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ABSTRACT: Asthma airway remodeling is linked to Th2 inflammation. Angiogenesis is a consistent feature of airway remodeling, but its contribution to pathophysiology remains unclear. We hypothesized that nascent endothelial cells in newly forming vessels are sufficient to initiate Th2-inflammation. Vascular endothelial (VE)-cadherin is a constitutively expressed endothelial cell adhesion molecule that is exposed in its monomer form on endothelial tip cells prior to adherens junction formation. Abs targeted to VE-cadherin monomers inhibit angiogenesis by blocking this adherens junction formation. In this study, VE-cadherin monomer Ab reduced angiogenesis in the lungs of the allergen-induced murine asthma model. Strikingly, Th2 responses including, IgE production, eosinophil infiltration of the airway, subepithelial fibrosis, mucus metaplasia, and airway-hyperreactivity were also attenuated by VE-cadherin blockade, via mechanisms that blunted endothelial IL-25 and proangiogenic progenitor cell thymic stromal lymphopoietin production. The results identify angiogenic responses in the origins of atopic inflammation.
The Journal of Immunology 02/2013; · 5.79 Impact Factor
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ABSTRACT: We tested the hypothesis that the artificial addition of heavy chains (HCs) from inter-α-inhibitor (IαI) to hyaluronan (HA), by adding recombinant tumor-necrosis-factor-induced-protein-6 (TSG-6) to the culturing media of murine airway smooth muscle (MASM) cells, would enhance leukocyte binding to HA cables produced in response to polyinosinic-polycytidylic acid (Poly(I:C)). As predicted, the addition of HCs to HA cables enhanced leukocyte adhesion to these cables, but it also had several unexpected effects: (i) It produced thicker, more pronounced, HA cables. (ii) It increased the accumulation of HA in the cell-associated matrix. and, (iii) It decreased the amount of HA in the conditioned media. Importantly, these effects were only observed when TSG-6 was administered in the presence of Poly(I:C) and did not exert any effect on its own. These phenomena occurred during active, Poly(I:C) - induced, HA synthesis, and did not occur when TSG-6 was added after Poly(I:C) - induced HA synthesis had completed. MASM cells derived from TSG-6 null, HAS1/3 null and CD44 null mice amplified HA synthesis in response to Poly(I:C) + TSG-6 in a manner similar to WT MASM, demonstrating that they are expendable in this process. We conclude that TSG-6 increases the accumulation of HA in the cell-associated matrix, partially by preventing its dissolution from the cell-associated matrix into the conditioned media, but primarily by also inducing HA synthesis.
Journal of Biological Chemistry 11/2012; · 4.77 Impact Factor
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ABSTRACT: Hyaluronan (HA) deposition is often correlated with mucosal inflammatory responses where HA mediates both protective as well as pathological responses. By modifying the HA matrix, tumor necrosis factor-alpha-induced protein-6 (Tnfip6; also known as tumor necrosis factor-stimulated gene-6 (TSG-6)), is thought to potentiate anti-inflammatory and anti-plasmin effects that are inhibitory to leukocyte extravasation. Our study examines the role of endogenous TSG-6 in the pathophysiological responses associated with acute allergic pulmonary inflammation. When compared to wild-type littermate controls, TSG-6-/- mice exhibited attenuated inflammation marked by a significant decrease of pulmonary HA concentrations measured in the bronchoalveolar lavage (BAL) and lung tissue. Interestingly, despite the equivalent induction of both humoral and cellular T helper type 2 (Th2) immunity, and the comparable levels of cytokines and chemokines typically associated with eosinophilic pulmonary inflammation, airway eosinophilia was significantly decreased in TSG-6-/- mice. Most importantly, contrary to their counterpart wild type littermates, TSG-6-/- mice were resistant to the induction of airway hyperresponsiveness (AHR) and manifested improved lung mechanics in response to methacholine challenge. Our study demonstrates that endogenous TSG-6 is dispensable for the induction of Th2 immunity, but is essential for the robust increase of pulmonary HA deposition, propagation of acute eosinophilic pulmonary inflammation, and the development of AHR. Thus, TSG-6 is implicated in the experimental murine model of allergic pulmonary inflammation and is likely to contribute to the pathogenesis of asthma.
Journal of Biological Chemistry 11/2012; · 4.77 Impact Factor
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ABSTRACT: Asthma is a chronic inflammatory disease that exhibits airway remodeling with changes in the extracellular matrix (ECM). The role of the ECM in mediating these changes is poorly understood. Hyaluronan (HA), a major component of the ECM, has been implicated in many biological processes in diseases. Our study investigates the processes involved in HA synthesis, deposition and localization during the propagation of cockroach-induced asthma. Mice were sensitized and challenged with cockroach antigen, and sacrificed at various time points during an 8-week challenge protocol. Analysis of bronchoalveolar lavage fluid (BAL) revealed an increase in total nucleated cells as early as 6 h, which peaked at 6 days. Histopathologic analysis of the lung tissue revealed an influx of inflammatory cells at the peribronchial and perivascular regions starting at 12 h, which peaked at 6 days and persisted to 8 weeks. Eosinophils predominated in the early time points while lymphocytes predominated during the late time points. QPCR data showed that hyaluronan synthase 1 (HAS1) mRNA peaked within 6 h and then declined. HAS2 mRNA also peaked within 6 h but remained elevated throughout the 8-week exposure course. HA levels in lung tissue and BAL increased at 12 h and peaked by 6 and 8 days respectively. Inflammatory cells and new collagen formation localized in areas of HA deposition. Taken together these data support a role for HA in the pathogenesis in asthma.
Glycobiology 08/2012; · 3.58 Impact Factor
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ABSTRACT: The central goal of our laboratory is to understand the regulation of lymphoid cells through molecular mechanisms of signal
transduction and transcriptional control. A long-standing focus has been on changes that influence the effector function of
mature lymphocytes. Work in the laboratory is oriented toward the identification of new regulatory mechanisms using cell lines
and primary cells, and the validation of these in vitro findings in mouse models of immune responses and diseases. In this
review, we summarize key insights into the regulation of T helper cell function during the phase of immunity where effector
responses arise de novo. Particular interest has been centered on cytokine gene regulation as part of T cell differentiation into the Th1 and Th2
subsets. Information on IL-4 receptor signaling and the role of NF-κB transcription factors is reviewed. Our more recent work
is designed to understand how regulation at the Th 1/2 effector stages is related to the control of memory T cell survival,
immune recall responses, and the role of these responses in immune-mediated disease.
Immunologic Research 04/2012; 23(2):179-191. · 3.03 Impact Factor
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ABSTRACT: Asthma is a chronic inflammatory disease of the airways characterized by airway remodeling, which includes changes in the extracellular matrix (ECM). However the role of the ECM in mediating these changes is poorly understood. Hyaluronan (HA), a major component of the ECM, has been implicated in asthma as well as in many other biological processes. Our study investigates the processes involved in HA synthesis, deposition, localization and degradation during an acute and chronic murine model of ovalbumin (OVA)-induced allergic pulmonary inflammation. Mice were sensitized, challenged to OVA and sacrificed at various time points during an 8-week challenge protocol. Bronchoalveolar lavage (BAL) fluids, blood, and lung tissue were collected for study. RNA, HA, protein and histopathology were analyzed. Analyses of lung sections and BAL fluids revealed an early deposition and an increase in HA levels within 24 h of antigen exposure. HA levels peaked at day 8 in BAL, while inflammatory cell recovery peaked at day 6. Hyaluronan synthase (HAS)1 and HAS2 on RNA levels peaked within 2 h of antigen exposure, while hyaluronidase (HYAL)1 and HYAL2 on RNA levels decreased. Both inflammatory cell infiltrates and collagen deposition co-localized with HA deposition within the lungs. These data support a role for HA in the pathogenesis of inflammation and airway remodeling in a murine model of asthma. HA deposition appears largely due to up regulation of HAS1 and HAS2. In addition, HA appears to provide the scaffolding for inflammatory cell accumulation as well as for new collagen synthesis and deposition.
Matrix biology: journal of the International Society for Matrix Biology 01/2011; 30(2):126-34. · 3.56 Impact Factor
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ABSTRACT: Eosinophilic inflammation is closely related to angiogenesis in asthmatic airway remodeling. In ovalbumin (OVA)-sensitized mice bone marrow-derived, proangiogenic endothelial progenitor cells (EPCs) are rapidly recruited into the lungs after OVA aerosol challenge and promptly followed by mobilization and recruitment of eosinophils.
We hypothesized that bone marrow-derived EPCs initiate the recruitment of eosinophils through expression of the eosinophil chemoattractant eotaxin-1.
EPCs were isolated from an OVA murine model of allergic airway inflammation and from asthmatic patients. Endothelial and smooth muscle cells were isolated from mice. Eotaxin-1 expression was analyzed by means of immunofluorescence, real-time PCR, or ELISA. In vivo recruitment of eosinophils by EPCs was analyzed in mice.
Circulating EPCs of asthmatic patients had higher levels of eotaxin-1 compared with those seen in control subjects. In the murine model OVA allergen exposure augmented eotaxin-1 mRNA and protein levels in EPCs. The EPCs from OVA-sensitized and OVA-challenged mice released high levels of eotaxin-1 on contact with lung endothelial cells from sensitized and challenged mice but not from control animals and not on contact with cardiac or hepatic endothelial cells from sensitized and challenged mice. Intranasal administration of the eotaxin-rich media overlying cultures of EPCs caused recruitment into the lungs, confirming functional chemoattractant activity.
Bone marrow-derived EPCs are early responders to environmental allergen exposures and initiate a parallel switch to a proangiogenic and proeosinophilic environment in the lungs of asthmatic patients.
The Journal of allergy and clinical immunology 03/2010; 125(4):918-25. · 9.17 Impact Factor
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ABSTRACT: Serum-derived hyaluronan (HA)-associated proteins (SHAPs), the heavy chains of inter-α-trypsin inhibitor, covalently bind to HA to form the SHAP-HA complex. The SHAP-HA complex is involved in the pathophysiology of inflammatory diseases, including rheumatoid arthritis. We investigated whether this complex is also involved in airway allergy.
SHAP-HA-deficient (bikunin knockout, KO) mice and wild-type (WT) mice were immunized twice by intraperitoneal injection of ovalbumin (OVA) and exposed to aerosol OVA for 30 min each day for 2 weeks. Twenty-four hours after the final OVA challenge, airway responsiveness to inhaled methacholine (MCh) was measured, and analysis of bronchoalveolar lavage fluid (BALF) and lung histological studies were done.
Compared to WT mice, KO mice showed higher airway hyperresponsiveness to inhaled MCh and higher late-phase responses to OVA whereas the early-phase responses were similar. Cell differentials of BALF showed an increased number of macrophages and neutrophils in KO mice. Furthermore, decreased concentrations of soluble tumor necrosis factor receptor-1 (sTNFR1) were found in BALF from KO mice whereas the levels of Th1 and Th2 cytokines were not different from WT mice. Immunochemical study of the lung tissues revealed stronger staining of sTNFR1 in KO than in WT mice.
Our results suggest that in this murine asthma model, the SHAP-HA complex has an inhibitory role in the development of airway hyperresponsiveness and allergic airway inflammation which may be attributed, at least in part, to negative feedback mechanisms exerted by sTNFR1, the shedding of which from the cell surface might also be promoted by the SHAP-HA complex.
International Archives of Allergy and Immunology 01/2010; 153(3):223-33. · 2.40 Impact Factor
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ABSTRACT: Allergic reactions to endoprostheses are uncommon and reported in association with orthopaedic, dental, endovascular and other implanted devices. Hypersensitivity reactions to the biomaterials used in endovascular prostheses are among the infrequent reactions that may lead to local or systemic complications following cardiovascular therapeutic interventions. This article reviews potential immunotoxic effects of commonly used biomaterials. Reports of putative hypersensitivity reactions to endovascular devices, including coronary stents, perforated foramen occluders, pacemakers and implantable cardioverter defibrillators are also reviewed.
Contact Dermatitis 08/2008; 59(1):7-22. · 3.51 Impact Factor
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ABSTRACT: Asthma is a syndrome whose common pathogenic expression is inflammation of the airways. Plasminogen plays an important role in cell migration and is also implicated in tissue remodeling, but its role in asthma has not been defined.
To test whether plasminogen is a critical component in the development of asthma.
We used a mouse model of ovalbumin-induced pulmonary inflammation in Plg(+/+), Plg(+/-), and Plg(-/-) mice.
The host responses measured included lung morphometry, and inflammatory mediators and cell counts were assessed in bronchoalveolar lavage fluid. Bronchoalveolar lavage demonstrated a marked increase in eosinophils and lymphocytes in ovalbumin-treated Plg(+/+) mice, which were reduced to phosphate-buffered saline-treated control levels in Plg(+/-) or Plg(-/-) mice. Lung histology revealed peribronchial and perivascular leukocytosis, mucus production, and increased collagen deposition in ovalbumin-treated Plg(+/+) but not in Plg(+/-) or Plg(-/-) mice. IL-5, tumor necrosis factor-alpha, and gelatinases, known mediators of asthma, were detected in bronchoalveolar lavage fluid of ovalbumin-treated Plg(+/+) mice, yet were reduced in Plg(-/-) mice. Administration of the plasminogen inhibitor, tranexamic acid, reduced eosinophil and lymphocyte numbers, mucus production, and collagen deposition in the lungs of ovalbumin-treated Plg(+/+) mice.
The decreased inflammation in the lungs of Plg(-/-) mice and its blockade with a plasminogen inhibitor indicate that plasminogen plays an important role in orchestrating the asthmatic response and suggests that plasminogen may be a therapeutic target for the treatment of asthma.
American Journal of Respiratory and Critical Care Medicine 09/2007; 176(4):333-42. · 11.08 Impact Factor
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Sudakshina Ghosh,
Allison J Janocha, Mark A Aronica,
Shadi Swaidani,
Suzy A A Comhair,
Weiling Xu,
Lemin Zheng,
Suma Kaveti,
Michael Kinter,
Stanley L Hazen,
Serpil C Erzurum
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ABSTRACT: Reactive oxygen species and reactive nitrogen species produced by epithelial and inflammatory cells are key mediators of the chronic airway inflammation of asthma. Detection of 3-nitrotyrosine in the asthmatic lung confirms the presence of increased reactive oxygen and nitrogen species, but the lack of identification of modified proteins has hindered an understanding of the potential mechanistic contributions of nitration/oxidation to airway inflammation. In this study, we applied a proteomic approach, using nitrotyrosine as a marker, to evaluate the oxidation of proteins in the allergen-induced murine model of asthma. Over 30 different proteins were targets of nitration following allergen challenge, including the antioxidant enzyme catalase. Oxidative modification and loss of catalase enzyme function were seen in this model. Subsequent investigation of human bronchoalveolar lavage fluid revealed that catalase activity was reduced in asthma by up to 50% relative to healthy controls. Analysis of catalase isolated from asthmatic airway epithelial cells revealed increased amounts of several protein oxidation markers, including chloro- and nitrotyrosine, linking oxidative modification to the reduced activity in vivo. Parallel in vitro studies using reactive chlorinating species revealed that catalase inactivation is accompanied by the oxidation of a specific cysteine (Cys(377)). Taken together, these studies provide evidence of multiple ongoing and profound oxidative reactions in asthmatic airways, with one early downstream consequence being catalase inactivation. Loss of catalase activity likely amplifies oxidative stress, contributing to the chronic inflammatory state of the asthmatic airway.
The Journal of Immunology 06/2006; 176(9):5587-97. · 5.79 Impact Factor
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ABSTRACT: Animal models and clinical studies of asthma have generated important insights into the first effector phase leading to the development of allergic airway disease and bronchial hyper-reactivity. In contrast, mechanisms related to asthma chronicity or persistence are less well understood. The CD4(+) T-helper 2 lymphocytes are known initiators of the inflammatory response associated with asthma. There is now increasing evidence that memory T-cells, sensitized against allergenic, occupational or viral antigens, are also involved in the persistence of asthma. Additionally, the role of pathogens in asthma has been linked to both the initial susceptibility to and flares of this disease. This review will discuss the potential links between infection and asthma, the role of the memory T-cells in asthma, and the potential mechanisms by which these factors interact to lead to the development and/or persistence of asthma.
Expert Review of Clinical Immunology 11/2005; 1(4):589-601. · 2.07 Impact Factor
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ABSTRACT: Microbial infections are associated with the initial susceptibility to and flares of asthma. However, immunologic mechanisms whereby infections might alter the asthmatic phenotype are lacking.
To test the hypothesis that memory T cells specific both for a viral antigen and an allergen could influence the pathogenesis of allergic disease in vivo .
We developed a system in which 2 distinct T-cell receptors coexist on the T-cell surface, 1 specific for a virus and the other for an inhaled antigen.
We show that a population of dual-receptor T cells, polarized through a virus-specific T-cell receptor to contain T(H)1 or T(H)2 cells, can be reactivated through an unrelated T-cell receptor in recall responses in vivo . Quiescent memory cells derived from a T(H)1-polarized effector population blocked the development of airway hyperreactivity in a model of allergic lung disease, in association with decreased induction of chemokines and eosinophil recruitment. Conversely, reactivation of quiescent T(H)2 cells after inhalation of antigen or virus infection was sufficient to lead to the development of airway hyperresponsiveness and allergic pulmonary inflammation in mice whose lungs were previously normal.
These data provide evidence that dual-receptor memory T cells can regulate allergic disease susceptibility and suggest that they may play a role in mediating the influence of microbes on asthma pathogenesis.
Journal of Allergy and Clinical Immunology 01/2005; 114(6):1441-8. · 11.00 Impact Factor
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ABSTRACT: Effector and memory T lymphocytes differ significantly, and there is no experimental evidence that memory cells are sufficient to render an otherwise normal individual susceptible to localized allergic inflammation. Furthermore, nothing is known about the kinetics of memory responses after inhalation of antigen or interplay between an allergen-specific memory helper T (Th) cell Th2 population and uncommitted or competing Th1 cells. To study these processes, T cell receptor-transgenic CD4(+) effector cells were generated in vitro, transferred into naive recipients, and allowed to resume a quiescent state. Inhalation of protein antigen reactivated these Ag-specific Th2 donor cells, leading to allergic pulmonary inflammation and airway hyperreactivity. Susceptibility was correlated with the size of the input Th2 population, but Th1 cells neither enhanced nor reduced inflammation in this model. Importantly, the reactivation of these antigen-experienced cells by inhaled antigen did not skew the cytokine balance of recipient-derived T cells recruited to the lung nor did it inhibit the development of donor-derived Th1 cells from uncommitted antigen-experienced cells that form a normal part of immune responses. These data indicate that a quiescent memory Th2-cell population can create susceptibility to allergic pulmonary inflammation in a manner refractory to inhibition by Th1 cells or endogenous inhibitory mechanisms.
American Journal of Respiratory and Critical Care Medicine 04/2004; 169(5):587-95. · 11.08 Impact Factor
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Radiah A Corn, Mark A Aronica,
Fuping Zhang,
Yingkai Tong,
Sarah A Stanley,
Se Ryoung Agnes Kim,
Linda Stephenson,
Ben Enerson,
Susan McCarthy,
Ana Mora,
Mark Boothby
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ABSTRACT: NF-kappaB/Rel transcription factors are linked to innate immune responses and APC activation. Whether and how the induction of NF-kappaB signaling in normal CD4(+) T cells regulates effector function are not well-understood. The liberation of NF-kappaB dimers from inhibitors of kappaB (IkappaBs) constitutes a central checkpoint for physiologic regulation of most forms of NF-kappaB. To investigate the role of NF-kappaB induction in effector T cell responses, we targeted inhibition of the NF-kappaB/Rel pathway specifically to T cells. The Th1 response in vivo is dramatically weakened when T cells defective in their NF-kappaB induction (referred to as IkappaBalpha(DeltaN) transgenic cells) are activated by a normal APC population. Analyses in vivo, and IL-12-supplemented T cell cultures in vitro, reveal that the mechanism underlying this T cell-intrinsic requirement for NF-kappaB involves activation of the IFN-gamma gene in addition to clonal expansion efficiency. The role of NF-kappaB in IFN-gamma gene expression includes a modest decrease in Stat4 activation, T box expressed in T cell levels, and differentiation efficiency along with a more prominent postdifferentiation step. Further, induced expression of Bcl-3, a trans-activating IkappaB-like protein, is decreased in T cells as a consequence of NF-kappaB inhibition. Together, these findings indicate that NF-kappaB induction in T cells regulates efficient clonal expansion, Th1 differentiation, and IFN-gamma production by Th1 lymphocytes at a control point downstream from differentiation.
The Journal of Immunology 09/2003; 171(4):1816-24. · 5.79 Impact Factor
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01/2003;
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ABSTRACT: Strength of T cell receptor (TCR) signaling, coreceptors, costimulation, antigen-presenting cell type, and cytokines all
play crucial roles in determining the efficiency with which type 2 T lymphocytes (Th2, Tc2) develop from uncommitted precursors.
To investigate in vivo regulatory mechanisms that control the population of type 2 T cells and disease susceptibility, we
have created lines of transgenic mice in which expression of a chimeric cytokine receptor (the mouse interleukin 2 receptor
β chain [IL-2Rβ] extracellular domain fused to the cytoplasmic tail of IL-4Rα) is targeted to the T lymphoid lineage using
the proximal lck promoter. This chimera transduced IL-4–specific signals in response to IL-2 binding and dramatically enhanced
type 2 responses (IL-4, IL-5, and immunoglobulin E production) upon in vitro TCR stimulation or in vivo antigen challenge.
Thus, type 2 effector function was augmented by IL-4 signals transduced through a chimeric receptor expressed in a T cell–specific
manner. This influence was sufficient for establishment of antigen-induced allergic airway hyperresponsiveness on a disease-resistant
background (C57BL/6).
Journal of Experimental Medicine 11/1998; 188(10):1803-1816. · 13.85 Impact Factor
