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Berkenfeld K, Carneiro S, Corzo C, Laffleur F, Salar-Behzadi S, Winkeljann B, Esfahani G. Formulation strategies, preparation methods, and devices for pulmonary delivery of biologics. Eur J Pharm Biopharm 2024; 204:114530. [PMID: 39393712 DOI: 10.1016/j.ejpb.2024.114530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2024] [Revised: 10/07/2024] [Accepted: 10/08/2024] [Indexed: 10/13/2024]
Abstract
Biological products, including vaccines, blood components, and recombinant therapeutic proteins, are derived from natural sources such as humans, animals, or microorganisms and are typically produced using advanced biotechnological methods. The success of biologics, particularly monoclonal antibodies, can be attributed to their favorable safety profiles and target specificity. However, their large molecular size presents significant challenges in drug delivery, particularly in overcoming biological barriers. Pulmonary delivery has emerged as a promising route for administering biologics, offering non-invasive delivery with rapid absorption, high systemic bioavailability, and avoidance of first-pass metabolism. This review first details the anatomy and physiological barriers of the respiratory tract and the associated challenges of pulmonary drug delivery (PDD). It further discusses innovations in PDD, the impact of particle size on drug deposition, and the use of secondary particles, such as nanoparticles, to enhance bioavailability and targeting. The review also explains various devices used for PDD, including dry powder inhalers (DPIs) and nebulizers, highlighting their advantages and limitations in delivering biologics. The role of excipients in improving the stability and performance of inhalation products is also addressed. Since dry powders are considered the suitable format for delivering biomolecules, particular emphasis is placed on the excipients used in DPI development. The final section of the article reviews and compares various dry powder manufacturing methods, clarifying their clinical relevance and potential for future applications in the field of inhalable drug formulation.
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Affiliation(s)
- Kai Berkenfeld
- Laboratory of Pharmaceutical Technology and Biopharmaceutics, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Street 3, 53121 Bonn, Germany; Pharmaceutical Engineering and Technology Research Scientists (PETRS)
| | - Simone Carneiro
- Department of Pharmacy, Ludwig-Maximilians-Universität Munich, Butenandtstrasse 5-13, Haus B, 81377 München, Germany; Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, München 80799, Germany; Pharmaceutical Engineering and Technology Research Scientists (PETRS)
| | - Carolina Corzo
- Research Center Pharmaceutical Engineering GmbH, Graz, Austria; Pharmaceutical Engineering and Technology Research Scientists (PETRS)
| | - Flavia Laffleur
- Department of Pharmaceutical Technology, Institute of Pharmacy, Center for Chemistry and Biomedicine, University of Innsbruck, Innrain 80-82, 6020 Innsbruck, Austria; Pharmaceutical Engineering and Technology Research Scientists (PETRS)
| | - Sharareh Salar-Behzadi
- Research Center Pharmaceutical Engineering GmbH, Graz, Austria; Institute of Pharmaceutical Sciences, Department of Pharmaceutical Technology, University of Graz, Graz, Austria; Pharmaceutical Engineering and Technology Research Scientists (PETRS)
| | - Benjamin Winkeljann
- Department of Pharmacy, Ludwig-Maximilians-Universität Munich, Butenandtstrasse 5-13, Haus B, 81377 München, Germany; Center for NanoScience (CeNS), Ludwig-Maximilians-Universität München, München 80799, Germany; RNhale GmbH, München 81371, Germany; Comprehensive Pneumology Center Munich (CPC-M), Helmholtz Munich, German Center for Lung Research (DZL), 81377 Munich, Germany; Pharmaceutical Engineering and Technology Research Scientists (PETRS)
| | - Golbarg Esfahani
- Department of Pharmaceutical Technology, Institute of Pharmacy, Martin Luther University Halle-Wittenberg, Wolfgang-Langenbeck-Straße 4, Halle 06120, Saale, Germany; Pharmaceutical Engineering and Technology Research Scientists (PETRS).
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Hamed M, Kotob MH, Abou Khalil NS, Anwari EA, El Gazzar WB, Idriss SKA, Fakhry ME, Farag AA, Sabra MS, Salaah SM, Abdel-Zaher S, Yehia Saad FA, Naguib M, Lee JS, Sayed AEDH. Hyaluronic acid impacts hematological endpoints and spleen histological features in African catfish (Clarias gariepinus). BMC Vet Res 2024; 20:294. [PMID: 38970005 PMCID: PMC11225171 DOI: 10.1186/s12917-024-04113-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Accepted: 06/04/2024] [Indexed: 07/07/2024] Open
Abstract
Since its identification in the vitreous humour of the eye and laboratory biosynthesis, hyaluronic acid (HA) has been a vital component in several pharmaceutical, nutritional, medicinal, and cosmetic uses. However, little is known about its potential toxicological impacts on aquatic inhabitants. Herein, we investigated the hematological response of Clarias gariepinus to nominal doses of HA. To achieve this objective, 72 adult fish were randomly and evenly distributed into four groups: control, low-dose (0.5 mg/l HA), medium-dose (10 mg/l HA), and high-dose (100 mg/l HA) groups for two weeks each during both the exposure and recovery periods. The findings confirmed presence of anemia, neutrophilia, leucopoenia, lymphopenia, and eosinophilia at the end of exposure to HA. In addition, poikilocytosis and a variety of cytomorphological disturbances were observed. Dose-dependent histological alterations in spleen morphology were observed in the exposed groups. After HA removal from the aquarium for 2 weeks, the groups exposed to the two highest doses still exhibited a notable decline in red blood cell count, hemoglobin concentration, mean corpuscular hemoglobin concentration, and an increase in mean corpuscular volume. Additionally, there was a significant rise in neutrophils, eosinophils, cell alterations, and nuclear abnormalities percentages, along with a decrease in monocytes, coupled with a dose-dependent decrease in lymphocytes. Furthermore, only the highest dose of HA in the recovered groups continued to cause a significant increase in white blood cells. White blood cells remained lower, and the proportion of apoptotic RBCs remained higher in the high-dose group. The persistence of most of the haematological and histological disorders even after recovery period indicates a failure of physiological compensatory mechanisms to overcome the HA-associated problems or insufficient duration of recovery. Thus, these findings encourage the inclusion of this new hazardous agent in the biomonitoring program and provide a specific pattern of hematological profile in HA-challenged fish. Further experiments are highly warranted to explore other toxicological hazards of HA using dose/time window protocols.
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Affiliation(s)
- Mohamed Hamed
- Department of Zoology, Faculty of Science, Al-Azhar University (Assiut Branch), Assiut, 71524, Egypt
- Department of Comparative Biomedical Sciences, School of Veterinary Medicine, Louisiana State University, Skip Bertman Drive, Baton Rouge, LA, 70803, USA
| | - Mohamed H Kotob
- Department of Pathology, Faculty of Veterinary Medicine, Assiut University, Assiut, 71526, Egypt
- Division of Pharmacology and Toxicology, Department of Pharmaceutical Sciences, University of Vienna, Vienna, 1090, Austria
| | - Nasser S Abou Khalil
- Department of Animal Physiology and Biochemistry, Faculty of Veterinary Medicine, Badr University, Assuit, Egypt
- Department of Medical Physiology, Faculty of Medicine, Assuit University, Assiut, 71516, Egypt
| | - Esraa A Anwari
- Department of Zoology, Faculty of Science, Assiut University, Assiut, 71516, Egypt
| | - Walaa Bayoumie El Gazzar
- Department of Anatomy, Physiology and Biochemistry, Faculty of Medicine, the Hashemite University, Zarqa, 13133, Jordan
- 9Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Benha University, Benha City, 13518, Egypt
| | - Shaimaa K A Idriss
- Department of Aquatic Animal Medicine and Management, Faculty of Veterinary Medicine, Assiut University, Assiut, 71516, Egypt
| | - Michel E Fakhry
- Department of Medical Biochemistry and molecular biology, Faculty of Medicine, Assiut University, Assiut, 71516, Egypt
| | - Amina A Farag
- Department of Forensic Medicine and Clinical Toxicology, Faculty of Medicine, Benha University, Benha City, 13518, Egypt
| | - Mahmoud S Sabra
- Department of Pharmacology, Faculty of Veterinary Medicine, Assiut University, Assiut, 71516, Egypt
| | - Sally M Salaah
- Fresh Water Division, National Institute of Oceanography and Fisheries, NIOF, Cairo, Egypt
| | - Souzan Abdel-Zaher
- Department of Molecular Biology, Molecular Biology Research & Studies Institute, Assiut University, Assiut, 71516, Egypt
| | - Fatma Alzahraa Yehia Saad
- Department of Biotechnology, Molecular Biology Research & Studies Institute, Assiut University, Assiut, 71516, Egypt
| | - Mervat Naguib
- Department of Zoology, Faculty of Science, Assiut University, Assiut, 71516, Egypt
| | - Jae-Seong Lee
- Department of Biological Sciences, College of Science, Sungkyunkwan University, Suwon, 16419, South Korea
| | - Alaa El-Din H Sayed
- Department of Zoology, Faculty of Science, Assiut University, Assiut, 71516, Egypt.
- Department of Molecular Biology, Molecular Biology Research & Studies Institute, Assiut University, Assiut, 71516, Egypt.
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Lierova A, Kasparova J, Filipova A, Cizkova J, Pekarova L, Korecka L, Mannova N, Bilkova Z, Sinkorova Z. Hyaluronic Acid: Known for Almost a Century, but Still in Vogue. Pharmaceutics 2022; 14:838. [PMID: 35456670 PMCID: PMC9029726 DOI: 10.3390/pharmaceutics14040838] [Citation(s) in RCA: 29] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 04/03/2022] [Accepted: 04/04/2022] [Indexed: 02/04/2023] Open
Abstract
Hyaluronic acid (HA) has a special position among glycosaminoglycans. As a major component of the extracellular matrix (ECM). This simple, unbranched polysaccharide is involved in the regulation of various biological cell processes, whether under physiological conditions or in cases of cell damage. This review summarizes the history of this molecule's study, its distinctive metabolic pathway in the body, its unique properties, and current information regarding its interaction partners. Our main goal, however, is to intensively investigate whether this relatively simple polymer may find applications in protecting against ionizing radiation (IR) or for therapy in cases of radiation-induced damage. After exposure to IR, acute and belated damage develops in each tissue depending upon the dose received and the cellular composition of a given organ. A common feature of all organ damage is a distinct change in composition and structure of the ECM. In particular, the important role of HA was shown in lung tissue and the variability of this flexible molecule in the complex mechanism of radiation-induced lung injuries. Moreover, HA is also involved in intermediating cell behavior during morphogenesis and in tissue repair during inflammation, injury, and would healing. The possibility of using the HA polymer to affect or treat radiation tissue damage may point to the missing gaps in the responsible mechanisms in the onset of this disease. Therefore, in this article, we will also focus on obtaining answers from current knowledge and the results of studies as to whether hyaluronic acid can also find application in radiation science.
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Affiliation(s)
- Anna Lierova
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence, 500 01 Hradec Kralove, Czech Republic; (A.F.); (J.C.); (L.P.); (Z.S.)
| | - Jitka Kasparova
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, 532 10 Pardubice, Czech Republic; (J.K.); (L.K.); (N.M.); (Z.B.)
| | - Alzbeta Filipova
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence, 500 01 Hradec Kralove, Czech Republic; (A.F.); (J.C.); (L.P.); (Z.S.)
| | - Jana Cizkova
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence, 500 01 Hradec Kralove, Czech Republic; (A.F.); (J.C.); (L.P.); (Z.S.)
| | - Lenka Pekarova
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence, 500 01 Hradec Kralove, Czech Republic; (A.F.); (J.C.); (L.P.); (Z.S.)
| | - Lucie Korecka
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, 532 10 Pardubice, Czech Republic; (J.K.); (L.K.); (N.M.); (Z.B.)
| | - Nikola Mannova
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, 532 10 Pardubice, Czech Republic; (J.K.); (L.K.); (N.M.); (Z.B.)
| | - Zuzana Bilkova
- Department of Biological and Biochemical Sciences, Faculty of Chemical Technology, University of Pardubice, 532 10 Pardubice, Czech Republic; (J.K.); (L.K.); (N.M.); (Z.B.)
| | - Zuzana Sinkorova
- Department of Radiobiology, Faculty of Military Health Sciences, University of Defence, 500 01 Hradec Kralove, Czech Republic; (A.F.); (J.C.); (L.P.); (Z.S.)
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Gao J, Xia Z, Mary HB, Joseph J, Luo JN, Joshi N. Overcoming barriers for intra-articular delivery of disease-modifying osteoarthritis drugs. Trends Pharmacol Sci 2022; 43:171-187. [PMID: 35086691 PMCID: PMC8840969 DOI: 10.1016/j.tips.2021.12.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2021] [Revised: 11/27/2021] [Accepted: 12/20/2021] [Indexed: 02/07/2023]
Abstract
Despite four decades of research in intra-articular drug delivery systems (DDS) and two decades of advances in disease-modifying osteoarthritis drugs (DMOADs), there is still no clinically available disease-modifying therapy for osteoarthritis (OA). Multiple barriers compromise intra-articular DMOAD delivery. Although multiple exciting approaches have been developed to overcome these barriers, there are still outstanding questions. We make several recommendations that can help in fully overcoming these barriers. Considering OA heterogeneity, we also propose a patient-centered, bottom-up workflow to guide preclinical development of DDS-based intra-articular DMOAD therapies. Overall, we expect this review to inspire paradigm-shifting innovations for developing next-generation DDS that can enable clinical translation of intra-articular DMOADs.
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Affiliation(s)
- Jingjing Gao
- Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - Ziting Xia
- Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Helna B Mary
- Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - John Joseph
- Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA
| | - James N Luo
- Harvard Medical School, Boston, MA 02115, USA; Department of Surgery, Brigham and Women's Hospital, Boston, MA 02115, USA
| | - Nitin Joshi
- Center for Nanomedicine, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, Boston, MA 02115, USA.
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Valente SA, Silva LM, Lopes GR, Sarmento B, Coimbra MA, Passos CP. Polysaccharide-based formulations as potential carriers for pulmonary delivery - A review of their properties and fates. Carbohydr Polym 2022; 277:118784. [PMID: 34893219 DOI: 10.1016/j.carbpol.2021.118784] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/28/2021] [Accepted: 10/14/2021] [Indexed: 12/31/2022]
Abstract
Polysaccharides can be elite carriers for therapeutic molecules due to their versatility and low probability to trigger toxicity and immunogenic responses. Local and systemic therapies can be achieved through particle pulmonary delivery, a promising non-invasive alternative. Successful pulmonary delivery requires particles with appropriate flowability to reach alveoli and avoid premature clearance mechanisms. Polysaccharides can form micro-, nano-in-micro-, and large porous particles, aerogels, and hydrogels. Herein, the characteristics of polysaccharides used in drug formulations for pulmonary delivery are reviewed, providing insights into structure-function relationships. Charged polysaccharides can confer mucoadhesion, whereas the ability for specific sugar recognition may confer targeting capacity for alveolar macrophages. The method of particle preparation must be chosen considering the properties of the components and the delivery device to be utilized. The fate of polysaccharide-based carriers is dependent on enzyme-triggered hydrolytic and/or oxidative mechanisms, allowing their complete degradation and elimination through urine or reutilization of released monosaccharides.
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Affiliation(s)
- Sara A Valente
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Lisete M Silva
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Guido R Lopes
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Bruno Sarmento
- INEB - Institute of Biomedical Engineering Instituto, University of Porto, 4150-180 Porto, Portugal; i3S - Institute for Research & Innovation in Health, University of Porto, 4150-180 Porto, Portugal; CESPU - Institute for Research and Advanced Training in Health Sciences and Technologies, 4585-116 Gandra, Portugal
| | - Manuel A Coimbra
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal
| | - Cláudia P Passos
- LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193 Aveiro, Portugal.
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Lee JH, Liu A, Park JH, Kato H, Hao Q, Zhang X, Zhou L, Lee JW. Therapeutic Effects of Hyaluronic Acid in Peritonitis-Induced Sepsis in Mice. Shock 2020; 54:488-497. [PMID: 31977961 PMCID: PMC7369239 DOI: 10.1097/shk.0000000000001512] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Intra-abdominal infection is the second most common cause of sepsis, and the mortality rate from abdominal sepsis remains high. High molecular weight (HMW) hyaluronic acid (HA) has been studied in sterile injury models as an anti-inflammatory and anti-permeability agent. This study evaluated the therapeutic effects of intraperitoneal HMW HA administration in mice with peritonitis-induced sepsis. Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP), followed 4 h later by an intraperitoneal injection of HMW HA (20 mg/kg) solution or phosphate buffered saline (PBS). Survival, physiological data, organ injury, bacterial burden, and inflammatory cytokine levels were assessed in the CLP mice. To assess the effect of HA on macrophage phagocytosis activity, RAW264.7 cells, primed with lipopolysaccharide, were exposed with either PBS or HMW HA (500 μg/mL) prior to exposure to 10 CFU of E coli bacteria. HMW HA instillation significantly improved blood oxygenation, lung histology, and survival in CLP mice. Inflammatory cytokine levels in the plasma and bacterial burdens in the lung and spleen were significantly decreased by HA administration at 24 h after CLP. At 6 h after CLP, HA significantly decreased bacterial burden in the peritoneal lavage fluid. HMW HA administration significantly increased E coli bacterial phagocytosis by RAW264.7 cells in part through increased phosphorylation of ezrin/radixin/moesin, a known downstream target of CD44 (a HA receptor); ezrin inhibition abolished the enhanced phagocytosis by RAW264.7 cells induced by HA. Intraperitoneal administration of HMW HA had therapeutic effects against CLP-induced sepsis in terms of suppressing inflammation and increasing antimicrobial activity.
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Affiliation(s)
- Jae Hoon Lee
- Department of Anesthesiology, University of California, San Francisco, San Francisco, California
- Department of Anesthesiology and Pain Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Airan Liu
- Department of Anesthesiology, University of California, San Francisco, San Francisco, California
| | - Jeong-Hyun Park
- Department of Anesthesiology, University of California, San Francisco, San Francisco, California
| | - Hideya Kato
- Department of Anesthesiology, University of California, San Francisco, San Francisco, California
| | - Qi Hao
- Department of Anesthesiology, University of California, San Francisco, San Francisco, California
| | - Xiwen Zhang
- Department of Anesthesiology, University of California, San Francisco, San Francisco, California
| | - Li Zhou
- Department of Anesthesiology, University of California, San Francisco, San Francisco, California
| | - Jae-Woo Lee
- Department of Anesthesiology, University of California, San Francisco, San Francisco, California
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Primavera R, Kevadiya BD, Swaminathan G, Wilson RJ, De Pascale A, Decuzzi P, Thakor AS. Emerging Nano- and Micro-Technologies Used in the Treatment of Type-1 Diabetes. NANOMATERIALS (BASEL, SWITZERLAND) 2020; 10:E789. [PMID: 32325974 PMCID: PMC7221526 DOI: 10.3390/nano10040789] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Revised: 04/07/2020] [Accepted: 04/14/2020] [Indexed: 02/06/2023]
Abstract
Type-1 diabetes is characterized by high blood glucose levels due to a failure of insulin secretion from beta cells within pancreatic islets. Current treatment strategies consist of multiple, daily injections of insulin or transplantation of either the whole pancreas or isolated pancreatic islets. While there are different forms of insulin with tunable pharmacokinetics (fast, intermediate, and long-acting), improper dosing continues to be a major limitation often leading to complications resulting from hyper- or hypo-glycemia. Glucose-responsive insulin delivery systems, consisting of a glucose sensor connected to an insulin infusion pump, have improved dosing but they still suffer from inaccurate feedback, biofouling and poor patient compliance. Islet transplantation is a promising strategy but requires multiple donors per patient and post-transplantation islet survival is impaired by inflammation and suboptimal revascularization. This review discusses how nano- and micro-technologies, as well as tissue engineering approaches, can overcome many of these challenges and help contribute to an artificial pancreas-like system.
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Affiliation(s)
- Rosita Primavera
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA 94304, USA; (R.P.); (B.D.K.); (G.S.); (R.J.W.)
- Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, 16163 Genoa, Italy
| | - Bhavesh D Kevadiya
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA 94304, USA; (R.P.); (B.D.K.); (G.S.); (R.J.W.)
| | - Ganesh Swaminathan
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA 94304, USA; (R.P.); (B.D.K.); (G.S.); (R.J.W.)
| | - Rudilyn Joyce Wilson
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA 94304, USA; (R.P.); (B.D.K.); (G.S.); (R.J.W.)
| | - Angelo De Pascale
- Unit of Endocrinology, Department of Internal Medicine & Medical Specialist (DIMI), University of Genoa, 16163 Genoa, Italy;
| | - Paolo Decuzzi
- Laboratory of Nanotechnology for Precision Medicine, Fondazione Istituto Italiano di Tecnologia, 16163 Genoa, Italy
| | - Avnesh S Thakor
- Interventional Regenerative Medicine and Imaging Laboratory, Department of Radiology, Stanford University, Palo Alto, CA 94304, USA; (R.P.); (B.D.K.); (G.S.); (R.J.W.)
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Breborowicz A, Oreopoulos DG. Evidence for the Presence of Chronic Inflammation during Peritoneal Dialysis: Therapeutic Implications. Perit Dial Int 2020. [DOI: 10.1177/089686089701702s07] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
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Breborowicz A, Korybalska K, Grzybowski A, Tobis KW, Oreopoulos DG, Martis L. Synthesis of Hyaluronic Acid by Human Peritoneal Mesothelial Cells: Effect of Cytokines and Dialysa Te. Perit Dial Int 2020. [DOI: 10.1177/089686089601600410] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Objective To assess effects of the inflammatory cytokines (IL-1-beta, TNF-alpha, TGF-beta 1) and dialysate effluent on synthesis of hyaluronic acid by human peritoneal mesothelial cells (HMC) in in vitro culture. Methods Dialysate effluent was collected after the overnight dwell of DianeaI 1.5% from patients during CAPD training. HMC were obtained from omentum from nonuremic donors or were harvested from the dialysate effluent from CAPD patients. Synthesis of hyaluronic acid was studied on monolayers of HMC, which were deprived of serum 48 hours priortoexperiment. Effects of cytokines were tested in a medium with low serum concentration (0.1%) or in medium mixed (1:1 v/v) with the autologous dialysate. Hyaluronic acid level in medium was measured with radioimmunoassay. Results Cytokines enhanced synthesis of hyaluronic acid by HMC, and the strongest effect was induced by IL-1. Effluent dialysate stimulates synthesis of hyaluronic acid stronger than 10% FCS. Effluent dialysate and IL-1 synergistically enhance synthesis of hyaluronic acid by HMC. Conclusion Effluent dialysate from CAPD patients stimulates production of hyaluronic acid by HMC and acts synergistically with cytokines.
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Affiliation(s)
| | | | | | | | | | - Leo Martis
- Baxter Healthcare Corporation, McGaw Park, Illinois, U.S.A
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Breborowicz A, Oreopoulos DG. Physiological Approaches to Increase Biocompatibility of Peritoneal Dialysis. Perit Dial Int 2020. [DOI: 10.1177/089686089501507s11] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Affiliation(s)
- Andrzej Breborowicz
- Department of Pathophysiology, Medical School Poznan, Poland
- Division of Nephrology, University of Toronto, Toronto, Canada
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11
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Neves MI, Araújo M, Moroni L, da Silva RM, Barrias CC. Glycosaminoglycan-Inspired Biomaterials for the Development of Bioactive Hydrogel Networks. Molecules 2020; 25:E978. [PMID: 32098281 PMCID: PMC7070556 DOI: 10.3390/molecules25040978] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 02/14/2020] [Accepted: 02/20/2020] [Indexed: 02/07/2023] Open
Abstract
Glycosaminoglycans (GAG) are long, linear polysaccharides that display a wide range of relevant biological roles. Particularly, in the extracellular matrix (ECM) GAG specifically interact with other biological molecules, such as growth factors, protecting them from proteolysis or inhibiting factors. Additionally, ECM GAG are partially responsible for the mechanical stability of tissues due to their capacity to retain high amounts of water, enabling hydration of the ECM and rendering it resistant to compressive forces. In this review, the use of GAG for developing hydrogel networks with improved biological activity and/or mechanical properties is discussed. Greater focus is given to strategies involving the production of hydrogels that are composed of GAG alone or in combination with other materials. Additionally, approaches used to introduce GAG-inspired features in biomaterials of different sources will also be presented.
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Affiliation(s)
- Mariana I. Neves
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (M.I.N.); (M.A.)
- INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
- FEUP-Faculdade de Engenharia da Universidade do Porto, Departamento de Engenharia Metalúrgica e de Materiais, Rua Dr Roberto Frias s/n, 4200-465 Porto, Portugal
| | - Marco Araújo
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (M.I.N.); (M.A.)
- INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
| | - Lorenzo Moroni
- MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, 6229 ET Maastricht, The Netherlands;
| | - Ricardo M.P. da Silva
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (M.I.N.); (M.A.)
- INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
| | - Cristina C. Barrias
- i3S-Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal; (M.I.N.); (M.A.)
- INEB-Instituto de Engenharia Biomédica, Universidade do Porto, Rua Alfredo Allen 208, 4200-135 Porto, Portugal
- ICBAS-Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Rua de Jorge Viterbo Ferreira 228, 4050-313 Porto, Portugal
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12
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Hyaluronan biology: A complex balancing act of structure, function, location and context. Matrix Biol 2019; 78-79:1-10. [PMID: 30802498 DOI: 10.1016/j.matbio.2019.02.002] [Citation(s) in RCA: 216] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 02/09/2019] [Accepted: 02/11/2019] [Indexed: 02/07/2023]
Abstract
Cell-matrix interactions are fundamental to many developmental, homeostatic, immune and pathologic processes. Hyaluronan (HA), a critical component of the extracellular matrix (ECM) that regulates normal structural integrity and development, also regulates tissue responses during injury, repair, and regeneration. Though simple in its primary structure, HA regulates biological responses in a highly complex manner with balanced contributions from its molecular size and concentration, synthesis versus enzymatic and/or oxidative-nitrative fragmentation, interactions with key HA binding proteins and cell associated receptors, and its cell context-specific signaling. This review highlights the different, but inter-related factors that dictate the biological activity of HA and introduces the overarching themes that weave throughout this special issue of Matrix Biology on hyaluronan.
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Abstract
Over 50 years after its first description, Bronchopulmonary Dysplasia (BPD) remains a devastating pulmonary complication in preterm infants with respiratory failure and develops in 30-50% of infants less than 1000-gram birth weight. It is thought to involve ventilator- and oxygen-induced damage to an immature lung that results in an inflammatory response and ends in aberrant lung development with dysregulated angiogenesis and alveolarization. Significant morbidity and mortality are associated with this most common chronic lung disease of childhood. Thus, any therapies that decrease the incidence or severity of this condition would have significant impact on morbidity, mortality, human costs, and healthcare expenditure. It is clear that an inflammatory response and the elaboration of growth factors and cytokines are associated with the development of BPD. Numerous approaches to control the inflammatory process leading to the development of BPD have been attempted. This review will examine the anti-inflammatory approaches that are established or hold promise for the prevention or treatment of BPD.
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Affiliation(s)
- Rashmin C Savani
- Center for Pulmonary & Vascular Biology, Division of Neonatal-Perinatal Medicine, The Department of Pediatrics, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9063, USA.
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14
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Faust HJ, Sommerfeld SD, Rathod S, Rittenbach A, Ray Banerjee S, Tsui BMW, Pomper M, Amzel ML, Singh A, Elisseeff JH. A hyaluronic acid binding peptide-polymer system for treating osteoarthritis. Biomaterials 2018; 183:93-101. [PMID: 30149233 DOI: 10.1016/j.biomaterials.2018.08.045] [Citation(s) in RCA: 63] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2018] [Revised: 08/13/2018] [Accepted: 08/20/2018] [Indexed: 01/20/2023]
Abstract
Hyaluronic acid (HA) is found naturally in synovial fluid and is utilized therapeutically to treat osteoarthritis (OA). Here, we employed a peptide-polymer cartilage coating platform to localize HA to the cartilage surface for the purpose of treating post traumatic osteoarthritis. The objective of this study was to increase efficacy of the peptide-polymer platform in reducing OA progression in a mouse model of post-traumatic OA without exogenous HA supplementation. The peptide-polymer is composed of an HA-binding peptide (HABP) conjugated to a heterobifunctional poly (ethylene glycol) (PEG) chain and a collagen binding peptide (COLBP). We created a library of different peptide-polymers and characterized their HA binding properties in vitro using quartz crystal microbalance (QCM-D) and isothermal calorimetry (ITC). The peptide polymers were further tested in vivo in an anterior cruciate ligament transection (ACLT) murine model of post traumatic OA. The peptide-polymer with the highest affinity to HA as tested by QCM-D (∼4-fold greater binding compared to other peptides tested) and by ITC (∼3.8-fold) was HABP2-8-arm PEG-COLBP. Biotin tagging demonstrated that HABP2-8-arm PEG-COLBP localizes to both cartilage defects and synovium. In vivo, HABP2-8-arm PEG-COLBP treatment and the clinical HA comparator Orthovisc lowered levels of inflammatory genes including IL-6, IL-1B, and MMP13 compared to saline treated animals and increased aggrecan expression in young mice. HABP2-8-arm PEG-COLBP and Orthovisc also reduced pain as measured by incapacitance and hotplate testing. Cartilage degeneration as measured by OARSI scoring was also reduced by HABP2-8-arm PEG-COLBP and Orthovisc. In aged mice, HABP2-8-arm PEG-COLBP therapeutic efficacy was similar to its efficacy in young mice, but Orthovisc was less efficacious and did not significantly improve OARSI scoring. These results demonstrate that HABP2-8-arm PEG-COLBP is effective at reducing PTOA progression.
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Affiliation(s)
- Heather J Faust
- Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21287, USA
| | - Sven D Sommerfeld
- Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21287, USA
| | - Sona Rathod
- Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21287, USA
| | - Andrew Rittenbach
- Information Sciences Institute, University of Southern California, Arlington, VA 22203, USA
| | | | - Benjamin M W Tsui
- Department of Radiology, Johns Hopkins University, Baltimore, MD, 21287, USA
| | - Martin Pomper
- Department of Radiology, Johns Hopkins University, Baltimore, MD, 21287, USA
| | - Mario L Amzel
- Department of Biophysics and Biophysical Chemistry, Johns Hopkins University, Baltimore, MD, 21218, USA
| | - Anirudha Singh
- Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21287, USA; Department of Urology, The James Buchanan Brady Urological Institute, The Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA; Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, MD, 21218, USA
| | - Jennifer H Elisseeff
- Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, 21287, USA.
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Smith TD, Nagalla RR, Chen EY, Liu WF. Harnessing macrophage plasticity for tissue regeneration. Adv Drug Deliv Rev 2017; 114:193-205. [PMID: 28449872 DOI: 10.1016/j.addr.2017.04.012] [Citation(s) in RCA: 81] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2017] [Revised: 04/19/2017] [Accepted: 04/21/2017] [Indexed: 12/25/2022]
Abstract
Macrophages are versatile and plastic effector cells of the immune system, and contribute to diverse immune functions including pathogen or apoptotic cell removal, inflammatory activation and resolution, and tissue healing. Macrophages function as signaling regulators and amplifiers, and influencing their activity is a powerful approach for controlling inflammation or inducing a wound-healing response in regenerative medicine. This review discusses biomaterials-based approaches for altering macrophage activity, approaches for targeting drugs to macrophages, and approaches for delivering macrophages themselves as a therapeutic intervention.
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16
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Kim M, Hwang Y, Tae G. The enhanced anti-tissue adhesive effect of injectable pluronic-HA hydrogel by poly(γ-glutamic acid). Int J Biol Macromol 2016; 93:1603-1611. [DOI: 10.1016/j.ijbiomac.2016.02.064] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 02/23/2016] [Accepted: 02/24/2016] [Indexed: 10/22/2022]
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Lee YJ, Kim SA, Lee SH. Hyaluronan suppresses lidocaine-induced apoptosis of human chondrocytes in vitro by inhibiting the p53-dependent mitochondrial apoptotic pathway. Acta Pharmacol Sin 2016; 37:664-73. [PMID: 27041463 DOI: 10.1038/aps.2015.151] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Accepted: 12/20/2015] [Indexed: 11/09/2022]
Abstract
AIM Intra-articular injection of local anesthetics (LAs) is a common procedure for therapeutic purposes. However, LAs have been found toxic to articular cartilage, and hyaluronan may attenuate this toxicity. In this study we investigated whether hyaluronan attenuated lidocaine-induced chondrotoxicity, and if so, to elucidate the underlying mechanisms. METHODS Human chondrocyte cell line SW1353 and newly isolated murine chondrocytes were incubated in culture medium containing hyaluronan and/or lidocaine for 72 h. Cell viability was evaluated using MTT assay. Cell apoptosis was detected with DAPI staining, caspase 3/7 activity assay and flow cytometry. Cell cycle distributions, ROS levels and mitochondrial membrane potential (ΔΨm) were determined using flow cytometry. The expression of p53 and p53-regulated gene products was measured with Western blotting. RESULTS Lidocaine (0.005%-0.03%) dose-dependently decreased the viability of SW1353 cells. This local anesthetic (0.015%, 0.025%) induced apoptosis, G2/M phase arrest and loss of ΔΨm, and markedly increased ROS production in SW1353 cells. Hyaluronan (50-800 μg/mL) alone did not affect the cell viability, but co-treatment with hyaluronan (200 μg/mL) significantly attenuated lidocaine-induced apoptosis and other abnormalities in SW1353 cells. Furthermore, co-treatment with lidocaine and hyaluronan significantly decreased the levels of p53 and its transcription targets Bax and p21 in SW1353 cells, although treatment with lidocaine alone did not significantly change these proteins. Similar results were obtained in ex vivo cultured murine chondrocytes. CONCLUSION Hyaluronan suppresses lidocaine-induced apoptosis of human chondrocytes in vitro through inhibiting the p53-dependent mitochondrial apoptotic pathway.
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18
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El-Sherbiny IM, El-Baz NM, Yacoub MH. Inhaled nano- and microparticles for drug delivery. Glob Cardiol Sci Pract 2015; 2015:2. [PMID: 26779496 PMCID: PMC4386009 DOI: 10.5339/gcsp.2015.2] [Citation(s) in RCA: 117] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Accepted: 01/28/2015] [Indexed: 12/23/2022] Open
Abstract
The 21st century has seen a paradigm shift to inhaled therapy, for both systemic and local drug delivery, due to the lung's favourable properties of a large surface area and high permeability. Pulmonary drug delivery possesses many advantages, including non-invasive route of administration, low metabolic activity, control environment for systemic absorption and avoids first bypass metabolism. However, because the lung is one of the major ports of entry, it has multiple clearance mechanisms, which prevent foreign particles from entering the body. Although these clearance mechanisms maintain the sterility of the lung, clearance mechanisms can also act as barriers to the therapeutic effectiveness of inhaled drugs. This effectiveness is also influenced by the deposition site and delivered dose. Particulate-based drug delivery systems have emerged as an innovative and promising alternative to conventional inhaled drugs to circumvent pulmonary clearance mechanisms and provide enhanced therapeutic efficiency and controlled drug release. The principle of multiple pulmonary clearance mechanisms is reviewed, including mucociliary, alveolar macrophages, absorptive, and metabolic degradation. This review also discusses the current approaches and formulations developed to achieve optimal pulmonary drug delivery systems.
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Affiliation(s)
- Ibrahim M El-Sherbiny
- Zewail City of Science and Technology, Center for Materials Science, 6 October City, 12588 Giza, Egypt
| | - Nancy M El-Baz
- Zewail City of Science and Technology, Center for Materials Science, 6 October City, 12588 Giza, Egypt
| | - Magdi H Yacoub
- Harefield Heart Science Centre, National Heart and Lung Institute, Imperial College, London, UK
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Braga PC, Dal Sasso M, Lattuada N, Greco V, Sibilia V, Zucca E, Stucchi L, Ferro E, Ferrucci F. Antioxidant activity of hyaluronic acid investigated by means of chemiluminescence of equine neutrophil bursts and electron paramagnetic resonance spectroscopy. J Vet Pharmacol Ther 2014; 38:48-54. [DOI: 10.1111/jvp.12141] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 05/14/2014] [Indexed: 01/18/2023]
Affiliation(s)
- P. C. Braga
- Centre of Respiratory Pharmacology; School of Medicine; Università degli Studi di Milano; Milano Italy
- Department of Medical Biotechnology and Translational Medicine; School of Medicine; Università degli Studi di Milano; Milano Italy
| | - M. Dal Sasso
- Department of Medical Biotechnology and Translational Medicine; School of Medicine; Università degli Studi di Milano; Milano Italy
| | - N. Lattuada
- Department of Medical Biotechnology and Translational Medicine; School of Medicine; Università degli Studi di Milano; Milano Italy
| | - V. Greco
- Department of Medical Biotechnology and Translational Medicine; School of Medicine; Università degli Studi di Milano; Milano Italy
| | - V. Sibilia
- Department of Medical Biotechnology and Translational Medicine; School of Medicine; Università degli Studi di Milano; Milano Italy
| | - E. Zucca
- Department of Health, Animal Science and Food Safety; School of Veterinary Medicine; Università degli Studi di Milano; Milano Italy
| | - L. Stucchi
- Department of Health, Animal Science and Food Safety; School of Veterinary Medicine; Università degli Studi di Milano; Milano Italy
| | - E. Ferro
- Department of Health, Animal Science and Food Safety; School of Veterinary Medicine; Università degli Studi di Milano; Milano Italy
| | - F. Ferrucci
- Department of Health, Animal Science and Food Safety; School of Veterinary Medicine; Università degli Studi di Milano; Milano Italy
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He H, Zhang S, Tighe S, Son J, Tseng SCG. Immobilized heavy chain-hyaluronic acid polarizes lipopolysaccharide-activated macrophages toward M2 phenotype. J Biol Chem 2013; 288:25792-25803. [PMID: 23878196 DOI: 10.1074/jbc.m113.479584] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Despite the known anti-inflammatory effect of amniotic membrane, its action mechanism remains largely unknown. HC-HA complex (HC-HA) purified from human amniotic membrane consists of high molecular weight hyaluronic acid (HA) covalently linked to the heavy chain (HC) 1 of inter-α-trypsin inhibitor. In this study, we show that soluble HC-HA also contained pentraxin 3 and induced the apoptosis of both formyl-Met-Leu-Phe or LPS-activated neutrophils and LPS-activated macrophages while not affecting the resting cells. This enhanced apoptosis was caused by the inhibition of cell adhesion, spreading, and proliferation caused by HC-HA binding of LPS-activated macrophages and preventing adhesion to the plastic surface. Preferentially, soluble HC-HA promoted phagocytosis of apoptotic neutrophils in resting macrophages, whereas immobilized HC-HA promoted phagocytosis in LPS-activated macrophages. Upon concomitant LPS stimulation, immobilized HC-HA but not HA polarized macrophages toward the M2 phenotype by down-regulating IRF5 protein and preventing its nuclear localization and by down-regulating IL-12, TNF-α, and NO synthase 2. Additionally, IL-10, TGF-β1, peroxisome proliferator-activated receptor γ, LIGHT (TNF superfamily 14), and sphingosine kinase-1 were up-regulated, and such M2 polarization was dependent on TLR ligation. Collectively, these data suggest that HC-HA is a unique matrix component different from HA and uses multiple mechanisms to suppress M1 while promoting M2 phenotype. This anti-inflammatory action of HC-HA is highly desirable to promote wound healing in diseases heightened by unsuccessful transition from M1 to M2 phenotypes.
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Affiliation(s)
| | | | | | - Ji Son
- the Ocular Surface Research Education Foundation, and
| | - Scheffer C G Tseng
- From the TissueTech, Inc.,; the Ocular Surface Research Education Foundation, and; the Ocular Surface Center, Miami, Florida 33173.
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21
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Bor E, Bourla DH, Kaiserman I, Kremer I, Bahar I. The use of ophthalmic viscosurgical devices during donor's corneal harvesting. Curr Eye Res 2013; 38:626-9. [PMID: 23550779 DOI: 10.3109/02713683.2012.753093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
PURPOSE OF THE STUDY To evaluate the protective effect of Biolon (sodium-hyaluronate 1%) use on corneal endothelium, during donor's corneal harvesting. MATERIALS AND METHODS A prospective, randomized, double blind, comparative study was performed on 120 corneas donated from 60 donors. One cornea from each donor (n = 60) was harvested using intracameral injection of ophthalmic viscosurgical device (OVD), and the fellow cornea with no use of OVD (n = 60, control group). Endothelial cell density (ECD) values were obtained at the center of each corneal graft with a specular microscope one day after harvesting. RESULTS ECD in the OVD group were 2839 ± 412.5 cells/mm(2) and in the control group 2748 ± 429.7 cells/mm(2). (p = 0.03). Distribution curve of the difference in ECD between the OVD and no OVD eyes showed that 47% of the donors had > 100 cells/mm2 difference, and 32% of donors had >200 cells/mm(2) difference in favor of the OVD group. CONCLUSIONS Intracameral OVD injection during corneal graft harvesting may protect the endothelium from the mechanical damage induced during the procedure. Further investigation is needed before routine the use of intracameral OVD should be considered in this setting.
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Affiliation(s)
- Elite Bor
- Department of Ophthalmology, Rabin medical Center, Petah-Tikva, Israel
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22
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Jang CH, Cho YB, Choi CH, Lee JS, Kang SI. Effect of anti-adhesion barrier solution containing ciprofloxacin-hydrocortisone on abraded mucosa with otitis media. Int J Pediatr Otorhinolaryngol 2013; 77:19-24. [PMID: 23044358 DOI: 10.1016/j.ijporl.2012.09.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2012] [Revised: 09/10/2012] [Accepted: 09/14/2012] [Indexed: 11/30/2022]
Abstract
OBJECTIVE No study to date has assessed the anti-adhesive effect of new middle ear (ME) packing agents in. This study compared the anti-inflammatory and anti-adhesive effect of antibiotic-steroid containing packing agents in abraded mucosa of the ME inflammation. MATERIALS AND METHODS Transbullar injection of a saline suspension of Pseudomonas aeruginosa lipopolysaccharide (LPS) induced otitis media. ME mucosa of guinea pigs was abraded using a pick 30 min after LPS inoculation. The animals were divided into four groups of 10 guinea pigs each. In group A, ME cavity was preserved without any packing. In group B, ME cavity was packed with soluble hyaluronic acid-carboxymethyl cellulose (HA-CMC). In group C, the ME cavity was packed with soluble HA-CMC. In group D, the ME cavity was packed with antibiotic-steroid containing soluble HA-CMC. Otoendoscopic examination, auditory brainstem responses (ABRs), and radiographic examination using computerized tomography (CT) were performed at 2 weeks post-surgery. Histopathological evaluation for ME mucosa was performed by light microscopy (LM) and scanning electron microscopy (SEM). RESULTS Otoendoscopic findings and CT findings revealed that group D showed the best recovery of aeration in the ME compared to other groups. Recovery of ABRs threshold was significantly attenuated in group D. In LM and SEM findings, group D showed normalized mucosal thickening compared to other groups. CONCLUSION ME packing by antibiotic-steroid containing soluble HA-CMC may be useful in the abraded mucosa of the ME inflammation.
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Affiliation(s)
- Chul Ho Jang
- Department of Otolaryngology, Chonnam National University Medical School, Gwangju, South Korea.
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Abstract
The immune system plays a central role before and during parturition, including the main physiological processes of parturition: uterine contractions and cervical ripening. The immune system comprises white blood cells and their secretions. Polymorphonuclear cells and macrophages invade the cervical tissue and release compounds, such as oxygen radicals and enzymes, which break down the cervical matrix to allow softening and dilatation. During this inflammatory process, white blood cells undergo chemotaxis, adherence to endothelial cells, diapedesis, migration and activation. Factors that regulate white blood cell invasion and secretion include cytokines such as tumour necrosis factor and interleukins. Glucocorticoids, sex hormones and prostaglandins, affect cytokine synthesis. They also modulate the target cells, resulting in altered responses to cytokines. On the other hand, the immune system has profound effects on the hormonal system and prostaglandin synthesis. In animals, nitric oxide has marked effects on uterine quiescence during gestation. At the same time, it plays an important role in regulating the vascular tone of uterine arteries and has anti-adhesive effects on leukocytes. Cytokines are found in amniotic fluid, and in maternal and foetal serum at term and preterm. Several intrauterine cells have been shown to produce these cytoldnes. Since neither white blood cells, cytokines nor nitric oxide seem to be the ultimate intermediate for human parturition, the immune system is an additional but obligatory and underestimated component in the physiology of delivery. Scientists, obstetricians and anaesthesiologists must thus be aware of these processes.
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Tolg C, Hamilton SR, Zalinska E, McCulloch L, Amin R, Akentieva N, Winnik F, Savani R, Bagli DJ, Luyt LG, Cowman MK, McCarthy JB, Turley EA. A RHAMM mimetic peptide blocks hyaluronan signaling and reduces inflammation and fibrogenesis in excisional skin wounds. THE AMERICAN JOURNAL OF PATHOLOGY 2012; 181:1250-70. [PMID: 22889846 DOI: 10.1016/j.ajpath.2012.06.036] [Citation(s) in RCA: 94] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/10/2011] [Revised: 06/14/2012] [Accepted: 06/27/2012] [Indexed: 10/28/2022]
Abstract
Hyaluronan is activated by fragmentation and controls inflammation and fibroplasia during wound repair and diseases (eg, cancer). Hyaluronan-binding peptides were identified that modify fibrogenesis during skin wound repair. Peptides were selected from 7- to 15mer phage display libraries by panning with hyaluronan-Sepharose beads and assayed for their ability to block fibroblast migration in response to hyaluronan oligosaccharides (10 kDa). A 15mer peptide (P15-1), with homology to receptor for hyaluronan mediated motility (RHAMM) hyaluronan binding sequences, was the most effective inhibitor. P15-1 bound to 10-kDa hyaluronan with an affinity of K(d) = 10(-7) and appeared to specifically mimic RHAMM since it significantly reduced binding of hyaluronan oligosaccharides to recombinant RHAMM but not to recombinant CD44 or TLR2,4, and altered wound repair in wild-type but not RHAMM(-/-) mice. One topical application of P15-1 to full-thickness excisional rat wounds significantly reduced wound macrophage number, fibroblast number, and blood vessel density compared to scrambled, negative control peptides. Wound collagen 1, transforming growth factor β-1, and α-smooth muscle actin were reduced, whereas tenascin C was increased, suggesting that P15-1 promoted a form of scarless healing. Signaling/microarray analyses showed that P15-1 blocks RHAMM-regulated focal adhesion kinase pathways in fibroblasts. These results identify a new class of reagents that attenuate proinflammatory, fibrotic repair by blocking hyaluronan oligosaccharide signaling.
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Affiliation(s)
- Cornelia Tolg
- Cancer Research Laboratory Program, Lawson Health Research Institute and London Regional Cancer Program, London Health Sciences Center, London, Ontario, Canada
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Østerholt HCD, Dannevig I, Wyckoff MH, Liao J, Akgul Y, Ramgopal M, Mija DS, Cheong N, Longoria C, Mahendroo M, Nakstad B, Saugstad OD, Savani RC. Antioxidant protects against increases in low molecular weight hyaluronan and inflammation in asphyxiated newborn pigs resuscitated with 100% oxygen. PLoS One 2012; 7:e38839. [PMID: 22701723 PMCID: PMC3372475 DOI: 10.1371/journal.pone.0038839] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2011] [Accepted: 05/11/2012] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Newborn resuscitation with 100% oxygen is associated with oxidative-nitrative stresses and inflammation. The mechanisms are unclear. Hyaluronan (HA) is fragmented to low molecular weight (LMW) by oxidative-nitrative stresses and can promote inflammation. We examined the effects of 100% oxygen resuscitation and treatment with the antioxidant, N-acetylcysteine (NAC), on lung 3-nitrotyrosine (3-NT), LMW HA, inflammation, TNFα and IL1ß in a newborn pig model of resuscitation. METHODS & PRINCIPAL FINDINGS Newborn pigs (n = 40) were subjected to severe asphyxia, followed by 30 min ventilation with either 21% or 100% oxygen, and were observed for the subsequent 150 minutes in 21% oxygen. One 100% oxygen group was treated with NAC. Serum, bronchoalveolar lavage (BAL), lung sections, and lung tissue were obtained. Asphyxia resulted in profound hypoxia, hypercarbia and metabolic acidosis. In controls, HA staining was in airway subepithelial matrix and no 3-NT staining was seen. At the end of asphyxia, lavage HA decreased, whereas serum HA increased. At 150 minutes after resuscitation, exposure to 100% oxygen was associated with significantly higher BAL HA, increased 3NT staining, and increased fragmentation of lung HA. Lung neutrophil and macrophage contents, and serum TNFα and IL1ß were higher in animals with LMW than those with HMW HA in the lung. Treatment of 100% oxygen animals with NAC blocked nitrative stress, preserved HMW HA, and decreased inflammation. In vitro, peroxynitrite was able to fragment HA, and macrophages stimulated with LMW HA increased TNFα and IL1ß expression. CONCLUSIONS & SIGNIFICANCE Compared to 21%, resuscitation with 100% oxygen resulted in increased peroxynitrite, fragmentation of HA, inflammation, as well as TNFα and IL1ß expression. Antioxidant treatment prevented the expression of peroxynitrite, the degradation of HA, and also blocked increases in inflammation and inflammatory cytokines. These findings provide insight into potential mechanisms by which exposure to hyperoxia results in systemic inflammation.
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Affiliation(s)
- Helene C. D. Østerholt
- Department of Pediatrics, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Institute for Surgical Research, Oslo University Hospital – Rikshospitalet, Oslo, Norway
| | - Ingrid Dannevig
- Department of Pediatrics, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
- Institute for Surgical Research, Oslo University Hospital – Rikshospitalet, Oslo, Norway
| | - Myra H. Wyckoff
- Divisions of Pulmonary and Vascular Biology and Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Jie Liao
- Divisions of Pulmonary and Vascular Biology and Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Yucel Akgul
- Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Mrithyunjay Ramgopal
- Divisions of Pulmonary and Vascular Biology and Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Dan S. Mija
- Divisions of Pulmonary and Vascular Biology and Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Naeun Cheong
- Divisions of Pulmonary and Vascular Biology and Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Christopher Longoria
- Divisions of Pulmonary and Vascular Biology and Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Mala Mahendroo
- Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
| | - Britt Nakstad
- Department of Pediatrics, Akershus University Hospital, Lørenskog, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Ola D. Saugstad
- Department of Pediatric Research, Oslo University Hospital – Rikshospitalet, Oslo, Norway
| | - Rashmin C. Savani
- Divisions of Pulmonary and Vascular Biology and Neonatal-Perinatal Medicine, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America
- * E-mail:
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Darzynkiewicz Z, Balazs EA. Genome integrity, stem cells and hyaluronan. Aging (Albany NY) 2012; 4:78-88. [PMID: 22383371 PMCID: PMC3314170 DOI: 10.18632/aging.100438] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2012] [Accepted: 02/24/2012] [Indexed: 12/12/2022]
Abstract
Faithful preservation of genome integrity is the critical mission of stem cells as well as of germ cells. Reviewed are the following mechanisms involved in protecting DNA in these cells: (a) The efflux machinery that can pump out variety of genotoxins in ATP-dependent manner; (b) the mechanisms maintaining minimal metabolic activity which reduces generation of reactive oxidants, by-products of aerobic respiration; (c) the role of hypoxic niche of stem cells providing a gradient of variable oxygen tension; (d)(e) the presence of hyaluronan (HA) and HA receptors on stem cells and in the niche; (f) the role of role of HA in protecting DNA from oxidative damage; (g) the specific role of HA that may play a role protecting DNA in stem cells; (h) the interactions of HA with sperm cells and oocytes that also may shield their DNA from oxidative damage, and (e) mechanisms by which HA exerts the anti-oxidant activity. While HA has multitude of functions its anti-oxidant capabilities are often overlooked but may be of significance in preservation of integrity of stem and germ cells genome.
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Affiliation(s)
- Zbigniew Darzynkiewicz
- Brander Cancer Research Institute & Department of Pathology, New York Medical College, Valhalla, NY 10595, USA.
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Abstract
Highly pure, recombinant human osteoinductive proteins make it possible to consider programmable osteoneogenesis. Until recently, it was believed that a bioresorbable excipient or physiologic solution would suffice to transport osteoinductive agents from source to wound. After considering surgical requirements, particular bone wound circumstances, scarcity of collateral circulation, phenotype plasticity of mesenchymal progenitor cells, and the morphogens' pleiotrophic effects, it becomes clear that the issue of controlled, programmable osteoneogenesis is a more complicated proposition than can be addressed solely by application of osteoinductive protein. The essential characteristics of a manufactured bone graft substitute (BGS) device are dictated by demands placed on such a device by the surgeons who will employ them and the cells that will occupy them. This review outlines a design process for BGS devices that (1) begins by surveying BGS requirements gathered from the literature from 1991 to 1995, (2) briefly reviews recent in vitro studies of rhBMP-2 and OP- 1, (3) describes commonly encountered circumstances of recipient wound beds, (4) describes behaviors of mesenchymal cells involved in connective tissue repair and regeneration, and (5) concludes with a rationale for design of an osteoinductive bone graft substitute. Emerging from this process is a composite device consisting of a bioresorbable structural polymer, a filamentous velour of hyaluronan (HY), and an osteoinductive protein. The structural polymer, D,D-L,L-polylactic acid, fabricated in the architecture of cancellous bone, is capable of maintaining its structural and architectural properties after being thoroughly saturated with water. Within its interstices is located a filamentous velour of hyaluronan which, when fully hydrated, becomes a viscoelastic gel. It is anticipated that the osteoinductive protein will either be carried on the dried hyaluronic acid velour or in solution via the viscoelastic HY gel.
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Affiliation(s)
- J H Brekke
- THM Biomedical, Inc., Waterfront Plaza-Suite #608, 325 Lake Ave. South, Duluth, Minnesota 55802
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Park JS, Cha SJ, Kim BG, Choi YS, Kwon GY, Kang H, An SS. An assessment of the effects of a hyaluronan-based solution on reduction of postsurgical adhesion formation in rats: a comparative study of hyaluronan-based solution and two film barriers. J Surg Res 2009; 168:49-55. [PMID: 20036381 DOI: 10.1016/j.jss.2009.09.025] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2009] [Revised: 07/12/2009] [Accepted: 09/09/2009] [Indexed: 11/24/2022]
Abstract
BACKGROUND Intra-abdominal application of anti-adhesive barriers may reduce the extent and severity of postoperative adhesions. This study was designed to compare the effectiveness of a sprayable liquid barrier (a mixed solution of sodium hyaluronate and carboxymethylcellulose) with two conventional sheets. METHODS Eighty male Sprague Dawley rats underwent laparotomy with subsequent multiple intestinal wall abrasions and abdominal wall injury. Afterwards, sodium hyaluronate and carboxymethylcellulose (HA-CMC) solutions were intraperitoneally sprayed or a film barrier of either oxidized regenerated cellulose (ORC) or polylactic acid (PA) was placed under the incision. At postoperative d 21, the rats underwent relaparotomy and complete adhesiolysis. Three investigators, who were blind to the group assignment, scored the extent of adhesion formation and resected specimens for histologic examination of fibrosis and inflammation. Expression profiles of parameters as mediators (macrophages [CD68]) in cellular inflammation response were analyzed. RESULTS Mean adhesion scores in rats that received HA-CMC solution (7.6±2.3) and ORC membrane (8.1±2.2) were lower than in rats that received PA film (10.7±2.5) and the control group (11.2±2.6) (P<0.05 for each comparison). In addition, there were significantly fewer adhesions located between large and small intestine in the HA-CMC solution group than in the control and each of the film barrier groups (P<0.05 for each comparison). CONCLUSIONS This study suggests that both HA-CMC solution and ORC membrane decrease the overall incidence of postoperative adhesions. However, the mixed solution of HA-CMC appeared to be superior to ORC membrane because this sprayable solution is easy to use and suitable for site-specific adhesion prevention after multifocal bowel trauma.
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Affiliation(s)
- Jun Seok Park
- Department of Surgery, Division of Colorectal Surgery, Kyungpook National University Hospital, School of Medicine, Kyungpook National University, Dae-gu, Korea
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Chen WY, Marcellin E, Hung J, Nielsen LK. Hyaluronan molecular weight is controlled by UDP-N-acetylglucosamine concentration in Streptococcus zooepidemicus. J Biol Chem 2009; 284:18007-14. [PMID: 19451654 DOI: 10.1074/jbc.m109.011999] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
The molecular weight of hyaluronan is important for its rheological and biological function. The molecular mechanisms underlying chain termination and hence molecular weight control remain poorly understood, not only for hyaluronan synthases but also for other beta-polysaccharide synthases, e.g. cellulose, chitin, and 1,3-betaglucan synthases. In this work, we manipulated metabolite concentrations in the hyaluronan pathway by overexpressing the five genes of the hyaluronan synthesis operon in Streptococcus equi subsp. zooepidemicus. Overexpression of genes involved in UDP-glucuronic acid biosynthesis decreased molecular weight, whereas overexpression of genes involved in UDP-N-acetylglucosamine biosynthesis increased molecular weight. The highest molecular mass observed was at 3.4 +/- 0.1 MDa twice that observed in the wild-type strain, 1.8 +/- 0.1 MDa. The data indicate that (a) high molecular weight is achieved when an appropriate balance of UDP-N-acetylglucosamine and UDP-glucuronic acid is achieved, (b) UDP-N-acetylglucosamine exerts the dominant effect on molecular weight, and (c) the wild-type strain has suboptimal levels of UDP-N-acetylglucosamine. Consistent herewith molecular weight correlated strongly (rho = 0.84, p = 3 x 10(-5)) with the concentration of UDP-N-acetylglucosamine. Data presented in this paper represent the first model for hyaluronan molecular weight control based on the concentration of activated sugar precursors. These results can be used to engineer strains producing high molecular weight hyaluronan and may provide insight into similar polymerization mechanisms in other polysaccharides.
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Affiliation(s)
- Wendy Yiting Chen
- Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Queensland 4072, Australia
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Sikkink CJJM, Reijnen MMPJ, Duffhues BAR, de Man BM, Lomme RMLM, van Goor H. Intercellular adhesion molecule-1 and gelatinase expression in human peritoneal mesothelial cells during propagation in culture. Transl Res 2009; 153:240-8. [PMID: 19375685 DOI: 10.1016/j.trsl.2009.01.003] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2008] [Revised: 01/05/2009] [Accepted: 01/11/2009] [Indexed: 11/29/2022]
Abstract
Mesothelial cells are involved in a variety of biological processes, which include the formation of peritoneal adhesions. The cultures of human peritoneal mesothelial cells comprise an important tool to investigate the behavior and functions of mesothelial cells. Very little is known about the differences among mesothelial cells isolated from different sources and about the changes in specific functions as caused by cell propagation in vitro or that result from storage of cells at low temperatures. This study aims to characterize 2 particular cellular activities relevant for tissue repair, which include the expression of intercellular adhesion molecule-1 (ICAM-1) and the gelatinase activity; in addition, this study will assess the effect of hyaluronan, which is an antiadhesive agent, on these cellular activities. Viable cell lines were established from both omentum and peritoneal lavage fluid from 7 patients. Both ICAM-1 expression, which was measured by enzyme-linked immunosorbent assay (ELISA), and matrix metalloproteinase (MMP) bioactivity, which was measured by zymography, were measured in the 2nd and 4th passage; the latter also was measured after freezing and storing of cells in liquid nitrogen. The effects of interleukin-1beta (IL-1beta), tumor necrosis factor-alpha (TNF-alpha), phorbol myristate acetate (PMA), and hyaluronan were analyzed. ICAM-1 was constitutively expressed and stimulated by IL-1beta, TNF-alpha, and PMA. All cell lines produced both MMP-2 and MMP-9. Only the latter activity was affected by TNF-alpha and, especially so, PMA. Differences were found between the 2nd and 4th passage, as well as between cells of different lineage, mostly so if the relative stimulation by the various agents was compared. The addition of sodium hyaluronate either to control cultures or to cultures together with any of the 3 stimuli examined did not significantly change either ICAM-1 expression or gelatinase activity. The freezing and storage of cells did not affect their functions. Both the human omentum and peritoneal lavage fluid are good sources to establish mesothelial cell lines, which can be propagated also after freezing without qualitative changes in their ability to express ICAM-1 and produce the gelatinases. For omental cells, a differential effect of stimulation occurs depending on whether the cells have been passaged 2 or 4 times. The presence of hyaluronan did not affect the expression of ICAM-1 or the gelatinases.
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Abstract
Nonpenetrating glaucoma surgeries have been developed in recent years in order to improve the safety of conventional filtering procedures. The goal of nonpenetrating filtering procedures is to reduce intraocular pressure by enhancing the natural aqueous outflow channels, while reducing outflow resistance located in the inner wall of the Schlemm's canal and the juxtacanalicular trabecular meshwork. In the last few years viscocanalostomy and deep sclerectomy with external trabeculectomy have become the most popular nonpenetrating filtering procedures. Both involve removal of a deep scleral flap, the external wall of Schlemm's canal and corneal stroma behind the anterior trabeculum and Descemet's membrane, thus creating an intrascleral space. The aqueous humour leaves the anterior chamber through the intact trabeculo-Descemet's membrane into the scleral space, from where it will egress into different pathways. The technique is associated with a long learning curve. Published clinical trials comparing nonpenetrating glaucoma surgery to full-thickness trabeculectomy have a consensus on the superior safety profile of nonpenetrating glaucoma surgery but are not in agreement when it comes to efficacy, where conflicting results have been found. This article reviews the nonpenetrating surgical techniques, mechanisms of action, indications, contraindications, complications, and results.
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Nagurskaya EV, Zaitseva LG, Kobets NV, Kireeva IV, Alimbarova LM, Samoilenko II, Barinskii IF. Functional activity of peritoneal macrophages from sensitive and resistant mouse strains during intravaginal infection with herpes simplex virus type 2 and mucosal vaccination. Bull Exp Biol Med 2008; 145:235-9. [PMID: 19023978 DOI: 10.1007/s10517-008-0059-9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
In the early period after intravaginal infection with herpes simplex virus type 2 (2 h), macrophages from sensitive DBA/2 mice were characterized by higher capacity to engulf the antigen, decreased function of the lysosomal apparatus, lower activity of cathepsin D, and reduced oxygen metabolism compared to cells from resistant BALB/c mice. Mucosal vaccination with herpes vaccine and hyaluronic acid promoted the increase in functional activity of macrophages and improved survival of sensitive mice (by 60%).
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Affiliation(s)
- E V Nagurskaya
- N. F. Gamaleya Institute of Epidemiology, Russian Academy of Medical Sciences, Moscow
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Zhao H, Tanaka T, Mitlitski V, Heeter J, Balazs EA, Darzynkiewicz Z. Protective effect of hyaluronate on oxidative DNA damage in WI-38 and A549 cells. Int J Oncol 2008; 32:1159-67. [PMID: 18497977 DOI: 10.3892/ijo_32_6_1159] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Progressive DNA damage in live cells by oxidants is the key factor contributing to cell aging and preconditioning to neoplastic transformation. The strategies to slow aging or prevent cancer rely on protection of DNA from the damage. Since cells reside within intercellular matrix it is of interest to know whether matrix constituents possess properties of modulating oxidative DNA damage. We explored, therefore, the effect of hyaluronate (HA), the ubiquitous component of the matrix, on extent of DNA damage induced by exogenous and endogenously generated oxidants. WI-38 and A549 cells were exposed to 200 microM H2O2 in the absence or presence of HA and induction of histone H2AX phosphorylation and activation of ATM, the reporters of DNA damage, was assessed by multiparameter cytometry. Also explored was effect of HA on constitutive H2AX phosphorylation that reflects DNA damage caused by endogenous oxidants generated during aerobic metabolism. HA of average MW 5.4 million (high MW) and 2 million (medium MW) at 0.1% (w/v) in culture medium totally prevented the H2O2-induced H2AX phosphorylation in both cell types whereas effect of 60,000 average MW (low MW) HA was somewhat less pronounced. Constitutive H2AX phosphorylation in WI-38 cells growing in the presence of 0.1% HA of low MW and medium MW was reduced by about 35 and 30%, respectively; no reduction was observed in A549 cells. The data indicate that HA protected DNA from damage caused by the exogenous oxidant H2O2. In WI-38 fibroblasts, the cells that express the HA-receptor CD44, HA also protected DNA from damage caused by endogenous oxidants. We postulate that expression of CD44 in some cell types such as stem cells may provide the means to internalize HA by endocytosis and one of the functions of the internalized HA may be protection of DNA from oxidants. The mechanism of protective effect of HA may either: i) involve entrapment of iron ions thereby inhibiting the Fenton's reaction that produces secondary oxidative species, and/or: ii) directly scavenging of primary and secondary ROIs, as an antioxidant, resulting in HA degradation. Since no significant degradation of HA upon its exposure in tissue culture medium to H2O2 was detected the scavenging may occur intracellularly.
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Affiliation(s)
- Hong Zhao
- Brander Cancer Research Institute and Department of Pathology, New York Medical College, Valhalla, NY 10595, USA
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Campo GM, Avenoso A, Campo S, D'Ascola A, Traina P, Samà D, Calatroni A. The antioxidant effect exerted by TGF-1beta-stimulated hyaluronan production reduced NF-kB activation and apoptosis in human fibroblasts exposed to FeSo4 plus ascorbate. Mol Cell Biochem 2008; 311:167-77. [PMID: 18224424 DOI: 10.1007/s11010-008-9707-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2007] [Accepted: 01/10/2008] [Indexed: 02/07/2023]
Abstract
Previous studies suggest that Transforming growth factor-1beta (TGF-1beta) administration in human fibroblasts exposed to oxidative stress is able to modulate hyaluronan synthases (HASs). HAS modulation in turn increases high molecular weight (Hyaluronan) HA concentration. Nuclear factor kB (NF-kB) is a response transcription factor involved in inflammation and acts by enabling the expression of certain detrimental molecules. Caspases are specific proteases responsible for regulating and programming cell death. HA at medium molecular weight together with chondroitin-4-sulphate proved to be effective on NF-kB and caspases. We investigated whether the protective effect afforded by the high molecular weight HA produced by TGF-1beta treatment has any effect on NF-kB and apoptosis activation in fibroblast cultures exposed to oxidative stress. Generation of free radicals gives rise to cell death, increases lipid peroxidation, activates NF-kB, reduces its cytoplasmic inhibitor IkBalpha, augments caspase-3 and caspase-7 gene expression and their relative protein activity, and depletes catalase (CAT) and glutathione peroxidase (GPx). Treatment of fibroblasts with TGF-1beta 12 h before inducing oxidative stress greatly increased HA levels, ameliorated cell survival, inhibited lipid peroxidation, blunted NF-kB translocation, normalized IkBalpha protein, reduced caspase gene expression and protein levels, and restored the endogenous antioxidants CAT and GPx. Since it was previously reported that antioxidants can work as inhibitors of NF-kB and apoptosis induction we can hypothesize that endogenous HA, by inhibiting lipid peroxidation, may block a step whereby free radical activity converges in the signal transduction pathway leading to NF-kB and caspase activation.
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Affiliation(s)
- Giuseppe M Campo
- Department of Biochemical, Physiological and Nutritional Sciences, School of Medicine, University of Messina, Policlinico Universitario, Torre Biologica, 5 degree piano, Via C. Valeria, 98125 Messina, Italy.
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Campo GM, Avenoso A, Campo S, D'Ascola A, Traina P, Samà D, Calatroni A. NF-kB and caspases are involved in the hyaluronan and chondroitin-4-sulphate-exerted antioxidant effect in fibroblast cultures exposed to oxidative stress. J Appl Toxicol 2008; 28:509-17. [PMID: 17879260 DOI: 10.1002/jat.1302] [Citation(s) in RCA: 30] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
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Khafagy ES, Morishita M, Onuki Y, Takayama K. Current challenges in non-invasive insulin delivery systems: a comparative review. Adv Drug Deliv Rev 2007; 59:1521-46. [PMID: 17881081 DOI: 10.1016/j.addr.2007.08.019] [Citation(s) in RCA: 281] [Impact Index Per Article: 15.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2007] [Accepted: 08/16/2007] [Indexed: 11/22/2022]
Abstract
The quest to eliminate the needle from insulin delivery and to replace it with non- or less-invasive alternative routes has driven rigorous pharmaceutical research to replace the injectable forms of insulin. Recently, various approaches have been studied involving many strategies using various technologies that have shown success in delivering insulin, which are designed to overcome the inherent barriers for insulin uptake across the gastrointestinal tract, mucosal membranes and skin. This review examines some of the many attempts made to develop alternative, more convenient routes for insulin delivery to avoid existing long-term dependence on multiple subcutaneous injections and to improve the pharmacodynamic properties of insulin. In addition, this article concentrates on the successes in this new millennium in developing potential non-invasive technologies and devices, and on major new milestones in modern insulin delivery for the effective treatment of diabetes.
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Affiliation(s)
- El-Sayed Khafagy
- Department of Pharmaceutics, Hoshi University, Ebara 2-4-41, Shinagawa, Tokyo 142-8501, Japan
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Campo GM, Avenoso A, Campo S, D'Ascola A, Ferlazzo AM, Calatroni A. Differential effect of growth factors on hyaluronan synthase gene expression in fibroblasts exposed to oxidative stress. BIOCHEMISTRY. BIOKHIMIIA 2007; 72:974-82, 4 p.. [PMID: 17922656 DOI: 10.1134/s0006297907090088] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The aim of this study was to evaluate how growth factors (PDGF-BB, EGF, and TGF-1beta) modulate hyaluronan synthase (HAS) activities in normal or stressed cultured human skin fibroblasts. The effects of concomitant treatment with cytokines and FeSO4 plus ascorbate on HAS mRNA expression, protein synthesis, and hyaluronic acid (HA) concentrations were also studied. Treatment of fibroblasts with growth factors up-regulated HAS gene expression and increased HAS enzymes and HA production. PDGF-BB induced HAS mRNA expression, protein synthesis, and HA production more efficiently than EGF and TGF-1beta. EGF was less effective than TGF-1beta. In addition, TGF-1beta reduced the expression and synthesis of HAS3, while PDGF-BB and EGF had the opposite effect. Concomitant treatment with growth factors and the oxidant was able to further increase HAS mRNA expression, once again with the exception of HAS3 with TGF-1beta. HAS protein synthesis was reduced, while HA levels were unaffected in comparison to those obtained from exposure to FeSO4 plus ascorbate alone. In conclusion, although growth factors plus the oxidant synergistically induced HAS mRNA expression in part, enzyme production was not correlated with this increase. Moreover, the increase in HAS mRNA levels was not translated into a consequent rise in HA concentration.
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Affiliation(s)
- G M Campo
- Department of Biochemical, Physiological, and Nutritional Sciences, School of Medicine, University of Messina, Policlinico Universitario, Torre Biologica, Messina 98125, Italy.
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Campo GM, Avenoso A, Campo S, Angela D, Ferlazzo AM, Calatroni A. TNF-alpha, IFN-gamma, and IL-1beta modulate hyaluronan synthase expression in human skin fibroblasts: synergistic effect by concomital treatment with FeSO4 plus ascorbate. Mol Cell Biochem 2006; 292:169-78. [PMID: 16786194 DOI: 10.1007/s11010-006-9230-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2006] [Accepted: 05/11/2006] [Indexed: 02/07/2023]
Abstract
Several reports have shown that a number of cytokines such as tumor necrosis-alpha (TNF-alpha), interferon-gamma (IFN-gamma), and interleukin-beta (IL-1beta) are capable to induce hyaluronan sinthases (HASs) mRNA expression in different cell culture types. The obvious consequence of this stimulation is a marked increment in hyaluronan (HA) production. It has been also reported that oxidative stress, by itself, may increase HA levels. The aim of this study was to evaluate how TNF-alpha, IFN-gamma,IL-1beta, and exposition to oxidative stress may modulate HAS activities in normal human skin fibroblasts. Moreover, the effects on HAS mRNA expression of the concomitant treatment with cytokines and oxidants, and the HA concentrations after treatments, were studied. TNF-alpha, IFN-gamma, and IL-1beta were added to normal or/and exposed to FeSO(4) plus ascorbate fibroblast cultures and HAS1, HAS2 and HAS3 mRNA content, by PCR-real time, was assayed 3,h later. HA levels were also evaluated after 24,h incubation. The treatment of fibroblasts with cytokines up-regulated HASs gene expression and increased HA production. IL-1beta induced HAS mRNA expression and HA production more efficiently than TNF-alpha and IFN-gamma. The exposition of the fibroblasts with the oxidant system markedly increased HAS activities while slightly HA production. The concomitant treatment of cells with the cytokines and the oxidant was able to further enhance, in a dose dependent way, with synergistic effect on HAS mRNA expression. On the contrary HA levels resulted unaffected by the concomitant treatment, and resemble those obtained with the exposure to FeSO(4) plus ascorbate only. This lack in HA production could be due to the deleterious action of free radicals on the HA synthesis.
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Affiliation(s)
- Giuseppe M Campo
- Department of Biochemical, Physiological and Nutritional Sciences, School of Medicine, University of Messina, Policlinico Universitario, 98125, Messina, Italy.
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Cartwright LM, Shou Z, Yeger H, Farhat WA. Porcine bladder acellular matrix porosity: impact of hyaluronic acid and lyophilization. J Biomed Mater Res A 2006; 77:180-4. [PMID: 16392132 DOI: 10.1002/jbm.a.30652] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Bladder acellular matrix (ACM) is being investigated as a urinary bladder replacement scaffold. We have demonstrated that ACM is porous and theorized that this contributes to ACM fibrosis and contracture over time in vivo and may preclude uptake and retention of molecules, which may aid cellular repopulation. We sought to determine if hyaluronic acid (HA) would decrease ACM porosity. Porcine ACM was lyophilized and rehydrated in HA (SIGMA) to form the hybrid HA-ACM construct. Three groups (n = 15/group: HA-ACM, ACM, and lyophilized/rehydrated ACM) were tested for porosity to a 10 cm column of distilled water, measuring the effluent hourly for 3 h. A porosity index was determined as the total effluent divided by time and area (cc/cm2 hr). Alcian blue staining and fluorophore-assisted carbohydrate electrophoresis qualitatively and quantitatively confirmed the uptake of HA. HA-ACM and lyophilized/rehydrated ACM were significantly less porous to water than untreated ACM [mean (+/-SE): 0.09 (+/-0.02), 0.74 (+/-0.4), and 9.8 (+/-1.6) cc/cm2 hr, respectively; Mann Whitney p < 0.0001 (HA) and p < 0.0001 (lyo)]. The difference between HA-ACM and lyophilized ACM was also statistically significant (p = 0.014). ACM hybridization with HA decreases ACM porosity, in part because of ACM lyophilization during the hybridization process. In future applications, HA may function as a carrier for smaller molecules such as growth factors, and as a bioactive molecule to improve wound healing and decrease fibrosis in tissue-engineered bladder constructs.
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Affiliation(s)
- Lisa M Cartwright
- Department of Surgery, Division of Urology, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
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Bae JS, Jang KH, Jin HK. Comparison of intraperitoneal anti-adhesive polysaccharides derived from Phellinus mushrooms in a rat peritonitis model. World J Gastroenterol 2005; 11:810-6. [PMID: 15682472 PMCID: PMC4250588 DOI: 10.3748/wjg.v11.i6.810] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the adhesion- and abscess-reducing capacities of various concentrations of polysaccharides derived from fungus, Phellinus gilvus (PG) or Phellinus linteus (PL) in a rat peritonitis model.
METHODS: In 96 SD rats, experimental peritonitis was induced using the cecal ligation and puncture model (CLP). Rats were randomly assigned to 8 groups; Ringer’s lactate solution (RL group), hyaluronic acid (HA group), 0.025%, 0.25%, and 0.5% polysaccharides from PG (PG0.025, 0.25, and 0.5 groups), and PL (PL0.025, 0.25, and 0.5 groups). Adhesions and abscesses were noted at 7 d after CLP. RT-PCR assay was performed to assess the cecal tissue.
RESULTS: Adhesion formation was significantly reduced in PG0.25, 0.5, PL0.25, 0.5, and HA groups (2.5±0.7, 2.4±0.7, 3.8±1.0, 3.6±0.8, and 2.7±1.1, P<0.05). The incidence of abscesses was significantly reduced in all treated groups compared to RL group (58%, P<0.05). The urokinase-type plasminogen activator (uPA) gene expression was greatly up-regulated by increasing the concentration of polysaccharides. The urokinase-type plasminogen activator receptor (uPAR) and tumor necrosis factor (TNF)-α mRNA were highly expressed in PG0.25, 0.5, PL0.25, and 0.5 groups.
CONCLUSION: We concluded that 0.5% polysaccharide derived from PG and PL was the optimal concentration in preventing adhesion and abscess formation and may act by modulating activity of uPA and TNF-α in a rat peritonitis model.
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Affiliation(s)
- Jae-Sung Bae
- Department of Surgery, College of Veterinary Medicine, Kyungpook National University, Daegu 702-701, Republic of Korea
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Chong BF, Blank LM, Mclaughlin R, Nielsen LK. Microbial hyaluronic acid production. Appl Microbiol Biotechnol 2004; 66:341-51. [PMID: 15599518 DOI: 10.1007/s00253-004-1774-4] [Citation(s) in RCA: 223] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2004] [Revised: 09/13/2004] [Accepted: 09/17/2004] [Indexed: 10/26/2022]
Abstract
Hyaluronic acid (HA) is a commercially valuable medical biopolymer increasingly produced through microbial fermentation. Viscosity limits product yield and the focus of research and development has been on improving the key quality parameters, purity and molecular weight. Traditional strain and process optimisation has yielded significant improvements, but appears to have reached a limit. Metabolic engineering is providing new opportunities and HA produced in a heterologous host is about to enter the market. In order to realise the full potential of metabolic engineering, however, greater understanding of the mechanisms underlying chain termination is required.
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Affiliation(s)
- Barrie Fong Chong
- Department of Chemical Engineering, The University of Queensland, Brisbane, QLD 4072, Australia
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42
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Campo GM, Avenoso A, Campo S, D'Ascola A, Ferlazzo AM, Calatroni A. Reduction of DNA fragmentation and hydroxyl radical production by hyaluronic acid and chondroitin-4-sulphate in iron plus ascorbate-induced oxidative stress in fibroblast cultures. Free Radic Res 2004; 38:601-11. [PMID: 15346651 DOI: 10.1080/10715760410001694017] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Glycosaminoglycans (GAGs), components of extracellular matrix, are thought to play important roles in cell proliferation and differentiation in the repair process of injured tissue. Oxidative stress is one of the most frequent causes of tissue and cell injury and the consequent lipid peroxidation is the main manifestation of free radical damage. It has been found to play an important role in the evolution of cell death. Since several reports have shown that hyaluronic acid (HYA) and chondroitin-4-sulphate (C4S) are able to inhibit lipid peroxidation during oxidative stress, We investigated the antioxidant capacity of these GAGs in reducing oxidative damage in fibroblast cultures. Free radicals production was induced by the oxidizing system employing iron (Fe2+) plus ascorbate. We evaluated cell death, membrane lipid peroxidation, DNA damage, protein oxidation, hydroxyl radical (OH*) generation and endogenous antioxidant depletion in human skin fibroblast cultures. The exposition of fibroblasts to FeSO4 and ascorbate caused inhibition of cell growth and cell death, increased OH* production determined by the aromatic trap method; furthermore it caused DNA strand breaks and protein oxidation as shown by the DNA fragments analysis and protein carbonyl content, respectively. Moreover, it enhanced lipid peroxidation evaluated by the analysis of conjugated dienes (CD) and decreased antioxidant defenses assayed by means of measurement of superoxide dismutase (SOD) and catalase (CAT) activities. When fibroblasts were treated with two different doses of HYA or C4S a protective effect, following oxidative stress induction, was shown. In fact these GAGs were able to limit cell death, reduced DNA fragmentation and protein oxidation, decreased OH* generation, inhibited lipid peroxidation and improved antioxidant defenses. Our results confirm the antioxidant activity of HYA and C4S and this could represent a useful step in the understanding of the exact role played by GAGs in living organisms.
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Affiliation(s)
- Giuseppe M Campo
- Department of Biochemical, Physiological and Nutritional Sciences, School of Medicine, University of Messina, Policlinico Universitario, Torre Biologica, Via C. Valeria 98125, Messina, Italy.
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43
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Ohri R, Hahn SK, Hoffman AS, Stayton PS, Giachelli CM. Hyaluronic acid grafting mitigates calcification of glutaraldehyde-fixed bovine pericardium. ACTA ACUST UNITED AC 2004; 70:328-34. [PMID: 15227678 DOI: 10.1002/jbm.a.30088] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Pathologic calcification is the leading cause of the clinical failure of glutaraldehyde-fixed bovine pericardium used in bioprosthetic valves. A novel surface modification of glutaraldehyde fixed bovine pericardium was carried out with high molecular weight hyaluronic acid (HA). HA was chemically modified with adipic dihydrazide (ADH) to introduce hydrazide functional groups onto the HA backbone. Glutaraldehyde-fixed bovine pericardium (GFBP) was modified by grafting this HA to the free aldehyde groups on the tissue via the hydrazide groups. Following a 2-week subcutaneous implantation in osteopontin (OPN)-null mice, the calcification of HA-modified bovine pericardium was drastically reduced (by 84.5%) compared to positive controls (tissue without HA-modification) (p = 0.005). The calcification-mitigating effect of HA surface modification was also confirmed by microscopic analysis of explanted tissue stained with Alizarin Red S for calcium.
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Affiliation(s)
- Rachit Ohri
- Department of Bioengineering, University of Washington, Box 351720, Bagley Hall, #479, Seattle, Washington 98195
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44
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Lym HS, Suh Y, Park CK. Effects of Hyaluronic Acid on the Polymorphonuclear Leukocyte (PMN) Release of Active Oxygen and Protection of Bovine Corneal Endothelial Cells from Activated PMNs. KOREAN JOURNAL OF OPHTHALMOLOGY 2004; 18:23-8. [PMID: 15255233 DOI: 10.3341/kjo.2004.18.1.23] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
The goal of this study was to evaluate the function of hyaluronic acid (HA) on the active oxygen release from polymorphonuclear leukocytes (PMNs) and the protective effect of bovine corneal endothelial cells (BCEC) from activated PMNs. We used HA with three different molecular weights (MW 700,000, 2,000,000, and 4,000,000) and five different concentrations (0, 0.1, 1, 2, and 3 mg/ml). We evaluated the amount of released superoxide from activated PMNs by using dismutase-inhibitable ferricytochrome C reduction. To compare the property and protective effect of HA with those of other viscoelastic substances, we used the same concentration of methylcellulose. HA suppressed superoxide release from PMNs and protected BCEC from activated PMNs in a dose-dependent, rather than a molecular weight-dependent, manner. The effect of HA reached almost a plateau at concentration above 2 mg/ml. However, methylcellulose, another viscoelastic substance, showed a similar effect. Therefore, it seems that the suppression of superoxide released from PMNs is not a property that is unique to HA, but is a general property of viscoelastic substances. Our results indicate that the action mechanism of HA proceeds not only through cell surface HA-receptor. We think that HA also acts as a physical barrier and/or a scavenger of superoxide.
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Affiliation(s)
- Hyun Soo Lym
- Department of Ophthalmology, St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
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45
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Chajara A, Raoudi M, Delpech B, Levesque H. Inhibition of arterial cells proliferation in vivo in injured arteries by hyaluronan fragments. Atherosclerosis 2003; 171:15-9. [PMID: 14642401 DOI: 10.1016/s0021-9150(03)00303-4] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
It has been demonstrated previously that administration of high levels of high molecular mass hyaluronan (hyaluronic acid, HA) to rats was able to reduce in a significant way neointima formation in the injured arteries. In the present study, our aim was to verify whether small forms of HA (4-16 saccharides) are still able to reduce the proliferative response of ASMC to aortic injury. Treated rats received a total of 8 injections of a fixed dose of HA fragments (27 mg/kg rat contained in a volume of 550 microl). Two injections were given on the day of balloon catheter injury (BCI): one, intravenous, 10 min before BCI and one, subcutaneous, immediately after the BCI. The others injections (subcutaneous) were at 2, 4, 6, 8, 10 and 12 days after BCI. Control rats received an equivalent volume of the dissolving buffer containing only hyaluronidase, which has been destroyed before injection to rats. Neointima formation was analysed 14 days after the BCI. Intima-media wet weight and DNA content were significantly reduced in rats receiving HA fragments in comparison to controls (2P=0.01 for wet weight and 0.03 for DNA). This finding was confirmed by the histomorphometric study which showed that both neointima area and the ratio neointima/neointima+media were significantly decreased in treated rats (2P=0.03 for intima area and 0.049 for the ratio). Our data showed thus and for the first time that administration of HA fragments with a very low molecular mass (4-16 saccharides) reduces the proliferative reaction of aorta to injury in vivo. In conclusion, HA fragments, which are components with an excellent safety profile, may offer hope for the prevention of restenosis after angioplasty.
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MESH Headings
- Adjuvants, Immunologic/administration & dosage
- Adjuvants, Immunologic/blood
- Animals
- Aorta, Thoracic/cytology
- Aorta, Thoracic/drug effects
- Aorta, Thoracic/injuries
- Catheterization/adverse effects
- Cell Division/drug effects
- DNA/drug effects
- Disease Models, Animal
- Dose-Response Relationship, Drug
- Enzyme-Linked Immunosorbent Assay
- Hyaluronic Acid/administration & dosage
- Hyaluronic Acid/blood
- Hyaluronoglucosaminidase/administration & dosage
- Hyaluronoglucosaminidase/blood
- Injections, Intravenous
- Male
- Models, Cardiovascular
- Muscle, Smooth, Vascular/cytology
- Rats
- Rats, Wistar
- Subclavian Artery/cytology
- Subclavian Artery/drug effects
- Subclavian Artery/injuries
- Tunica Intima/cytology
- Tunica Intima/drug effects
- Tunica Intima/injuries
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Affiliation(s)
- Abdesslam Chajara
- Faculté de Médecine, Groupe MERCI, 22 Boulevard Gambetta, 76183 Rouen, France.
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46
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Surendrakumar K, Martyn GP, Hodgers ECM, Jansen M, Blair JA. Sustained release of insulin from sodium hyaluronate based dry powder formulations after pulmonary delivery to beagle dogs. J Control Release 2003; 91:385-94. [PMID: 12932716 DOI: 10.1016/s0168-3659(03)00263-3] [Citation(s) in RCA: 110] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
Hyaluronic acid (HA) and recombinant human insulin were co-spray dried to form a dry powder suitable for inhalation (Mass Median Aerodynamic Diameter, MMAD=1 to 4 microm). Insulin systemic levels and corresponding glucose levels were monitored following administration of the microparticles to the lungs of male Beagle dogs. Release kinetics were modified by addition of excess zinc ions (Zn2+) or hydroxypropyl cellulose (HPC). HA formulations containing insulin (10%w/w) were found to extend the mean residence time (MRT) and terminal half-life (t(1/2)) when compared to spray dried pure insulin. Addition of Zn2+ also improved MRT (>9 fold), AUC/dose (2.5 fold) and Tmax (by a factor of 3) when compared to spray dried pure insulin. Addition of HPC improved MRT (>7 fold), AUC/dose (5 fold) and Tmax (by a factor of 3) when compared to spray dried pure insulin. Our results demonstrate the potential of HA-based dry powder drug delivery systems in the pulmonary controlled release of insulin.
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Affiliation(s)
- K Surendrakumar
- Elan Drug Delivery Limited, 1 Mere Way, Ruddington, Nottingham, NG11 6JS, UK
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47
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Sheehan KM, DeLott LB, Day SM, DeHeer DH. Hyalgan has a dose-dependent differential effect on macrophage proliferation and cell death. J Orthop Res 2003; 21:744-51. [PMID: 12798077 DOI: 10.1016/s0736-0266(03)00007-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
The intra-articular injection of high molecular weight hyaluronic acid (HA) has been reported to be an effective treatment for pain of osteoarthritis of the knee. However, the mechanism by which HA exerts its effect is unknown. To explore HA's influence on the growth of U937 human macrophages, cells were incubated for 168 h with three concentrations, 1, 0.1 and 0.01 mg/mL, of Hyalgan, a high molecular weight HA preparation. At 24-h increments, the cells were examined for proliferation, cell cycle distribution as well as the number of apoptotic and dead cells. Exposing macrophages to 1 mg/mL Hyalgan significantly reduced the rate of cellular proliferation and altered the cell cycle distribution to yield decreased proportions of G0/G1 cells but increased S and G2/M cells. Concomitantly, a 10-fold increase in apoptotic cells and a 12-fold increase in dead cells were observed. The population doubling time (PDT) for cells treated with 1.0 mg/mL Hyalgan increased from 23.6 to 52.9 h. By contrast, the two lower Hyalgan concentrations significantly promoted macrophage proliferation in a dose-dependent manner. They also increased the proportion of G2/M cells, but had no effect on the number of apoptotic or dead cells. The PDTs of 21.5 and 22.2 h were less than the control time of 23.6 h. These results demonstrate that Hyalgan concentrations have a differential effect on macrophage growth dynamics and suggest an anti-inflammatory effect at high HA concentrations.
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Affiliation(s)
- Kyle M Sheehan
- Calvin College, Department of Biology, S.E. Grand Rapids, MI 49546, USA
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48
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Moseley R, Walker M, Waddington RJ, Chen WYJ. Comparison of the antioxidant properties of wound dressing materials--carboxymethylcellulose, hyaluronan benzyl ester and hyaluronan, towards polymorphonuclear leukocyte-derived reactive oxygen species. Biomaterials 2003; 24:1549-57. [PMID: 12559815 DOI: 10.1016/s0142-9612(02)00540-9] [Citation(s) in RCA: 71] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
Abstract
In chronic wounds, factors are released which perpetuate inflammatory processes, including polymorphonuclear leukocyte (PMN)-derived reactive oxygen species (ROS), such as superoxide radical (O(2)*-) and hydroxyl radical (*OH) species. The glycosaminoglycan, hyaluronan, has established antioxidant properties towards ROS, although the antioxidant potential of wound dressing biomaterials, such as 75% benzyl esterified hyaluronan (BEHA) and carboxymethylcellulose (CMCH), are less characterised. This study compared the antioxidant properties of high and low molecular weight hyaluronan (HMWT HA and LMWT HA), BEHA and CMCH towards ROS, generated by stimulated PMN in vitro. The antioxidant capacities of each biomaterial were assessed by their inhibition of O(2)*- -induced cytochrome C reduction, generated via PMN stimulation by phorbol myristyl acetate (PMA); and their inhibition of *OH-induced 2-deoxy-D-ribose degradation, generated by PMA stimulated PMN in the presence of a ferric chloride-EDTA chelate. All biomaterials, except LMWT HA, possessed dose-dependent antioxidant properties against O(2)*-, BEHA having greatest antioxidant potential, followed by HMWT HA and CMCH. HMWT HA exhibited the highest dose-dependent antioxidant properties towards *OH, followed by BEHA and CMCH. LMWT HA demonstrated no antioxidant properties towards *OH. These antioxidant activities, particularly towards O(2)*-, may be beneficial in removing the initial source of ROS necessary for the secondary formation of *OH, implicated as a causal factor for the extensive metabolic alterations observed in chronic wounds.
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Affiliation(s)
- R Moseley
- Department of Oral Surgery, Medicine, and Pathology, Dental School, University of Wales College of Medicine, Heath Park, Cardiff, UK.
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49
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Moseley R, Leaver M, Walker M, Waddington RJ, Parsons D, Chen WYJ, Embery G. Comparison of the antioxidant properties of HYAFF-11p75, AQUACEL and hyaluronan towards reactive oxygen species in vitro. Biomaterials 2002; 23:2255-64. [PMID: 11962667 DOI: 10.1016/s0142-9612(01)00360-x] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Abstract
In chronic wounds, a number of host factors are released which perpetuate the inflammatory process, including polymorphonuclear leukocyte (PMN)-derived reactive oxygen species (ROS), such as superoxide radical (O2*-) and hydroxyl radical (*OH) species. The glycosaminoglycan. hyaluronan, has been shown to act as an antioxidant towards ROS, although the potential for biomaterials, such as HYAFF -11p75 (the 75% benzyl ester of hyaluronan) and AQUACEL (carboxymethylcellulose), to act in this manner has yet to be elucidated. This study compared the antioxidant properties of high and low molecular weight hyaluronan (HMWT HA and LMWT HA), HYAFF -11p75, AQUACEL and an AQUACEL /hyaluronan composite (AQUACEL /HA) against O2*- and *OH. The antioxidant capacities of each material were assessed by their ability to inhibit cytochrome C reduction by O2*- fluxes, generated via the oxidation of hypoxanthine by xanthine oxidase, and their inhibition of 2-deoxy-D-ribose degradation by *OH fluxes, generated by the reaction of hydrogen peroxide (H2O2) and iron (Fe2+). All materials studied possessed dose dependent antioxidant properties towards O2*-, with HYAFF 11p75 having the greatest antioxidant potential towards these species, followed by AQUACEL, HMWT HA, AQUACEL /HA and LMWT HA. Only HMWT HA exhibited dose dependent antioxidant properties towards *OH at the fluxes examined. Gas chromatography/mass spectrometry analysis implied that ester bonds between the hyaluronan backbone and benzyl groups of HYAFF -11p75 are highly susceptible to O2*- hydrolysis, with the de-esterified benzyl alcohol being rapidly degraded in the presence of *OH. This data supports the hypothesis that HYAFF -11p75 has greater antioxidant capacity towards O2*-, due to the esterified benzyl groups providing alternative sites for O2*- attack other than the hyaluronan backbone of HYAFF -11p75 itself and explains the inability of HYAFF -11p75 to scavenge *OH, due to benzyl alcohol degradation by *OH. The antioxidant activities of these biomaterials, particularly HYAFF -11p75 and AQUACEL, towards O2*- could be beneficial, as the scavenging of PMN-derived O2*- may remove initial sources of O2*- and further prevent the secondary formation of *OH. These ROS are thought to be a primary causal factor for the extensive degradation and metabolic alterations observed in chronic wounds.
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Affiliation(s)
- R Moseley
- Department of Basic Dental Science, Dental School, University of Wales College of Medicine, Cardiff, UK.
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50
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Breborowicz A, Polubinska A, Moberly J, Ogle K, Martis L, Oreopoulos D. Hyaluronan modifies inflammatory response and peritoneal permeability during peritonitis in rats. Am J Kidney Dis 2001; 37:594-600. [PMID: 11228185 DOI: 10.1053/ajkd.2001.22086] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
The effect of high-molecular-weight hyaluronan (HA) on peritoneal and systemic inflammation and peritoneal permeability to water and solutes was studied during endotoxin-induced peritonitis in rats. Acute peritonitis was induced by adding lipopolysaccharide (LPS) to the dialysis fluid (Dianeal 3.86; Baxter Healthcare, Ireland, Castlebar). HA was added to the dialysis solution in a concentration of 10 mg/dL. During 4- and 8-hour dwells of the dialysis fluid, we studied the intensity of peritoneal (dialysate) and systemic (blood) inflammation (dialysate cell count and differential, cytokine and HA levels), as well as the transperitoneal transport of solutes and water. In rats, the addition of LPS to the dialysis fluid induced changes in inflammatory reaction and transperitoneal transport similar to those seen in continuous ambulatory peritoneal dialysis patients with peritonitis. During peritonitis, the addition of HA to the dialysis fluid reduced the loss of ultrafiltration, which resulted in a greater peritoneal creatinine clearance during the 8 hours of dwell (29.9 +/- 6.7 mL/8 h in the HA-LPS group versus 19.7 +/- 7.8 mL/8 h in the LPS group; P < 0.05). Dialysate interferon-gamma (INF-gamma) levels during peritonitis were greater in HA-treated animals (536.8 +/- 296.6 pg/mL in the HA-LPS group versus 169.8 +/- 137.8 pg/mL in the LPS group; P < 0.05). Dialysate elastase activity increased during peritonitis (44.4 +/- 9.3 versus 14.2 +/- 4.1 U/mL in peritonitis-free rats); during peritonitis, the increase in dialysate elastase activity was less pronounced in the rats that had HA in the dialysate (27.3 +/- 4.1 U/mL versus the LPS group; P: < 0.01). We conclude that HA added to the dialysis fluid reduces loss of ultrafiltration during peritonitis in rats. In the presence of HA dialysate, INF-gamma levels during peritonitis increased, whereas elastase activity decreased; these changes might improve the peritoneal immune reaction during peritonitis and at the same time prevent peritoneal membrane injury.
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Affiliation(s)
- A Breborowicz
- Department of Pathophysiology, Poznan Medical School, Poznan, Poland.
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