DOCSLIB.ORG

Platelet Factor 4 and Von Willebrand Factor Form an Immunogenic, Prothrombotic Complex in Heparin-Induced Thrombocytopenia

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Platelet Factor 4 and Von Willebrand Factor Form an Immunogenic, Prothrombotic Complex in Heparin-Induced Thrombocytopenia University of Pennsylvania ScholarlyCommons Publicly Accessible Penn Dissertations 2018 Platelet Factor 4 And Von Willebrand Factor Form An Immunogenic, Prothrombotic Complex In Heparin-Induced Thrombocytopenia Ian Johnston University of Pennsylvania, [email protected] Follow this and additional works at: https://repository.upenn.edu/edissertations Part of the Pharmacology Commons Recommended Citation Johnston, Ian, "Platelet Factor 4 And Von Willebrand Factor Form An Immunogenic, Prothrombotic Complex In Heparin-Induced Thrombocytopenia" (2018). Publicly Accessible Penn Dissertations. 2907. https://repository.upenn.edu/edissertations/2907 This paper is posted at ScholarlyCommons. https://repository.upenn.edu/edissertations/2907 For more information, please contact [email protected]. Platelet Factor 4 And Von Willebrand Factor Form An Immunogenic, Prothrombotic Complex In Heparin-Induced Thrombocytopenia Abstract Heparin-induced thrombocytopenia (HIT) is a prothrombotic, thrombocytopenic disorder that occurs in patients exposed to heparin due to the development of antibodies directed against complexes of platelet factor 4 (PF4) with heparin with other polyanions . We have recently shown that the perithrombus endothelium is targeted in HIT. Using a photochemical injury model and an endothelialized microfluidic system, we now show that PF4 binds to elongated strands of von Willebrand factor (VWF) released from injured endothelium. This binding appears to be periodic along the VWF strand and to favor larger VWF strands, suggesting formation of oligomers that may cross-link individual VWF subunits. KKO, a monoclonal HIT-like antibody, and HIT patient plasma form PF4-VWF-HIT antibody complexes that may stabilize the complexes which, in turn, avidly bind platelets, exacerbating thrombus growth in a human whole blood microfluidic system. This increase in platelet binding is attenuated by blocking either the platelet FcRIIA or the glycoprotein Ib/IX receptor. Charge-based as well as VWF-binding drugs can disrupt the PF4-VWF-HIT complexes. Dynamic light scattering studies provide additional support for the concept that PF4 and VWF form complexes in vitro. In vivo studies in a passive immunization model of HIT indicate a potential role for VWF in the prothrombotic nature of HIT. Thus, these studies newly identify VWF as a potentially important polymer involved in the formation of HIT antigenic complexes that contribute to the prothrombotic nature of HIT and offer a potential new therapeutic target to mitigate the thrombotic complications of affected patients. Degree Type Dissertation Degree Name Doctor of Philosophy (PhD) Graduate Group Pharmacology First Advisor Mortimer Poncz Second Advisor Lawrence F. Brass Subject Categories Pharmacology This dissertation is available at ScholarlyCommons: https://repository.upenn.edu/edissertations/2907 PLATELET FACTOR 4 AND VON WILLEBRAND FACTOR FORM AN IMMUNOGENIC, PROTHROMBOTIC COMPLEX IN HEPARIN-INDUCED THROMBOCYTOPENIA Ian Johnston A DISSERTATION in Pharmacology Presented to the Faculties of the University of Pennsylvania in Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy 2018 Supervisor of Dissertation _________________________ Mortimer Poncz M.D., Professor of Pharmacology and Pediatrics Graduate Group Chairperson _________________________ Julie A. Blendy, Ph.D., Professor of Pharmacology Dissertation Committee Lawrence F. Brass, M.D., PhD., Professor of Pharmacology and Medicine (Chair) John W. Weisel, PhD., Professor of Cell and Developmental Biology Doug B. Cines, M.D., Professor of Pathology and Laboratory Medicine Robert J. Levy, M.D., Professor of Pediatric Cardiology i Dedication page I dedicate this work to my wife, Courtney, whose love and support made all of this possible. ii ACKNOWLEDGMENT I’d like to thank Dr. Mortimer Poncz for his guidance and support. He allowed me to integrate my engineering background with the biology of the lab and venture into very interesting scientific realms. This translated into various conference presentations and collaborations that weren’t always available to other graduate students. So I thank him for these opportunities as I know they will be valuable to my future career. I’d also like to thank my thesis committee members, Dr. Skip Brass, Dr. Doug Cines, Dr. John Weisel, and Dr. Robert Levy. Their input provided the extra push which helped me overcome the challenges of graduate school and helped me hone the skills I’ll use for years to come. I’d also like to thank Dr. Carlos Villa, Dr. Colin Greineder, and Dr. Jacob Myerson from the Muzykantov Lab. Their collaborations helped broaden my view of science and research and were essential to the development of the microfluidic model. Lastly, I’d like to thank a few members of the Poncz lab. I’d like to thank Dr. Randy Lyde and Vincent Hayes for their friendship and support during graduate school. iii ABSTRACT PLATELET FACTOR 4 AND VON WILLEBRAND FACTOR FORM AN IMMUNOGENIC, PROTHROMBOTIC COMPLEX IN HEPARIN-INDUCED THROMBOCYTOPENIA Ian H. Johnston Mortimer Poncz, M.D. Heparin-induced thrombocytopenia (HIT) is a prothrombotic, thrombocytopenic disorder that occurs in patients exposed to heparin due to the development of antibodies directed against complexes of platelet factor 4 (PF4) with heparin with other polyanions . We have recently shown that the perithrombus endothelium is targeted in HIT. Using a photochemical injury model and an endothelialized microfluidic system, we now show that PF4 binds to elongated strands of von Willebrand factor (VWF) released from injured endothelium. This binding appears to be periodic along the VWF strand and to favor larger VWF strands, suggesting formation of oligomers that may cross-link individual VWF subunits. KKO, a monoclonal HIT-like antibody, and HIT patient plasma form PF4-VWF-HIT antibody complexes that may stabilize the complexes which, in turn, avidly bind platelets, exacerbating thrombus growth in a human whole blood microfluidic system. This increase in platelet binding is attenuated by blocking either the platelet FcRIIA or the glycoprotein Ib/IX receptor. Charge-based as well as VWF-binding drugs can disrupt the PF4-VWF-HIT complexes. Dynamic light scattering studies provide additional support for the concept that PF4 and VWF form complexes in vitro. In vivo studies in a passive immunization model of HIT indicate a potential role for VWF in the prothrombotic nature of HIT. Thus, these studies newly identify VWF as a potentially important polymer involved in the formation of HIT antigenic complexes that contribute to the prothrombotic nature of HIT and offer a potential new therapeutic target to mitigate the thrombotic complications of affected patients. iv TABLE OF CONTENTS ACKNOWLEDGMENT ............................................................................................................. III ABSTRACT .................................................................................................................................. IV TABLE OF CONTENTS .............................................................................................................. V LIST OF TABLES ..................................................................................................................... VIII LIST OF ILLUSTRATIONS ....................................................................................................... IX CHAPTER 1 - INTRODUCTION .............................................................................................. 1 Hemostasis: Pro-coagulative Factors .......................................................................................... 2 Hemostasis: Anti-coagulative Factors ......................................................................................... 3 Thrombosis ..................................................................................................................................... 4 Heparin-Induced Thrombocytopenia (HIT): An Iatrogenic Prothrombotic Disease ................ 5 HIT Modeling ................................................................................................................................... 7 Sepsis: An Immune-Based Systemic Disorder ........................................................................... 8 Summary ......................................................................................................................................... 9 Figures .......................................................................................................................................... 12 CHAPTER 2 – MICROFLUIDIC SYSTEM MODELING ...................................................... 18 Motivation for Developing an Endothelialized Microfluidic System ....................................... 19 Microfluidic Device and Setup .................................................................................................... 19 Injury Settings: Hematoporphyrin-Induced Endothelial Injury ............................................... 21 Injury Settings: TNFα-Induced Endothelial Injury .................................................................... 22 Discussion .................................................................................................................................... 22 Figures .......................................................................................................................................... 23 v CHAPTER 3 – ENDOTHELIAL ANTIGEN ASSEMBLY LEADS TO
Load more

Recommended publications
  • Recapitulates Some Features of Psoriasis Α , And
    The Journal of Immunology Skin Inflammation Induced by the Synergistic Action of IL-17A, IL-22, Oncostatin M, IL-1a, and TNF-a Recapitulates Some Features of Psoriasis Karline Guilloteau,*,† Isabelle Paris,*,‡ Nathalie Pedretti,*,† Katia Boniface,*,1 Franck Juchaux,*,† Vincent Huguier,x Gerard Guillet,{ Franc¸ois-Xavier Bernard,*,† Jean-Claude Lecron,*,‡ and Franck Morel* Keratinocytes play a crucial role in the regulation of skin inflammation, responding to environmental and immune cells stimuli. They produce soluble factors that can act in an autocrine or paracrine manner on immune cells or directly on aggressors. A screen- ing of the activities of 36 cytokines on keratinocyte gene expression identified IL-17A, IL-22, oncostatin M, TNF-a, and IL-1a as potent cytokines in inducing cutaneous inflammation. These five proinflammatory cytokines synergistically increased production of CXCL8 and b-defensin 2 (BD2). In addition, ex vivo studies on human skin explants demonstrated upregulation of BD2, S100A7, and CXCL8 expression in response to the same combination of cytokines. In vivo intradermal injection of these five cytokines in mouse increased CXCL1, CXCL2, CXCL3, S100A9, and BD3 expression, associated with neutrophil infiltration. We confirmed and extended this synergistic effect using quantitative real-time PCR analysis and observed increased expression of nine chemokines and 12 antimicrobial peptides. Production of CXCL, CXCL5, and CXCL8 by keratinocytes stimulated in the presence of this cytokine combination was associated with increased neutrophil chemotactic activity. Similarly, high production of BD2, BD3, and S100A7 was associated with an increased antimicrobial activity. Finally, the transcriptional profile observed in this in vitro model of inflammatory keratinocytes correlated with the one of lesional psoriatic skin.
    [Show full text]
  • Human Plasma and Recombinant Hemopexins: Heme Binding Revisited
    International Journal of Molecular Sciences Article Human Plasma and Recombinant Hemopexins: Heme Binding Revisited Elena Karnaukhova 1,*, Catherine Owczarek 2, Peter Schmidt 2, Dominik J. Schaer 3 and Paul W. Buehler 4,5,* 1 Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA 2 CSL Limited, Bio21 Institute, Parkville, Victoria 3010, Australia; [email protected] (C.O.); [email protected] (P.S.) 3 Division of Internal Medicine, University Hospital of Zurich, 8091 Zurich, Switzerland; [email protected] 4 Department of Pathology, The University of Maryland School of Medicine, Baltimore, MD 21201, USA 5 The Center for Blood Oxygen Transport and Hemostasis, Department of Pediatrics, The University of Maryland School of Medicine, Baltimore, MD 21201, USA * Correspondence: [email protected] (E.K.); [email protected] (P.W.B.) Abstract: Plasma hemopexin (HPX) is the key antioxidant protein of the endogenous clearance pathway that limits the deleterious effects of heme released from hemoglobin and myoglobin (the term “heme” is used in this article to denote both the ferrous and ferric forms). During intra-vascular hemolysis, heme partitioning to protein and lipid increases as the plasma concentration of HPX declines. Therefore, the development of HPX as a replacement therapy during high heme stress could be a relevant intervention for hemolytic disorders. A logical approach to enhance HPX yield involves recombinant production strategies from human cell lines. The present study focuses on a biophysical assessment of heme binding to recombinant human HPX (rhHPX) produced in the Expi293FTM (HEK293) cell system.
    [Show full text]
  • Inhibition of CCL7 Derived from Mo-Mdscs Prevents Metastatic
    Ren et al. Cell Death and Disease (2021) 12:484 https://doi.org/10.1038/s41419-021-03698-5 Cell Death & Disease ARTICLE Open Access Inhibition of CCL7 derived from Mo-MDSCs prevents metastatic progression from latency in colorectal cancer Xiaoli Ren1,2, Jianbiao Xiao1,3, Wanning Zhang1,3,FeifeiWang1,3, Yongrong Yan1,3,XuehuiWu 1,3, Zhicheng Zeng1,3, Yumei He4,WeiYang1,3, Wangjun Liao5,YanqingDing1,3 and Li Liang 1,3 Abstract In colorectal cancer (CRC), overt metastases often appear after years of latency. But the signals that cause micro- metastatic cells to remain indolent, thereby enabling them to survive for extended periods of time, are unclear. Immunofluorescence and co-immunoprecipitation assays were used to explore the co-localization of CCL7 and CCR2. Immunohistochemical (IHC) assays were employed to detect the characters of metastatic HT29 cells in mice liver. Flow cytometry assays were performed to detect the immune cells. Bruberin vivo MS FX Pro Imager was used to observe the liver metastasis of CRC in mice. Quantitative real-time PCR (qRT-PCR) and western blot were employed to detect the expressions of related proteins. Trace RNA sequencing was employed to identify differentially expressed genes in MDSCs from liver micro-M and macro-M of CRC in mice. Here, we firstly constructed the vitro dormant cell models and metastatic dormant animal models of colorectal cancer. Then we found that myeloid-derived suppressor cells (MDSCs) were increased significantly from liver micro-metastases to macro-metastases of CRC in mice. Moreover, monocytic MDSCs (Mo-MDSC) significantly promoted the dormant activation of micro-metastatic cells compared to 1234567890():,; 1234567890():,; 1234567890():,; 1234567890():,; polymorphonuclear MDSCs (PMN-MDSC).
    [Show full text]
  • Mrna Vaccine Era—Mechanisms, Drug Platform and Clinical Prospection
    International Journal of Molecular Sciences Review mRNA Vaccine Era—Mechanisms, Drug Platform and Clinical Prospection 1, 1, 2 1,3, Shuqin Xu y, Kunpeng Yang y, Rose Li and Lu Zhang * 1 State Key Laboratory of Genetic Engineering, Institute of Genetics, School of Life Science, Fudan University, Shanghai 200438, China; [email protected] (S.X.); [email protected] (K.Y.) 2 M.B.B.S., School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; [email protected] 3 Shanghai Engineering Research Center of Industrial Microorganisms, Shanghai 200438, China * Correspondence: [email protected]; Tel.: +86-13524278762 These authors contributed equally to this work. y Received: 30 July 2020; Accepted: 30 August 2020; Published: 9 September 2020 Abstract: Messenger ribonucleic acid (mRNA)-based drugs, notably mRNA vaccines, have been widely proven as a promising treatment strategy in immune therapeutics. The extraordinary advantages associated with mRNA vaccines, including their high efficacy, a relatively low severity of side effects, and low attainment costs, have enabled them to become prevalent in pre-clinical and clinical trials against various infectious diseases and cancers. Recent technological advancements have alleviated some issues that hinder mRNA vaccine development, such as low efficiency that exist in both gene translation and in vivo deliveries. mRNA immunogenicity can also be greatly adjusted as a result of upgraded technologies. In this review, we have summarized details regarding the optimization of mRNA vaccines, and the underlying biological mechanisms of this form of vaccines. Applications of mRNA vaccines in some infectious diseases and cancers are introduced. It also includes our prospections for mRNA vaccine applications in diseases caused by bacterial pathogens, such as tuberculosis.
    [Show full text]
  • The CXCL7/CXCR1/2 Axis Is a Key Driver in the Growth of Clear Cell Renal Cell Carcinoma
    Published OnlineFirst December 12, 2013; DOI: 10.1158/0008-5472.CAN-13-1267 Cancer Therapeutics, Targets, and Chemical Biology Research The CXCL7/CXCR1/2 Axis Is a Key Driver in the Growth of Clear Cell Renal Cell Carcinoma Renaud Grepin 5,Melanie Guyot1, Sandy Giuliano1, Marina Boncompagni1, Damien Ambrosetti1,2, Emmanuel Chamorey3, Jean-Yves Scoazec4, Sylvie Negrier4,Hel ene Simonnet4, and Gilles Pages 1 Abstract Mutations in the von Hippel–Lindau gene upregulate expression of the central angiogenic factor VEGF, which drives abnormal angiogenesis in clear cell renal cell carcinomas (ccRCC). However, the overexpression of VEGF in these tumors was not found to correlate with overall survival. Here, we show that the proangiogenic, proin- flammatory cytokine CXCL7 is an independent prognostic factor for overall survival in this setting. CXCL7 antibodies strongly reduced the growth of ccRCC tumors in nude mice. Conversely, conditional overexpression of CXCL7 accelerated ccRCC development. CXCL7 promoted cell proliferation in vivo and in vitro, in which expression of CXCL7 was induced by the central proinflammatory cytokine interleukin (IL)-1b. ccRCC cells normally secrete low amounts of CXCL7; it was more highly expressed in tumors due to high levels of IL-1b there. We found that a pharmacological inhibitor of the CXCL7 receptors CXCR1 and CXCR2 (SB225002) was sufficient to inhibit endothelial cell proliferation and ccRCC growth. Because CXCR1 and CXCR2 are present on both endothelial and ccRCC cells, their inhibition affected both the tumor vasculature and the proliferation of tumor cells. Our results highlight the CXCL7/CXCR1/CXCR2 axis as a pertinent target for the treatment of ccRCC.
    [Show full text]
  • Mechanisms of Immunothrombosis in Vaccine-Induced Thrombotic Thrombocytopenia (VITT) Compared to Natural SARS-Cov-2 Infection
    Journal of Autoimmunity 121 (2021) 102662 Contents lists available at ScienceDirect Journal of Autoimmunity journal homepage: www.elsevier.com/locate/jautimm Mechanisms of Immunothrombosis in Vaccine-Induced Thrombotic Thrombocytopenia (VITT) Compared to Natural SARS-CoV-2 Infection Dennis McGonagle a,b, Gabriele De Marco a, Charles Bridgewood a,* a Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK b National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), Leeds Teaching Hospitals, Leeds, UK ARTICLE INFO ABSTRACT Keywords: Herein, we consider venous immunothrombotic mechanisms in SARS-CoV-2 infection and anti-SARS-CoV-2 DNA COVID-19 pneumonia related thrombosis vaccination. Primary SARS-CoV-2 infection with systemic viral RNA release (RNAaemia) contributes to innate Vaccine induced thrombotic thrombocytopenia immune coagulation cascade activation, with both pulmonary and systemic immunothrombosis - including (VITT) venous territory strokes. However, anti-SARS-CoV-2 adenoviral-vectored-DNA vaccines -initially shown for the Heparin induced thrombocytopenia (HIT) ChAdOx1 vaccine-may rarely exhibit autoimmunity with autoantibodies to Platelet Factor-4 (PF4) that is termed DNA-PF4 interactions. VITT model Vaccine-Induced Thrombotic Thrombocytopenia (VITT), an entity pathophysiologically similar to Heparin- Induced Thrombocytopenia (HIT). The PF4 autoantigen is a polyanion molecule capable of independent in­ teractions with negatively charged bacterial cellular wall, heparin and DNA molecules, thus linking intravascular innate immunity to both bacterial cell walls and pathogen-derived DNA. Crucially, negatively charged extra­ cellular DNA is a powerful adjuvant that can break tolerance to positively charged nuclear histone proteins in many experimental autoimmunity settings, including SLE and scleroderma. Analogous to DNA-histone inter­ actons, positively charged PF4-DNA complexes stimulate strong interferon responses via Toll-Like Receptor (TLR) 9 engagement.
    [Show full text]
  • CCL5 Secreted by Senescent Aged Fibroblasts Induces Proliferation of Prostate Epithelial Cells and Expression of Genes That Modu
    JCP-09-0003.R1(21776) ORIGINAL ARTICLE 1 JJ o o u u r r n n a a l l oo f f Cellular CCL5 Secreted by Senescent Aged Physiology Fibroblasts Induces Proliferation of Prostate Epithelial Cells and Expression of Genes that Modulate AngiogenesisQ1 1 1 2 1 D. EYMAN, M. DAMODARASAMY, S.R. PLYMATE, AND M.J. REED * 1Department of Medicine, Harborview Medical Center, University of Washington, Seattle, Washington 2Veterans Affairs Puget Sound Health Care System, Seattle Washington There is increased interest in the effects of secretory products from aged cells on promoting both benign and malignant cell growth. We identified a human fibroblast line, AG04382, from an aged donor that naturally demonstrated senescence-associated features and whose conditioned media significantly induced proliferation of benign prostatic hyperplasia (BPH1) cells. Candidate cytokines mediating this effect were identified with protein arrays and validated by ELISA. We found that the AG04382 fibroblast line secreted high levels of CXCL5, CCL5, and CCL2, but relative to the other lines, its conditioned media was unique in its increased expression of CCL5. Blocking studies using specific antibodies against CXCL5, CCL5, and CCL2 in the conditioned media of AG04382 showed that only CCL5 contributed significantly to BPH1 proliferation. Stimulation of BPH1 cells with rhuCCL5 resulted in increased proliferation and migration, as well as significant changes in the expression of genes that influence angiogenesis. These data suggest that CCL5 is a candidate chemokine secreted by aged cells that promotes prostate growth and regulates angiogenesis. J. Cell. Physiol. 9999: 1–6, 2009. ß 2009 Wiley-Liss, Inc. There is a close correlation between host age and the analyses for potential paracrine modulators demonstrated that prevalence of both benign (prostatic hyperplasia) and malignant the chemokine, CCL5, in the conditioned media of the aged (cancer) prostate disease (Balducci and Ershler, 2005; fibroblasts was responsible, in part, for inducing proliferation of Untergasser et al., 2005; Nelen, 2007).
    [Show full text]
  • Nano-Lactoferrin in Diagnostic, Imaging and Targeted Delivery for Cancer and Infectious Diseases Jagat R
    cer Scien an ce C & f o T Kanwar et al., J Cancer Sci Ther 2012, 4.3 l h a e n r a Journal of 1000107 r p u DOI: 10.4172/1948-5956. y o J ISSN: 1948-5956 Cancer Science & Therapy Review Article Open Access Nano-Lactoferrin in Diagnostic, Imaging and Targeted Delivery for Cancer and Infectious Diseases Jagat R. Kanwar1*, Rasika M. Samarasinghe1, Rakesh Sehgal2 and Rupinder K. Kanwar1 1Nanomedicine-Laboratory of Immunology and Molecular Biomedical Research (LIMBR), Centre for Biotechnology and Interdisciplinary Biosciences (BioDeakin), Institute for Technology & Research Innovation (ITRI), Deakin University, Geelong, Technology Precinct (GTP), Pigdons Road, Waurn Ponds, Geelong, Victoria 3217, Australia 2Professor, Department of Parasitology, Postgraduate Institute of Medical Education & Research, Chandigarh, India-160012 Abstract Lactoferrin (Lf) is a natural occurring iron binding protein present in many mammalian excretions and involved in various physiological processes. Lf is used in the transport of iron along with other molecules and ions from the digestive system. However its the modulatory functions exhibited by Lf in connection to immune response, disease regression and diagnosis that has made this protein an attractive therapeutic against chronic diseases. Further, the exciting potentials of employing nanotechnology in advancing drug delivery systems, active disease targeting and prognosis have also shown some encouraging outcomes. This review focuses on the role of Lf in diagnosing infection, cancer, neurological and inflammatory diseases and the recent nanotechnology based strategies. Keywords: Lactoferrin; Nanodelivery; Cancer; Inflammation; fluids, mucosal secretions, pancreatic fluids and in neutrophils cells [8]. Infection; Oral administration Structurally, Lf weighs approximately 80kDa and the polypeptide folds into two globular lobes.
    [Show full text]
  • The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors—A Review of Literature
    International Journal of Molecular Sciences Review The Effect of Hypoxia on the Expression of CXC Chemokines and CXC Chemokine Receptors—A Review of Literature Jan Korbecki 1 , Klaudyna Kojder 2, Patrycja Kapczuk 1, Patrycja Kupnicka 1 , Barbara Gawro ´nska-Szklarz 3 , Izabela Gutowska 4 , Dariusz Chlubek 1 and Irena Baranowska-Bosiacka 1,* 1 Department of Biochemistry and Medical Chemistry, Pomeranian Medical University in Szczecin, Powsta´nców Wielkopolskich 72 Av., 70-111 Szczecin, Poland; [email protected] (J.K.); [email protected] (P.K.); [email protected] (P.K.); [email protected] (D.C.) 2 Department of Anaesthesiology and Intensive Care, Pomeranian Medical University in Szczecin, Unii Lubelskiej 1, 71-281 Szczecin, Poland; [email protected] 3 Department of Pharmacokinetics and Therapeutic Drug Monitoring, Pomeranian Medical University in Szczecin, Powsta´nców Wielkopolskich 72 Av., 70-111 Szczecin, Poland; [email protected] 4 Department of Medical Chemistry, Pomeranian Medical University in Szczecin, Powsta´nców Wlkp. 72 Av., 70-111 Szczecin, Poland; [email protected] * Correspondence: [email protected]; Tel.: +48-914661515 Abstract: Hypoxia is an integral component of the tumor microenvironment. Either as chronic or cycling hypoxia, it exerts a similar effect on cancer processes by activating hypoxia-inducible factor-1 (HIF-1) and nuclear factor (NF-κB), with cycling hypoxia showing a stronger proinflammatory influ- ence. One of the systems affected by hypoxia is the CXC chemokine system. This paper reviews all available information on hypoxia-induced changes in the expression of all CXC chemokines (CXCL1, CXCL2, CXCL3, CXCL4, CXCL5, CXCL6, CXCL7, CXCL8 (IL-8), CXCL9, CXCL10, CXCL11, CXCL12 Citation: Korbecki, J.; Kojder, K.; Kapczuk, P.; Kupnicka, P.; (SDF-1), CXCL13, CXCL14, CXCL15, CXCL16, CXCL17) as well as CXC chemokine receptors— Gawro´nska-Szklarz,B.; Gutowska, I.; CXCR1, CXCR2, CXCR3, CXCR4, CXCR5, CXCR6, CXCR7 and CXCR8.
    [Show full text]
  • Predictive Biomarkers for the Ranking of Pulmonary Toxicity of Nanomaterials
    nanomaterials Article Predictive Biomarkers for the Ranking of Pulmonary Toxicity of Nanomaterials Chinatsu Nishida 1, Hiroto Izumi 2, Taisuke Tomonaga 2 , Jun-ichi Takeshita 3 , Ke-Yong Wang 4, Kei Yamasaki 1, Kazuhiro Yatera 1 and Yasuo Morimoto 2,* 1 Department of Respiratory Medicine, University of Occupational and Environmental Health, Japan. 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu, Fukuoka 807-8555, Japan; [email protected] (C.N.); [email protected] (K.Y.); [email protected] (K.Y.) 2 Department of Occupational Pneumology, Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, Japan. 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu, Fukuoka 807-8555, Japan; [email protected] (H.I.); [email protected] (T.T.) 3 Research Institute of Science for Safety and Sustainability, National Institute of Advanced Industrial Science and Technology (AIST), Tsukuba, Japan. 16-1 Onogawa, Tsukuba, Ibaraki 305-8569, Japan; [email protected] 4 Shared-Use Research Center, University of Occupational and Environmental Health, Japan. 1-1 Iseigaoka, Yahata-nishi-ku, Kitakyushu, Fukuoka 807-8555, Japan; [email protected] * Correspondence: [email protected]; Tel.: +81-93-691-7136 Received: 3 September 2020; Accepted: 9 October 2020; Published: 15 October 2020 Abstract: We analyzed the mRNA expression of chemokines in rat lungs following intratracheal instillation of nanomaterials in order to find useful predictive markers of the pulmonary toxicity of nanomaterials. Nickel oxide (NiO) and cerium dioxide (CeO2) as nanomaterials with high pulmonary toxicity, and titanium dioxide (TiO2) and zinc oxide (ZnO) as nanomaterials with low pulmonary toxicity, were administered into rat lungs (0.8 or 4 mg/kg BW).
    [Show full text]
  • Critical Role of CXCL4 in the Lung Pathogenesis of Influenza (H1N1) Respiratory Infection
    ARTICLES Critical role of CXCL4 in the lung pathogenesis of influenza (H1N1) respiratory infection L Guo1,3, K Feng1,3, YC Wang1,3, JJ Mei1,2, RT Ning1, HW Zheng1, JJ Wang1, GS Worthen2, X Wang1, J Song1,QHLi1 and LD Liu1 Annual epidemics and unexpected pandemics of influenza are threats to human health. Lung immune and inflammatory responses, such as those induced by respiratory infection influenza virus, determine the outcome of pulmonary pathogenesis. Platelet-derived chemokine (C-X-C motif) ligand 4 (CXCL4) has an immunoregulatory role in inflammatory diseases. Here we show that CXCL4 is associated with pulmonary influenza infection and has a critical role in protecting mice from fatal H1N1 virus respiratory infection. CXCL4 knockout resulted in diminished viral clearance from the lung and decreased lung inflammation during early infection but more severe lung pathology relative to wild-type mice during late infection. Additionally, CXCL4 deficiency decreased leukocyte accumulation in the infected lung with markedly decreased neutrophil infiltration into the lung during early infection and extensive leukocyte, especially lymphocyte accumulation at the late infection stage. Loss of CXCL4 did not affect the activation of adaptive immune T and B lymphocytes during the late stage of lung infection. Further study revealed that CXCL4 deficiency inhibited neutrophil recruitment to the infected mouse lung. Thus the above results identify CXCL4 as a vital immunoregulatory chemokine essential for protecting mice against influenza A virus infection, especially as it affects the development of lung injury and neutrophil mobilization to the inflamed lung. INTRODUCTION necrosis factor (TNF)-a, interleukin (IL)-6, and IL-1b, to exert Influenza A virus (IAV) infections cause respiratory diseases in further antiviral innate immune effects.2 Meanwhile, the innate large populations worldwide every year and result in seasonal immune cells act as antigen-presenting cells and release influenza epidemics and unexpected pandemic.
    [Show full text]
  • CXCL5 Signaling Is a Shared Pathway of Neuroinflammation and Blood
    Wang et al. Journal of Neuroinflammation (2016) 13:6 DOI 10.1186/s12974-015-0474-6 RESEARCH Open Access CXCL5 signaling is a shared pathway of neuroinflammation and blood–brain barrier injury contributing to white matter injury in the immature brain Lin-Yu Wang1,2, Yi-Fang Tu3,4, Yung-Chieh Lin3,4 and Chao-Ching Huang3,5,6* Abstract Background: In very preterm infants, white matter injury is a prominent brain injury, and hypoxic ischemia (HI) and infection are the two primary pathogenic factors of this injury. Microglia and microvascular endothelial cells closely interact; therefore, a common signaling pathway may cause neuroinflammation and blood–brain barrier (BBB) damage after injury to the immature brain. CXC chemokine ligand 5 (CXCL5) is produced in inflammatory and endothelial cells by various organs in response to insults. CXCL5 levels markedly increased in the amniotic cavity in response to intrauterine infection and preterm birth in clinical studies. The objective of this study is to determine whether CXCL5 signaling is a shared pathway of neuroinflammation and BBB injury that contributes to white matter injury in the immature brain. Methods: Postpartum day 2 (P2) rat pups received lipopolysaccharide (LPS) followed by 90-min HI. Immunohistochemical analyses were performed to determine microglial activation, neutrophil infiltration, BBB damage, and myelin basic protein and glial fibrillary acidic protein expression. Immunofluorescence experiments were performed to determine the cellular distribution of CXCL5. Pharmacological tests were performed to inhibit or enhance CXCL5 activity. Results: On P2, predominant increases in microglial activation and BBB damage were observed 24 h after LPS-sensitized HI induction, and white matter injury (decreasedmyelinationandincreasedastrogliosis) was observed on P12 compared with controls.
    [Show full text]