of Allergy, Pulmonary and Critical Care
      Нашвилл, Michigan, United States
  • 2009-2013
    • U.S. Department of Veterans Affairs
      Washington, Washington, D.C., United States
  • 2007-2013
    • United States Department of Veterans Affairs
      Бедфорд, Massachusetts, United States
    • Johns Hopkins University
      Baltimore, Maryland, United States