Lynn M Schnapp

Hanyang University, Ansan, Gyeonggi, South Korea

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Publications (67)320.18 Total impact

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    ABSTRACT: Background:The association between HIV and emphysema remains incompletely understood. We sought to determine whether HIV is an independent risk factor for emphysema severity and whether markers of HIV severity and systemic biomarkers of inflammation (interleukin-6), altered coagulation (D-dimer) and immune activation (soluble CD14) are associated with emphysema. Methods:We performed a cross-sectional analysis of 114 HIV-infected and 89 HIV-uninfected participants in the Examinations of HIV-Associated Lung Emphysema study. Subjects underwent chest CT with blinded semi-quantitative interpretation of emphysema severity, distribution and type. We generated multivariable logistic regression models to determine the risk of HIV for radiographic emphysema, defined as >10% lung involvement. Similar analyses examined associations of plasma biomarkers, HIV RNA, and recent and nadir CD4 cell counts with emphysema among HIV-infected subjects. Results:HIV-infected individuals had greater radiographic emphysema severity with increased lower lung zone and diffuse involvement. HIV was associated with significantly increased risk for >10% emphysema in analyses adjusted for cigarette smoking pack-years (OR 2.24; 95% CI, 1.12 - 4.48). In multivariable analyses restricted to HIV-infected individuals, nadir CD4 <200 (OR 2.98; 95% CI, 1.14 - 7.81) and high soluble CD14 (upper 25th percentile) (OR 2.55; 95% CI, 1.04 - 6.22) were associated with increased risk of >10% emphysema. Interleukin-6 and D-dimer were not associated with emphysema in HIV. Conclusions:HIV is an independent risk factor for radiographic emphysema. Emphysema severity was significantly greater among HIV-infected individuals. Among those with HIV, nadir CD4 <200 and elevated soluble CD14 were associated with emphysema, highlighting potential mechanisms linking HIV with emphysema.
    Chest 07/2014; · 7.13 Impact Factor
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    ABSTRACT: We provide a review of proteomic techniques used to characterize the bronchoalveolar lavage fluid (BALF) proteome of normal healthy subjects. Bronchoalveolar lavage (BAL) is the most common technique for sampling the components of the alveolar space. The proteomic techniques used to study normal BALF include protein separation by 2D gel electrophoresis whereby proteins were identified by comparison to a reference gel as well as high pressure liquid chromatography (HPLC)-tandem mass spectrometry technique, also known as shotgun proteomics. We summarize recent progress using shotgun MS technologies to define the normal BALF proteome. Surprisingly, we find that despite advances in shotgun proteomic technologies over the course of the last ten years, which have resulted in greater numbers of proteins being identified, the functional landscape of normal BALF proteome was similarly described by all methods examined. This article is protected by copyright. All rights reserved.
    PROTEOMICS - CLINICAL APPLICATIONS 02/2014; · 1.81 Impact Factor
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    ABSTRACT: Optimal skin wound healing relies on tight balance between collagen synthesis and degradation in new tissue formation and remodeling phases. The endocytic receptor uPARAP regulates collagen uptake and intracellular degradation. In this study we examined cutaneous wound repair response of uPARAP null (uPARAP-/-) mice. Full thickness wounds were created on dorsal surface of uPARAP-/- or their wildtype littermates. Wound healing evaluation was done by macroscopic observation, histology, gene transcription and biochemical analysis at specific intervals. We found that absence of uPARAP delayed re-epithelialization during wound closure, and altered stiffness of the scar tissue. Despite the absence of the uPARAP-mediated intracellular pathway for collagen degradation, there was no difference in total collagen content of the wounds in uPARAP-/- compared to wildtype mice. This suggests in the absence of uPARAP, a compensatory feedback mechanism functions to keep net collagen in balance.
    PLoS ONE 01/2014; 9(3):e92660. · 3.53 Impact Factor
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    ABSTRACT: Background: The lung is an important reservoir of human immunodeficiency virus (HIV). Individuals infected with HIV are more prone to pulmonary infections and chronic lung disorders. We hypothesized that comprehensively profiling the proteomic landscape of bronchoalveolar lavage fluid (BALF) in patients with HIV would provide insights into how this virus alters the lung milieu and contributes to pathogenesis of HIV-related lung diseases. Methods: BALF was obtained from five HIV-negative (HIV(-)) and six asymptomatic HIV-positive (HIV(+)) subjects not on anti-retroviral therapy (ART). Each sample underwent shotgun proteomic analysis based on HPLC-tandem mass spectrometry. Differentially expressed proteins between the groups were identified using statistical methods based on spectral counting. Mechanisms of disease were explored using functional annotation to identify overlapping and distinct pathways enriched between the BALF proteome of HIV(+) and HIV(-) subjects. Results: We identified a total of 318 unique proteins in BALF of HIV(-) and HIV(+) subjects. Of these, 87 were differentially up or down-regulated between the two groups. Many of these differentially expressed proteins are known to interact with key HIV proteins. Functional analysis of differentially regulated proteins implicated down-regulation of immune responses in lungs of HIV(+) patients. Conclusions: Combining shotgun proteomic analysis with computational methods demonstrated that the BALF proteome is significantly altered during HIV infection. We found that immunity-related pathways are under-represented in HIV+ patients. These findings implicate mechanisms whereby HIV invokes local immunosuppression in the lung and increases the susceptibility of HIV(+) patients to develop a wide range of infectious and noninfectious pulmonary diseases.
    AJP Lung Cellular and Molecular Physiology 11/2013; · 3.52 Impact Factor
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    ABSTRACT: IGF-1 is elevated in pulmonary fibrosis and acute lung injury, where fibroblast activation is a prominent feature. We previously demonstrated that blockade of IGF pathway in murine model of lung fibrosis improved outcome and decreased fibrosis. We now expand that study to examine effects of IGF pathway on lung fibroblast behaviors that could contribute to fibrosis. We first examined mice that express alphaSMA promoter upstream of GFP reporter treated with A12, a blocking antibody to IGF-1 receptor, after bleomycin induced lung injury. We then examined the effect of IGF-1 alone, or in combination with the pro-fibrotic cytokine TGFbeta on expression of markers of myofibroblast activation in vitro, including alphaSMA, collagen alpha1, type 1, collagen alpha1, type III, and TGFbeta expression. After bleomycin injury, we found decreased number of alphaSMA-GFP + cells in A12 treated mice, validated by alphaSMA immunofluorescent staining. We found that IGF-1, alone or in combination with TGF-beta, did not affect alphaSMA RNA expression, promoter activity, or protein levels when fibroblasts were cultured on stiff substrate. IGF-1 stimulated Col1a1 and Col3a1 expression on stiff substrate. In contrast, IGF-1 treatment on soft substrate resulted in upregulation of alphaSMA gene and protein expression, as well as Col1a1 and Col3a1 transcripts. In conclusion, IGF-1 stimulates differentiation of fibroblasts into a myofibroblast phenotype in a soft matrix environment and has a modest effect on alphaSMA stress fiber organization in mouse lung fibroblasts.
    Respiratory research 10/2013; 14(1):102. · 3.64 Impact Factor
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    ABSTRACT: Mentoring serves to guide early stage researchers toward opportunities which can further their careers. The most beneficial mentoring experience occurs when both the mentor and mentee share a common background and have appropriate expectations. Our CTSA serves individuals in a five state region with widely disparate needs and we have often struggled to provide appropriate guidance for those requesting mentoring services. Here we present an overview of our past mentor identification strategy along with a proposed new direction to increase flexibility, sustainability and better serve researchers in our region.
    Clinical and Translational Science 10/2013; 6(5):414-416. · 2.33 Impact Factor
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    ABSTRACT: Rationale: The origin of cells that make pathological fibrillar collagen matrix in lung disease has been controversial. Recent studies suggest mesenchymal cells may contribute directly to fibrosis. Objectives: 1) Characterize discrete populations of mesenchymal cells in the normal mouse lung and 2) map their fate after bleomycin-induced lung injury. Methods: We mapped the fate of Foxd1-expressing embryonic progenitors and their progeny during lung development, adult homeostasis and following fibrosing injury in Foxd1-Cre; Rs26-tdTomato-R mice. We studied Collagen-I(α)1 producing cells in normal and diseased lungs using Coll-GFPTg mice. Results: Foxd1 expressing embryonic progenitors enter lung buds before 13.5 days post conception, expand and form an extensive lineage of mesenchymal cells that have characteristics of pericytes. A Collagen-I(α)1-expressing mesenchymal population of distinct lineage is also found in adult lung, with features of a resident fibroblast. In contrast to resident fibroblasts, Foxd1 progenitor-derived pericytes are enriched in transcripts for innate immunity, vascular development, WNT signaling pathway and cell migration. Foxd1 progenitor-derived pericytes expand following bleomycin lung injury, activate expression of Collagen-I(α)1 and the myofibroblast marker αSMA in fibrotic foci. In addition, our studies suggest a distinct lineage of Collagen-I(α)1 expressing resident fibroblasts that also expands following lung injury, is a second major source of myofibroblasts. We conclude that the lung contains an extensive population of Foxd1 progenitor-derived pericytes that are an important lung myofibroblast precursor population.
    American Journal of Respiratory and Critical Care Medicine 08/2013; · 11.04 Impact Factor
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    ABSTRACT: Ventilator-associated pneumonia (VAP) is a common complication in patients with acute lung injury (ALI) and can lead to increased morbidity and mortality. Identifying protein profiles specific to VAP in bronchoalveolar lavage fluid (BALF) may aid in earlier diagnosis, elucidate mechanisms of disease, and identify putative targets for therapeutic intervention. BALF was obtained from 5 normal subjects and 30 ALI patients: 14 with VAP (VAP(+)) and 16 without VAP (VAP(-)). Each sample underwent shotgun proteomic analysis based on tandem mass spectrometry. Differentially expressed proteins between the groups were identified using statistical methods based on spectral counting. Mechanisms of disease were explored using functional annotation and protein interaction network analysis. Supervised classification algorithms were implemented to discover a proteomic classifier for identifying critically ill patients with VAP. ALI patients had distinct BALF proteomic profiles compared to normal controls. Within the ALI group, we identified 76 differentially expressed proteins between VAP(+) and VAP(-). Functional analysis of these proteins suggested activation of pro-inflammatory pathways during VAP. We identified and validated a limited proteomic signature that discriminated VAP(+) from VAP(-) patients comprised of three proteins: S100A8, lactotransferrin (LTF), and actinin 1 (ACTN1). Combining proteomic with computational analyses is a powerful approach to study the BALF proteome during lung injury and development of VAP. This integrative methodology is a promising strategy to differentiate clinically relevant subsets of ALI patients, including those suffering from VAP.
    PLoS ONE 01/2013; 8(3):e58782. · 3.53 Impact Factor
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    ABSTRACT: Translational behavioral medicine involves experts from different disciplines and professions interacting to solve complex problems. Coordinating this expertise can be frustrated by the partially tacit nature of expertise and by the various ways in which it manifests in different communities. We describe a method-the Toolbox dialogue method-for addressing these challenges by means of a structured dialogue among team members concerning their respective approaches to complex problems. The Toolbox dialogue method consists of a philosophically grounded questionnaire-the "Toolbox"-deployed in workshops by collaborators from different disciplines and professions. The Health Science Toolbox was modified from an extensively utilized questionnaire designed for Science-Technology-Engineering-Mathematics (STEM) research and has been piloted with translational medicine teams. Eighty-five percent of participants in STEM workshops indicated a positive impact on awareness of the knowledge, opinions, or scientific approach of teammates. In the Health Science Toolbox, 35 % of questionnaire responses changed substantially from pre- to post-workshop, demonstrating impact of the workshops. The Toolbox dialogue method is a relatively brief workshop encounter that can have a positive impact on mutual understanding within translational medicine teams.
    Translational behavioral medicine. 12/2012; 2(4):469-79.
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    ABSTRACT: Targeting cell populations via endogenous carbohydrate receptors is an appealing approach for drug delivery. However, to be effective, this strategy requires the production of high affinity carbohydrate ligands capable of engaging with specific cell-surface lectins. To develop materials that exhibit high affinity towards these receptors, we synthesized glycopolymers displaying pendent carbohydrate moieties from carbohydrate-functionalized monomer precursors via reversible addition-fragmentation chain transfer (RAFT) polymerization. These glycopolymers were fluorescently labeled and used to determine macrophage-specific targeting both in vitro and in vivo. Mannose- and N-acetylglucosamine-containing glycopolymers were shown to specifically target mouse bone marrow-derived macrophages (BMDMs) in vitro in a dose-dependent manner as compared to a galactose-containing glycopolymer (30- and 19-fold higher uptake, respectively). In addition, upon macrophage differentiation, the mannose glycopolymer exhibited enhanced uptake in M2-polarized macrophages, an anti-inflammatory macrophage phenotype prevalent in injured tissue. This carbohydrate-specific uptake was retained in vivo, as alveolar macrophages demonstrated 6-fold higher internalization of mannose glycopolymer, as compared to galactose, following intratracheal administration in mice. We have shown the successful synthesis of a class of functional RAFT glycopolymers capable of macrophage-type specific uptake both in vitro and in vivo, with significant implications for the design of future targeted drug delivery systems.
    Biomaterials 07/2012; 33(28):6889-97. · 8.31 Impact Factor
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    ABSTRACT: OBJECTIVE: To determine the utility of soluble Triggering Receptor Expressed on Myeloid cells-1 (sTREM-1) levels in bronchoalveolar lavage fluid (BALF) and exhaled breath condensate (EBC) samples from patients who underwent bronchoscopy for a clinical suspicion of ventilatorassociated pneumonia (VAP) to categorize patients as VAP positive and VAP negative when compared to quantitative culture results of BALF. DESIGN AND SETTING: Observational study conducted on admitted patients in the trauma-surgical, medical-cardiac, burn, and neurosurgical ICUs of Harborview Medical Center between March 2009 and May 2010. BALF and EBC samples were obtained from 45 patients with clinically suspected VAP. Bronchoscopy was performed on the day of clinically suspected VAP. METHODS: sTREM-1 levels in EBC and BAL fluid were measured using Quantikine Human TREM-1 Immunoassay. VAP was diagnosed by quantitative cultures of BALF. RESULTS: The concentrations of sTREM-1 in BALF and EBC did not correlate with VAP status. sTREM-1 levels did not discriminate VAP positive from VAP negative patients when compared to quantitative cultures of BALF as the ?gold standard?. Using a cutoff value of 204pg/ml for BALF sTREM-1 levels resulted in a sensitivity of 79% and specificity of 23%. A cutoff value of 10pg/ml for EBC sTREM-1 levels resulted in a sensitivity of 42% and specificity of 50%. CONCLUSIONS: EBC and BALF sTREM-1 levels did not effectively categorize patients as VAP positive or VAP negative when using direct bronchoscopic quantitative culture samples as the comparison standard.
    Respiratory care 05/2012; · 2.03 Impact Factor
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    ABSTRACT: Insulin-like growth factor (IGF)-1 is increased in different models of acute lung injury, and is an important determinant of survival and proliferation in many cells. We previously demonstrated that treatment of mice with IGF-1 receptor-blocking antibody (A12) improved early survival in bleomycin-induced lung injury. We have now examined whether administration of A12 improved markers of lung injury in hyperoxia model of lung injury. C57BL/6 mice underwent intraperitoneal administration of A12 or control antibody (keyhole limpet hemocyanin [KLH]), then were exposed to 95% hyperoxia for 88-90 hours. Mice were killed and bronchoalveolar lavage (BAL) and lung tissue were obtained for analysis. Hyperoxia caused a significant increase in IGF levels in BAL and lung lysates. Peripheral blood neutrophils expressed IGF-1R at baseline and after hyperoxia. BAL neutrophils from hyperoxia-treated mice and patients with acute lung injury also expressed cell surface IGF-1R. A12-treated mice had significantly decreased polymorphonuclear cell (PMN) count in BAL compared with KLH control mice (P = 0.02). BAL from A12-treated mice demonstrated decreased PMN chemotactic activity compared with BAL from KLH-treated mice. Pretreatment of PMNs with A12 decreased their chemotactic response to BAL from hyperoxia-exposed mice. Furthermore, IGF-1 induced a dose-dependent chemotaxis of PMNs. There were no differences in other chemotactic cytokines in BAL, including CXCL1 and CXCL2. In summary, IGF blockade decreased PMN recruitment to the alveolar space in a mouse model of hyperoxia. Furthermore, the decrease in BAL PMNs was at least partially due to a direct effect of A12 on PMN chemotaxis.
    American Journal of Respiratory Cell and Molecular Biology 04/2012; 47(3):372-8. · 4.15 Impact Factor
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    ABSTRACT: Abstract We recently reported a novel adhesion pathway in lymphocytes that is mediated by cyclin-dependent kinase (Cdk) 4 activity and mediates lymphocyte interactions with endothelial matrix. We now demonstrate that HIV-infected lymphocytes also use Cdk4 to mediate spontaneous adhesion to fibronectin and endothelial matrix. We further demonstrate that HIV-infected lymphocytes require Rap-1 activity for phorbol-stimulated adhesion. Understanding adhesion pathways used by HIV-infected lymphocytes may lead to interventions to regulate aberrant adhesion and migration.
    AIDS research and human retroviruses 03/2012; · 2.18 Impact Factor
  • Steven J Palazzo, Terri Simpson, Lynn M Schnapp
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    ABSTRACT: Excessive and unregulated inflammation contributes to multiorgan failure and death in sepsis. Triggering receptor expressed on myeloid cells type 1(TREM-1) is expressed on neutrophils and monocytes and is upregulated in the presence of bacterial pathogens. Engagement of TREM-1 results in increased expression of proinflammatory chemokines and cytokines and amplifies the inflammatory response. In this article, we will review the structure and signaling pathway of TREM-1 and review the role of TREM-1 and soluble TREM-1 in the inflammatory response during sepsis. Based on these studies, modulation of the TREM-1 signaling pathway has been suggested as a potential therapeutic strategy for the treatment of sepsis, to dampen the inflammatory response without interrupting the ability of the host to clear pathogens. This basic science research may someday lead to other treatments for sepsis and other diseases.
    Dimensions of critical care nursing: DCCN 01/2012; 31(1):1-6.
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    ABSTRACT: Cell surface mucins configure the cell surface by presenting extended protein backbones that are heavily O-glycosylated. The glycopeptide structures establish physicochemical properties at the cell surface that enable and block the formation of biologically important molecular complexes. Some mucins, such as MUC1, associate with receptor tyrosine kinases and other cell surface receptors, and engage in signal transduction in order to communicate information regarding conditions at the cell surface to the nucleus. In that context, the MUC1 cytoplasmic tail (MUC1CT) receives phosphorylation signals from receptor tyrosine kinases and serine/threonine kinases, which enables its association with different signaling complexes that conduct these signals to the nucleus and perhaps other subcellular organelles. We have detected the MUC1CT at promoters of over 500 genes, in association with several different transcription factors, and have shown that promoter occupancy can vary under different growth factor conditions. However, the full biochemical nature of the nuclear forms of MUC1 and its function at these promoter regions remain undefined. I will present evidence that nuclear forms of the MUC1CT include extracellular and cytoplasmic tail domains. In addition, I will discuss evidence for a hypothesis that the MUC1CT possesses a novel catalytic function that enables remodeling of the transcription factor occupancy of promoters, and thereby engages in regulation of gene expression.
    Glycobiology 11/2011; 21(11):1454-531. · 3.54 Impact Factor
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    ABSTRACT: Urokinase plasminogen activator receptor-associated protein (uPARAP, or Endo180) is a transmembrane endocytic receptor that mediates collagen internalization and degradation. uPARAP may be a novel pathway for collagen turnover and matrix remodeling in the lung. The function of uPARAP in lung injury has not been described. We analyzed the pulmonary mechanics of uPARAP(-/-) and wild-type mice at baseline and examined their response after bleomycin instillation. We compared collagen internalization in primary mouse lung fibroblasts (MLFs) from wild-type and uPARAP(-/-) mice using flow cytometry and fluorescent microscopy, and we examined the role of cytokines in regulating uPARAP expression and collagen internalization. We show that uPARAP is highly expressed in the lung, and that uPARAP(-/-) mice have increased lung elastance at baseline and after injury. uPARAP(-/-) mice are protected from changes in lung permeability after acute lung injury and have increased collagen content after bleomycin injury. uPARAP is the primary pathway for internalization of collagens in MLFs. Furthermore, collagen internalization through uPARAP does not require matrix metalloproteinase digestion and is independent of integrins. Mediators of lung injury, including transforming growth factor-β, TNF-α, and IL-1, down-regulate both uPARAP expression and collagen internalization. uPARAP is highly expressed in the murine lung, and loss of uPARAP leads to differences in lung mechanics, lung permeability, and collagen content after injury. uPARAP is required for collagen internalization by MLFs. Thus, uPARAP is a novel pathway that regulates matrix remodeling in the lung after injury.
    American Journal of Respiratory Cell and Molecular Biology 09/2011; 46(2):233-9. · 4.15 Impact Factor
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    ABSTRACT: Ventilator-associated pneumonia (VAP) contributes significantly to morbidity and mortality in critically ill patients, but it can be difficult to diagnose. Clinical criteria, Clinical Pulmonary Infection Score, and quantitative culture of bronchoalveolar lavage have been used to distinguish between patients who are likely positive (sensitivity) and patients who are likely negative (specificity). Despite these test methods, patients continue to be misclassified. False-positive results may lead to inappropriate antibiotic use in patients. For those misclassified as test negative, appropriate treatment may be delayed. Biomarkers have been suggested as another method to enhance the ability to predict VAP. This article analyzes the evidence for the usefulness of 3 biomarkers that have been proposed as possible biomarkers of VAP: soluble triggering receptor expressed on myeloid type 1 cells, procalcitonin, and C-reactive protein. A Medline search was conducted for the years between 1990 and 2009 to locate articles on the subject of biomarkers for predicting VAP in critically ill adult patients. Analysis of the literature does not currently support a clinical role for these biomarkers in predicting VAP. Variations in the diagnostic methods, antimicrobial use, cutoff values, and patient populations limit comparisons among the studies. Recommendations are offered to strengthen and standardize methods in future studies to clarify the utility of biomarkers for predicting VAP in specific patient populations.
    Heart & lung: the journal of critical care 03/2011; 40(4):293-8. · 1.04 Impact Factor
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    ABSTRACT: We recently described a new adhesion pathway in lymphocytes that is dependent on Cyclin-dependent kinase (Cdk) 4 activity and mediates lymphocyte interactions with endothelial matrix. We showed that Cdk4(-/-) mice had impaired recruitment of lymphocytes following bleomycin model of acute lung injury. In this study, we characterized the development and function of hematopoietic cells in Cdk4(-/-) mice and assessed the response of Cdk4(-/-) mice to allergen challenge. Cdk4(-/-) mice had hypoplastic thymuses with decreased total thymocyte cell numbers and increased CD4/CD8 double negative cells. Cdk4(-/-) bone marrow (BM) chimeric mice showed similar findings. Thymocytes from either Cdk4(-/-) or Cdk4(-/-) BM chimeric mice proliferated equally well as wild type controls in response to IL-2 activation. However Cdk4(-/-) thymocytes had decreased adhesion to both endothelial cell matrix and fibronectin compared to wildtype (WT) controls, whereas Cdk4(-/-) and WT splenocytes had similar adhesion. When Cdk4(-/-) BM chimeric mice and wild type BM chimeric mice were sensitized and challenged by intranasal administration of ovalbumin, we found no differences in allergic responses in the lung and airways between the two groups, as measured by inflammatory cell infiltrate, airway hyperreactivity, IgE levels and cytokine levels. In summary, we show that Cdk4 plays a previously unrecognized role in thymocyte maturation and adhesion, but is not required for thymocyte proliferation. In addition, Cdk4 is not required for lymphocyte trafficking to the lung following allergen sensitization and challenge.
    Cell cycle (Georgetown, Tex.) 12/2010; 9(24):4922-30. · 5.24 Impact Factor
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    ABSTRACT: We hypothesised that comparing the protein mixture in bronchoalveolar lavage fluid (BALF) between humans and mice may lead to mechanistic insights into common and divergent pathways that evolved in each species. BALF from four humans and six mice was pooled separately and underwent identical shotgun proteomic analysis. Functional and network analysis was applied to identify overlapping and distinct pathways enriched in the BALF. Follow-up experiments using Western analysis in unpooled BALF samples were performed. We identified 91 unique proteins in human and 117 unique proteins in mouse BALF samples. Functional analysis of the proteins revealed conservation of several key processes between the species, including defence response. Oxidative stress response, however, was selectively enriched only in mouse BALF. Differences in the expression of peroxiredoxin-1, a key member of the defence pathway against oxidative injury, were confirmed between normal human and mouse BALF and in models of lung injury. A computational proteomics approach of mouse and human BALF confirms the conservation of immune and defence-mediated pathways while highlighting differences in response to oxidative stress. These observations suggest that the use of mice models to study human lung disorders should be undertaken with an appreciation of interspecies variability.
    European Respiratory Journal 06/2010; 35(6):1388-95. · 6.36 Impact Factor
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    ABSTRACT: Prenatal inflammation prevents normal lung morphogenesis and leads to bronchopulmonary dysplasia (BPD), a common complication of preterm birth. We previously demonstrated in a bacterial endotoxin mouse model of BPD that disrupting fibronectin localization in the fetal lung mesenchyme causes arrested saccular airway branching. In this study we show that expression of the fibronectin receptor, integrin alpha8beta1 is decreased in the lung mesenchyme in the same inflammation model suggesting it is required for normal lung development. We verified a role for integrin alpha8beta1 in lung development using integrin alpha8-null mice, which develop fusion of the medial and caudal lobes as well as abnormalities in airway division. We further show in vivo and in vitro that alpha8-null fetal lung mesenchymal cells fail to form stable adhesions and have increased migration. Thus we propose that integrin alpha8beta1 plays a critical role in lung morphogenesis by regulating mesenchymal cell adhesion and migration. Furthermore, our data suggest that disruption of the interactions between extracellular matrix and integrin alpha8beta1 may contribute to the pathogenesis of BPD.
    Developmental Biology 09/2009; 335(2):407-17. · 3.87 Impact Factor

Publication Stats

1k Citations
320.18 Total Impact Points

Institutions

  • 2012
    • Hanyang University
      • Department of Medicine
      Ansan, Gyeonggi, South Korea
  • 2001–2012
    • University of Washington Seattle
      • • Division of Pulmonary and Critical Care Medicine
      • • Division of Hematology
      Seattle, WA, United States
  • 2011
    • Trinity Washington University
      Washington, Washington, D.C., United States
  • 1998–2005
    • Mount Sinai School of Medicine
      • • Department of Medicine
      • • Department of Pediatrics
      Manhattan, NY, United States
  • 1990–1996
    • University of California, San Francisco
      • • Cardiovascular Research Institute
      • • Division of Hospital Medicine
      San Francisco, CA, United States