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Lim BY, Azmi F, Ng SF. Activated carbon-chitosan hydrogel dressing loaded with LL37 microspheres for the treatment of infected wounds: In vivo antimicrobial and antitoxin assessment. Drug Deliv Transl Res 2025:10.1007/s13346-025-01835-7. [PMID: 40120022 DOI: 10.1007/s13346-025-01835-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/28/2025] [Indexed: 03/25/2025]
Abstract
Wound healing is a complex process which is crucial for recovery. Delayed wound healing which is caused by the presence of pathogens has posed significant clinical implications affecting millions of patients globally. Wounds infection caused by Pseudomonas aeruginosa present significant challenges due to their resistance to multiple antimicrobial drugs. The Gram-negative bacteria secretes endotoxin lipopolysaccharide (LPS), which impede wound healing and may lead to severe complications, including life-threatening sepsis. Previously, our laboratory has successfully developed a new hydrogel containing a synthetic antimicrobial peptide as an alternative therapy to conventional antibiotics. This hydrogel contains LL37 microspheres embedded into activated carbon-chitosan hydrogel (LL37-AC-CS). LL37-AC-CS has shown desirable physicochemical properties as well as promising antimicrobial and antitoxin activities in vitro. This current study has two main objectives. The first is to evaluate the in vivo antimicrobial efficacy of LL37-AC-CS hydrogel in full-thickness rat wounds infected with P. aeruginosa. The second objective is to investigate the antitoxin efficacy on the rat wound models treated with E. coli endotoxins LPS. The wound healing efficacy was assessed in terms of the macroscopic appearance, wound contraction rate, histology, and wound tissue biochemical markers. As a result, the LL37-AC-CS hydrogel exhibited remarkable antimicrobial and antitoxin efficacy as compared to the controls. The wound healing efficacy was evident in increased wound closure rate and decrease in bacterial bioburden, and favourable changes in wound healing biomarkers namely the myeloperoxidase, interleukin-6 and tumour necrosis factor α. The elevation of hydroxyproline levels in the LPS-treated wound model indicates there was collagen synthesis. In conclusion, the results presented in this study have significantly enhanced our comprehension of the LL37-AC-CS hydrogel's potential in wound healing. Specifically, the research highlights its effectiveness in eliminating endotoxins and preventing bacterial growth.
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Affiliation(s)
- Bee-Yee Lim
- National Pharmaceutical Regulatory Agency, 36, Jalan Profesor Diraja Ungku Aziz, PJS 13, 46200, Petaling Jaya, Selangor, Malaysia
- Centre for Drug Delivery Technology and Vaccine, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, 50300, Kuala Lumpur, Malaysia
| | - Fazren Azmi
- Centre for Drug Delivery Technology and Vaccine, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, 50300, Kuala Lumpur, Malaysia
| | - Shiow-Fern Ng
- Centre for Drug Delivery Technology and Vaccine, Faculty of Pharmacy, Universiti Kebangsaan Malaysia, 50300, Kuala Lumpur, Malaysia.
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2
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Burgan J, Rahmati M, Lee M, Saiz AM. Innate immune response to bone fracture healing. Bone 2025; 190:117327. [PMID: 39522707 DOI: 10.1016/j.bone.2024.117327] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2024] [Revised: 11/05/2024] [Accepted: 11/07/2024] [Indexed: 11/16/2024]
Abstract
The field of osteoimmunology has primarily focused on fracture healing in isolated musculoskeletal injuries. The innate immune system is the initial response to fracture, with inflammatory macrophages, cytokines, and neutrophils arriving first at the fracture hematoma, followed by an anti-inflammatory phase to begin the process of new bone formation. This review aims to first discuss the current literature and knowledge gaps on the immune responses governing single fracture healing by encompassing the individual role of macrophages, neutrophils, cytokines, mesenchymal stem cells, bone cells, and other immune cells. This paper discusses the interactive effects of these cellular responses underscoring the field of osteoimmunology. The critical role of the metabolic environment in guiding the immune system properties will be highlighted along with some effective therapeutics for fracture healing in the context of osteoimmunology. However, compared to isolated fractures, which frequently heal well, long bone fractures in over 30 % of polytrauma patients exhibit impaired healing. Clinical evidence suggests there may be distinct physiologic and inflammatory pathways altered in polytrauma resulting in nonunion. Nonunion is associated with worse patient outcomes and increased societal healthcare costs. The dysregulated immunomodulatory/inflammatory response seen in polytrauma may lead to this increased nonunion rate. This paper will investigate the differences in immune response between isolated and polytrauma fractures. Finally, future directions for fracture studies are explored with consideration of the emerging roles of newly discovered immune cell functions in fracture healing, the existing challenges and conflicting results in the field, the translational potential of these studies in clinic, and the more complex nature of polytrauma fractures that can alter cell functions in different tissues.
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Affiliation(s)
- Jane Burgan
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA; Renaissance School of Medicine, Stony Brook University, Stony Brook, NY 11794, USA
| | - Maryam Rahmati
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA; Department of Biomaterials, Institute for Clinical Dentistry, University of Oslo, PO Box 1109, Blindern, NO-0317 Oslo, Norway
| | - Mark Lee
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA
| | - Augustine Mark Saiz
- Department of Orthopaedic Surgery, UC Davis Health, 4860 Y Street, Suite 3800, Sacramento, CA 95817, USA.
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Lui PP, Xu JZ, Aziz H, Sen M, Ali N. Jagged-1+ skin Tregs modulate cutaneous wound healing. Sci Rep 2024; 14:20999. [PMID: 39251686 PMCID: PMC11385218 DOI: 10.1038/s41598-024-71512-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 08/28/2024] [Indexed: 09/11/2024] Open
Abstract
Skin-resident regulatory T cells (Tregs) play an irreplaceable role in orchestrating cutaneous immune homeostasis and repair, including the promotion of hair regeneration via the Notch signaling ligand Jagged-1 (Jag1). While skin Tregs are indispensable for facilitating tissue repair post-wounding, it remains unknown if Jag1-expressing skin Tregs impact wound healing. Using a tamoxifen inducible Foxp3creERT2Jag1fl/fl model, we show that loss of functional Jag1 in Tregs significantly delays the rate of full-thickness wound closure. Unlike in hair regeneration, skin Tregs do not utilize Jag1 to impact epithelial stem cells during wound healing. Instead, mice with Treg-specific Jag1 ablation exhibit a significant reduction in Ly6G + neutrophil accumulation at the wound site. However, during both homeostasis and wound healing, the loss of Jag1 in Tregs does not impact the overall abundance or activation profile of immune cell targets in the skin, such as CD4+ and CD8+ T cells, or pro-inflammatory macrophages. This collectively suggests that skin Tregs may utilize Jag1-Notch signalling to co-ordinate innate cell recruitment under conditions of injury but not homeostasis. Overall, our study demonstrates the importance of Jag1 expression in Tregs to facilitate adequate wound repair in the skin.
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Affiliation(s)
- Prudence PokWai Lui
- Peter Gorer Department of Immunobiology, King's College London, London, SE1 9RT, UK
- Centre for Gene Therapy and Regenerative Medicine, King's College London, London, SE1 9RT, UK
| | - Jessie Z Xu
- Peter Gorer Department of Immunobiology, King's College London, London, SE1 9RT, UK
- Centre for Gene Therapy and Regenerative Medicine, King's College London, London, SE1 9RT, UK
| | - Hafsah Aziz
- Peter Gorer Department of Immunobiology, King's College London, London, SE1 9RT, UK
- Centre for Gene Therapy and Regenerative Medicine, King's College London, London, SE1 9RT, UK
| | - Monica Sen
- Peter Gorer Department of Immunobiology, King's College London, London, SE1 9RT, UK
- Centre for Gene Therapy and Regenerative Medicine, King's College London, London, SE1 9RT, UK
| | - Niwa Ali
- Peter Gorer Department of Immunobiology, King's College London, London, SE1 9RT, UK.
- Centre for Gene Therapy and Regenerative Medicine, King's College London, London, SE1 9RT, UK.
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Ishi S, Kanno E, Tanno H, Kurosaka S, Shoji M, Imai T, Yamaguchi K, Kotsugai K, Niiyama M, Kurachi H, Makabe F, Watanabe T, Sato K, Ishii K, Hara H, Imai Y, Kawakami K. Cutaneous wound healing promoted by topical administration of heat-killed Lactobacillus plantarum KB131 and possible contribution of CARD9-mediated signaling. Sci Rep 2023; 13:15917. [PMID: 37741861 PMCID: PMC10517988 DOI: 10.1038/s41598-023-42919-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 09/16/2023] [Indexed: 09/25/2023] Open
Abstract
Optimal conditions for wound healing require a smooth transition from the early stage of inflammation to proliferation, and during this time alternatively activated (M2) macrophages play a central role. Recently, heat-killed lactic acid bacteria (LAB), such as Lactobacillus plantarum (L. plantarum) have been reported as possible modulators affecting the immune responses in wound healing. However, how signaling molecules regulate this process after the administration of heat-killed LAB remains unclear. In this study, we examined the effect of heat-killed L. plantarum KB131 (KB131) administration on wound healing and the contribution of CARD9, which is an essential signaling adaptor molecule for NF-kB activation upon triggering through C-type lectin receptors, in the effects of this bacterium. We analyzed wound closure, histological findings, and inflammatory responses. We found that administration of KB131 accelerated wound closure, re-epithelialization, granulation area, CD31-positive vessels, and α-SMA-positive myofibroblast accumulated area, as well as the local infiltration of leukocytes. In particular, M2 macrophages were increased, in parallel with CCL5 synthesis. The acceleration of wound healing responses by KB131 was canceled in CARD9-knockout mice. These results indicate that the topical administration of KB131 accelerates wound healing, accompanying increased M2 macrophages, which suggests that CARD9 may be involved in these responses.
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Affiliation(s)
- Shinyo Ishi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
| | - Emi Kanno
- Department of Translational Science for Nursing, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
| | - Hiromasa Tanno
- Department of Translational Science for Nursing, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Shiho Kurosaka
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
- Bio-Lab Co., Ltd, 2-1-3 Komagawa, Hidaka-shi, Japan
| | - Miki Shoji
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
| | - Toshiro Imai
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
| | - Kenji Yamaguchi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
| | - Kanna Kotsugai
- Department of Translational Science for Nursing, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Momoko Niiyama
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
| | - Haruko Kurachi
- Department of Translational Science for Nursing, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Miyagi, 980-8575, Japan
| | - Fuko Makabe
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
| | | | - Ko Sato
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
- Department of Clinical Microbiology and Infection, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
| | - Keiko Ishii
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
| | - Hiromitsu Hara
- Department of Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yoshimichi Imai
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
| | - Kazuyoshi Kawakami
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai, Japan
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Bormann D, Gugerell A, Ankersmit HJ, Mildner M. Therapeutic Application of Cell Secretomes in Cutaneous Wound Healing. J Invest Dermatol 2023; 143:893-912. [PMID: 37211377 DOI: 10.1016/j.jid.2023.02.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 02/02/2023] [Accepted: 02/10/2023] [Indexed: 05/23/2023]
Abstract
Although the application of stem cells to chronic wounds emerged as a candidate therapy in the previous century, the mechanism of action remains unclear. Recent evidence has implicated secreted paracrine factors in the regenerative properties of cell-based therapies. In the last two decades, considerable research advances involving the therapeutic potential of stem cell secretomes have expanded the scope of secretome-based therapies beyond stem cell populations. In this study, we review the modes of action of cell secretomes in wound healing, important preconditioning strategies for enhancing their therapeutic efficacy, and clinical trials on secretome-based wound healing.
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Affiliation(s)
- Daniel Bormann
- Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Alfred Gugerell
- Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Hendrik Jan Ankersmit
- Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Department of Thoracic Surgery, Medical University of Vienna, Vienna, Austria
| | - Michael Mildner
- Department of Dermatology, Medical University of Vienna, Vienna, Austria.
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6
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Association between impaired healing after orthognathic surgery and irritable bowel syndrome: A case report and literature review. Int J Surg Case Rep 2022; 100:107745. [PMID: 36252543 PMCID: PMC9579328 DOI: 10.1016/j.ijscr.2022.107745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2022] [Revised: 10/08/2022] [Accepted: 10/08/2022] [Indexed: 11/12/2022] Open
Abstract
Introduction In the disease irritable bowel syndrome (IBS), gastrointestinal function is worsened even though no organic abnormalities are observed in the gastrointestinal mucosa. We report the case of an orthognathic surgery patient with suspected irritable bowel syndrome. Case In September 2017, a 15-year-old Japanese female was referred to us with dental crowding, malocclusion, and mandibular protrusion. In June 2019, a disagreement with classmates led to abdominal pain, diarrhea, and hemorrhage; in August 2019, a preoperative blood test showed sudden anemia, and her surgery was thus postponed. Subsequent upper and lower gastrointestinal endoscopy revealed no organic abnormality, and no definitive diagnosis was made. In March 2020, after an improvement in anemia was observed, a segmental Le Fort I osteotomy and bilateral sagittal split ramus osteotomy (BSSRO) were performed under general anesthesia. On the third post-operative day, due to the mucosal dehiscence adjacent to the suture part, the titanium plate was exposed, and irrigation of the wound with normal saline solution and oral hygiene instruction was continued daily for 2 weeks. Two years and eight months have passed since the surgery, and the healing of the oral mucosa and bone has been uneventful. Discussion The relationship between IBS and post-operative impaired healing associated with the fragility of the oral mucosa is unknown. However, psychological stress has been reported as a cause of IBS and to be related to oral microorganisms. Conclusion Reducing risk factors for IBS and maintaining proper perioperative oral hygiene is essential in managing similar cases.
Irritable bowel syndrome (IBS) is a functional gastrointestinal disease with recurrent abdominal pain. It is difficult to diagnose IBS since the clinical symptoms are confusing. IBS and psychological stress affect post-surgical healing. Reducing risk factors for IBS and maintaining proper perioperative oral hygiene is essential in the management.
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7
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Guo X, Schaudinn C, Blume-Peytavi U, Vogt A, Rancan F. Effects of Adipose-Derived Stem Cells and Their Conditioned Medium in a Human Ex Vivo Wound Model. Cells 2022; 11:cells11071198. [PMID: 35406762 PMCID: PMC8998073 DOI: 10.3390/cells11071198] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/23/2022] [Accepted: 03/30/2022] [Indexed: 12/14/2022] Open
Abstract
Adult stem cells have been extensively investigated for tissue repair therapies. Adipose-derived stem cells (ASCs) were shown to improve wound healing by promoting re-epithelialization and vascularization as well as modulating the inflammatory immune response. In this study, we used ex vivo human skin cultured in a six-well plate with trans-well inserts as a model for superficial wounds. Standardized wounds were created and treated with allogeneic ASCs, ASCs conditioned medium (ASC-CM), or cell culture medium (DMEM) supplemented with fetal calf serum (FCS). Skin viability (XTT test), histology (hematoxylin and eosin, H and E), β-catenin expression as well as inflammatory mediators and growth factors were monitored over 12 days of skin culture. We observed only a moderate time-dependent decrease in skin metabolic activity while skin morphology was preserved, and re-epithelialization occurred at the wound edges. An increase in β-catenin expression was observed in the newly formed epithelia, especially in the samples treated with ASC-CM. In general, increased growth factors and inflammatory mediators, e.g., hepatocytes growth factor (HGF), platelet-derived growth factor subunit AA (PDGF-AA), IL-1α, IL-7, TNF-α, and IL-10, were observed over the incubation time. Interestingly, different expression profiles were observed for the different treatments. Samples treated with ASC-CM significantly increased the levels of inflammatory cytokines and PDGF-AA with respect to control, whereas the treatment with ASCs in DMEM with 10% FCS resulted in significantly increased levels of fibroblast growth factor-basic (FGF-basic) and moderate increases of immunomodulatory cytokines. These results confirm that the wound microenvironment can influence the type of mediators secreted by ASCs and the mode as to how they improve the wound healing process. Comparative investigations with pre-activated ASCs will elucidate further aspects of the wound healing mechanism and improve the protocols of ACS application.
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Affiliation(s)
- Xiao Guo
- Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venerology and and Allergy, Charité–Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (X.G.); (U.B.-P.); (A.V.)
| | - Christoph Schaudinn
- Advanced Light and Electron Microscopy, Zentrum für Biologische Gefahren und Spezielle Pathogene 4 (ZBS4), Robert Koch Institute, 13353 Berlin, Germany;
| | - Ulrike Blume-Peytavi
- Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venerology and and Allergy, Charité–Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (X.G.); (U.B.-P.); (A.V.)
| | - Annika Vogt
- Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venerology and and Allergy, Charité–Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (X.G.); (U.B.-P.); (A.V.)
| | - Fiorenza Rancan
- Clinical Research Center for Hair and Skin Science, Department of Dermatology, Venerology and and Allergy, Charité–Universitaetsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany; (X.G.); (U.B.-P.); (A.V.)
- Correspondence: ; Tel.: +49-30-450518347
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Farhangi ghaleh joughi N, Reza Farahpour M, Mohammadi M, Jafarirad S, Mahmazi S. Investigation on the antibacterial properties and rapid infected wound healing activity of Silver/Laterite/Chitosan nanocomposites. J IND ENG CHEM 2022. [DOI: 10.1016/j.jiec.2022.03.034] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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Ehnert S, Relja B, Schmidt-Bleek K, Fischer V, Ignatius A, Linnemann C, Rinderknecht H, Huber-Lang M, Kalbitz M, Histing T, Nussler AK. Effects of immune cells on mesenchymal stem cells during fracture healing. World J Stem Cells 2021; 13:1667-1695. [PMID: 34909117 PMCID: PMC8641016 DOI: 10.4252/wjsc.v13.i11.1667] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/31/2021] [Accepted: 09/03/2021] [Indexed: 02/06/2023] Open
Abstract
In vertebrates, bone is considered an osteoimmune system which encompasses functions of a locomotive organ, a mineral reservoir, a hormonal organ, a stem cell pool and a cradle for immune cells. This osteoimmune system is based on cooperatively acting bone and immune cells, cohabitating within the bone marrow. They are highly interdependent, a fact that is confounded by shared progenitors, mediators, and signaling pathways. Successful fracture healing requires the participation of all the precursors, immune and bone cells found in the osteoimmune system. Recent evidence demonstrated that changes of the immune cell composition and function may negatively influence bone healing. In this review, first the interplay between different immune cell types and osteoprogenitor cells will be elaborated more closely. The separate paragraphs focus on the specific cell types, starting with the cells of the innate immune response followed by cells of the adaptive immune response, and the complement system as mediator between them. Finally, a brief overview on the challenges of preclinical testing of immune-based therapeutic strategies to support fracture healing will be given.
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Affiliation(s)
- Sabrina Ehnert
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Borna Relja
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Magdeburg 39120, Germany
| | - Katharina Schmidt-Bleek
- Julius Wolff Institute and Berlin Institute of Health Center of Regenerative Therapies, Charité - University Medicine Berlin, Berlin 13353, Germany
| | - Verena Fischer
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm 89091, Germany
| | - Anita Ignatius
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm 89091, Germany
| | - Caren Linnemann
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Helen Rinderknecht
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Markus Huber-Lang
- Institute for Clinical and Experimental Trauma-Immunology (ITI), University Hospital Ulm, Ulm 89091, Germany
| | - Miriam Kalbitz
- Department of Trauma and Orthopedic Surgery, University Hospital Erlangen Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany
| | - Tina Histing
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Andreas K Nussler
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
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10
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The Association of Irritable Bowel Complaints and Perceived Immune Fitness among Individuals That Report Impaired Wound Healing: Supportive Evidence for the Gut–Brain–Skin Axis. GASTROENTEROLOGY INSIGHTS 2021. [DOI: 10.3390/gastroent12040040] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The gut–brain–skin axis is important in wound healing. The aim of this study was to investigate the association between experiencing irritable bowel syndrome (IBS) symptoms, perceived immune fitness, and impaired wound healing. N = 1942 Dutch students (mean (SD) age 21.3 (2.1), 83.6% women) completed an online survey. They were allocated to one of four groups: (1) control group (N = 1544), (2) wound infection (WI) group (N = 65), (3) slow healing wounds (SHW) group (N = 236), or (4) a combination group (COMBI), which experienced both WI and SHW (N = 87). Participants rated their perceived immune fitness on a scale ranging from very poor (0) to excellent (10), and the severity of IBS symptoms (constipation, diarrhea, and pain) was assessed with the Birmingham IBS Symptom Questionnaire. Compared to the control group, perceived immune fitness was significantly poorer for the SHW group (p < 0.001) and COMBI group (p < 0.001), but not for the WI group. Compared to the control group, constipation was reported significantly more frequently by the SHW group (p < 0.001) and the WI group (p = 0.012), diarrhea was reported significantly more frequent by the SHW group (p = 0.038) and the COMBI group (p = 0.004), and pain was reported significantly more frequent by the SHW group (p = 0.020) and COMBI group (p = 0.001). Correlations between IBS complaints and perceived immune fitness were statistically significant (p < 0.001), and also a highly significant and negative association was found between the percentage of participants that reported impaired wound healing and perceived immune fitness (r = −0.97, p < 0.001). In conclusion, among participants with self-reported impaired wound healing, IBS complaints were significantly more severe, and accompanied by a significantly reduced perceived immune fitness.
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11
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Nolan E, Malanchi I. Connecting the dots: Neutrophils at the interface of tissue regeneration and cancer. Semin Immunol 2021; 57:101598. [PMID: 35221216 PMCID: PMC9232712 DOI: 10.1016/j.smim.2022.101598] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 01/19/2022] [Accepted: 02/08/2022] [Indexed: 11/28/2022]
Abstract
Knowledge about neutrophil biology has exponentially grown over the past decades. A high volume of investigations focusing on the characterization of their initially unappreciated multifaceted functions have grown in parallel with the immunity and the cancer fields. This has led to a significant gain in knowledge about their functions not only in tissue defence against pathogens and the collateral damage their overactivation can cause, but also their role in tissue repair and regeneration especially in the context of sterile injuries. On the other hand, the cancer field has also intensively focused its attention on neutrophil engagement in the many steps of the tumorigenic process. This review aims to draw the readers' attention to the similar functions described for neutrophils in tissue repair and in cancer. By bridging the two fields, we provide support for the hypothesis that the underlying program driving cancer-dependent exploitation of neutrophils is rooted in their physiologic tissue protection functions. In this view, cross-fertilization between the two fields will expedite the discovery of therapeutic interventions based on neutrophil targeting or their manipulation.
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Affiliation(s)
- Emma Nolan
- Tumour Host Interaction Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, United Kingdom
| | - Ilaria Malanchi
- Tumour Host Interaction Laboratory, The Francis Crick Institute, 1 Midland Road, NW1 1AT London, United Kingdom.
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12
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Bobrov AG, Getnet D, Swierczewski B, Jacobs A, Medina-Rojas M, Tyner S, Watters C, Antonic V. Evaluation of Pseudomonas aeruginosa pathogenesis and therapeutics in military-relevant animal infection models. APMIS 2021; 130:436-457. [PMID: 34132418 DOI: 10.1111/apm.13119] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2020] [Accepted: 01/21/2021] [Indexed: 01/02/2023]
Abstract
Modern combat-related injuries are often associated with acute polytrauma. As a consequence of severe combat-related injuries, a dysregulated immune response results in serious infectious complications. The gram-negative bacterium Pseudomonas aeruginosa is an opportunistic pathogen that often causes life-threatening bloodstream, lung, bone, urinary tract, and wound infections following combat-related injuries. The rise in the number of multidrug-resistant P. aeruginosa strains has elevated its importance to civilian clinicians and military medicine. Development of novel therapeutics and treatment options for P. aeruginosa infections is urgently needed. During the process of drug discovery and therapeutic testing, in vivo testing in animal models is a critical step in the bench-to-bedside approach, and required for Food and Drug Administration approval. Here, we review current and past literature with a focus on combat injury-relevant animal models often used to understand infection development, the interplay between P. aeruginosa and the host, and evaluation of novel treatments. Specifically, this review focuses on the following animal infection models: wound, burn, bone, lung, urinary tract, foreign body, and sepsis.
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Affiliation(s)
- Alexander G Bobrov
- Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
| | - Derese Getnet
- Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
| | - Brett Swierczewski
- Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
| | - Anna Jacobs
- Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
| | - Maria Medina-Rojas
- Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
| | - Stuart Tyner
- US Army Medical Research and Development Command Military Infectious Diseases Research Program, Frederick, Maryland, USA
| | - Chase Watters
- Naval Medical Research Unit-3, Ghana Detachment, Accra, Ghana
| | - Vlado Antonic
- Wound Infections Department, Bacterial Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA
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13
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Tanno H, Kanno E, Sato S, Asao Y, Shimono M, Kurosaka S, Oikawa Y, Ishi S, Shoji M, Sato K, Kasamatsu J, Miyasaka T, Yamamoto H, Ishii K, Imai Y, Tachi M, Kawakami K. Contribution of Invariant Natural Killer T Cells to the Clearance of Pseudomonas aeruginosa from Skin Wounds. Int J Mol Sci 2021; 22:3931. [PMID: 33920301 PMCID: PMC8070359 DOI: 10.3390/ijms22083931] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/05/2021] [Accepted: 04/08/2021] [Indexed: 12/13/2022] Open
Abstract
Chronic infections are considered one of the most severe problems in skin wounds, and bacteria are present in over 90% of chronic wounds. Pseudomonas aeruginosa is frequently isolated from chronic wounds and is thought to be a cause of delayed wound healing. Invariant natural killer T (iNKT) cells, unique lymphocytes with a potent regulatory ability in various inflammatory responses, accelerate the wound healing process. In the present study, we investigated the contribution of iNKT cells in the host defense against P. aeruginosa inoculation at the wound sites. We analyzed the re-epithelialization, bacterial load, accumulation of leukocytes, and production of cytokines and antimicrobial peptides. In iNKT cell-deficient (Jα18KO) mice, re-epithelialization was significantly decreased, and the number of live colonies was significantly increased, when compared with those in wild-type (WT) mice on day 7. IL-17A, and IL-22 production was significantly lower in Jα18KO mice than in WT mice on day 5. Furthermore, the administration of α-galactosylceramide (α-GalCer), a specific activator of iNKT cells, led to enhanced host protection, as shown by reduced bacterial load, and to increased production of IL-22, IL-23, and S100A9 compared that of with WT mice. These results suggest that iNKT cells promote P. aeruginosa clearance during skin wound healing.
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Grants
- a Grant-in-Aid for Scientific Research (B) (19H03918), The Ministry of Education, Culture, Sports, Science and Technology of Japan
- a Grant-in-Aid for Challenging Exploratory Research (17K19710) The Ministry of Education, Culture, Sports, Science and Technology of Japan
- a Grant-in-Aid for Young Scientists (17K17393) the Ministry of Education, Culture, Sports, Science and Technology of Japan
- a Grant-in-Aid for Young Scientists (19K19494) The Ministry of Education, Culture, Sports, Science and Technology of Japan
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Affiliation(s)
- Hiromasa Tanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (E.K.); (S.S.); (Y.A.); (M.S.)
| | - Emi Kanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (E.K.); (S.S.); (Y.A.); (M.S.)
| | - Suzuna Sato
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (E.K.); (S.S.); (Y.A.); (M.S.)
| | - Yu Asao
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (E.K.); (S.S.); (Y.A.); (M.S.)
| | - Mizuki Shimono
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (E.K.); (S.S.); (Y.A.); (M.S.)
| | - Shiho Kurosaka
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (S.K.); (S.I.); (M.S.); (Y.I.); (M.T.)
| | - Yukari Oikawa
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (Y.O.); (K.I.); (K.K.)
| | - Shinyo Ishi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (S.K.); (S.I.); (M.S.); (Y.I.); (M.T.)
| | - Miki Shoji
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (S.K.); (S.I.); (M.S.); (Y.I.); (M.T.)
| | - Ko Sato
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (K.S.); (J.K.)
| | - Jun Kasamatsu
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (K.S.); (J.K.)
| | - Tomomitsu Miyasaka
- Division of Pathophysiology, Department of Pharmaceutical Sciences, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, Sendai 981-8558, Japan;
| | - Hideki Yamamoto
- Graduate School of Health Sciences, Niigata University, 2-746 Asahimachi-dori, Chuo-ku, Niigata 951-8518, Japan;
| | - Keiko Ishii
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (Y.O.); (K.I.); (K.K.)
| | - Yoshimichi Imai
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (S.K.); (S.I.); (M.S.); (Y.I.); (M.T.)
| | - Masahiro Tachi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (S.K.); (S.I.); (M.S.); (Y.I.); (M.T.)
| | - Kazuyoshi Kawakami
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (Y.O.); (K.I.); (K.K.)
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980-8575, Japan; (K.S.); (J.K.)
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14
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Zhao M, Shi J, Cai W, Liu K, Shen K, Li Z, Wang Y, Hu D. Advances on Graphene-Based Nanomaterials and Mesenchymal Stem Cell-Derived Exosomes Applied in Cutaneous Wound Healing. Int J Nanomedicine 2021; 16:2647-2665. [PMID: 33854313 PMCID: PMC8040697 DOI: 10.2147/ijn.s300326] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2021] [Accepted: 02/27/2021] [Indexed: 12/15/2022] Open
Abstract
Graphene is a new type of carbon nanomaterial discovered after fullerene and carbon nanotube. Due to the excellent biological properties such as biocompatibility, cell proliferation stimulating, and antibacterial properties, graphene and its derivatives have become emerging candidates for the development of novel cutaneous wound dressings and composite scaffolds. On the other hand, pre-clinical research on exosomes derived from mesenchymal stem cells (MSC-Exos) has been intensified for cell-free treatment in wound healing and cutaneous regeneration, via ameliorating the damaged microenvironment of the wound site. Here, we provide a comprehensive understanding of the latest studies and observations on the various effects of graphene-based nanomaterials (GBNs) and MSC-Exos during the cutaneous wound repair process, as well as the putative mechanisms thereof. In addition, we propose the possible forward directions of GBNs and MSC-Exos applications, expecting to promote the clinical transformation.
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Affiliation(s)
- Ming Zhao
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shannxi, 710032, People’s Republic of China
| | - Jihong Shi
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shannxi, 710032, People’s Republic of China
| | - Weixia Cai
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shannxi, 710032, People’s Republic of China
| | - Kaituo Liu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shannxi, 710032, People’s Republic of China
| | - Kuo Shen
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shannxi, 710032, People’s Republic of China
| | - Zichao Li
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shannxi, 710032, People’s Republic of China
| | - Yunchuan Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shannxi, 710032, People’s Republic of China
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, Shannxi, 710032, People’s Republic of China
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15
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Russell T, Bridgewood C, Rowe H, Altaie A, Jones E, McGonagle D. Cytokine "fine tuning" of enthesis tissue homeostasis as a pointer to spondyloarthritis pathogenesis with a focus on relevant TNF and IL-17 targeted therapies. Semin Immunopathol 2021; 43:193-206. [PMID: 33544244 PMCID: PMC7990848 DOI: 10.1007/s00281-021-00836-1] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Accepted: 01/04/2021] [Indexed: 12/17/2022]
Abstract
A curious feature of axial disease in ankylosing spondylitis (AS) and related non-radiographic axial spondyloarthropathy (nrAxSpA) is that spinal inflammation may ultimately be associated with excessive entheseal tissue repair with new bone formation. Other SpA associated target tissues including the gut and the skin have well established paradigms on how local tissue immune responses and proven disease relevant cytokines including TNF and the IL-23/17 axis contribute to tissue repair. Normal skeletal homeostasis including the highly mechanically stressed entheseal sites is subject to tissue microdamage, micro-inflammation and ultimately repair. Like the skin and gut, healthy enthesis has resident immune cells including ILCs, γδ T cells, conventional CD4+ and CD8+ T cells and myeloid lineage cells capable of cytokine induction involving prostaglandins, growth factors and cytokines including TNF and IL-17 that regulate these responses. We discuss how human genetic studies, animal models and translational human immunology around TNF and IL-17 suggest a largely redundant role for these pathways in physiological tissue repair and homeostasis. However, disease associated immune system overactivity of these cytokines with loss of tissue repair “fine tuning” is eventually associated with exuberant tissue repair responses in AS. Conversely, excessive biomechanical stress at spinal enthesis or peripheral enthesis with mechanically related or degenerative conditions is associated with a normal immune system attempts at cytokine fine tuning, but in this setting, it is commensurate to sustained abnormal biomechanical stressing. Unlike SpA, where restoration of aberrant and excessive cytokine “fine tuning” is efficacious, antagonism of these pathways in biomechanically related disease may be of limited or even no value.
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Affiliation(s)
- Tobias Russell
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
| | - Charlie Bridgewood
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
| | - Hannah Rowe
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
| | - Ala Altaie
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
| | - Elena Jones
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK
| | - Dennis McGonagle
- Leeds Institute of Rheumatic and Musculoskeletal Medicine (LIRMM), University of Leeds, Leeds, UK.
- Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds, NIHR Leeds Musculoskeletal Biomedical Research Unit, Chapel Allerton Hospital, Leeds, UK.
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16
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Yamaguchi K, Kanno E, Tanno H, Sasaki A, Kitai Y, Miura T, Takagi N, Shoji M, Kasamatsu J, Sato K, Sato Y, Niiyama M, Goto Y, Ishii K, Imai Y, Saijo S, Iwakura Y, Tachi M, Kawakami K. Distinct Roles for Dectin-1 and Dectin-2 in Skin Wound Healing and Neutrophilic Inflammatory Responses. J Invest Dermatol 2020; 141:164-176.e8. [PMID: 32511980 DOI: 10.1016/j.jid.2020.04.030] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 04/29/2020] [Accepted: 04/30/2020] [Indexed: 12/12/2022]
Abstract
C-type lectin receptors recognize microbial polysaccharides. The C-type lectin receptors such as dendritic cell-associated C-type lectin (Dectin)-1 and Dectin-2, which are triggered by β-glucan and α-mannan, respectively, contribute to upregulation of the inflammatory response. Recently, we demonstrated that activation of the Dectin-2 signal delayed wound healing; in previous studies, triggering the Dectin-1 signal promoted this response. However, the precise roles of these C-type lectin receptors in skin wound healing remain unclear. This study was conducted to determine the roles of Dectin-1 and Dectin-2 in skin wound healing, with a particular focus on the kinetics of neutrophilic inflammatory response. Full-thickness wounds were created on the backs of C57BL/6 mice, and the effects of Dectin-1 or Dectin-2 deficiency and those of β-glucan or α-mannan administration were examined. We also analyzed wound closure, histological findings, and neutrophilic inflammatory response, including neutrophil extracellular trap formation at the wound sites. We found that Dectin-1 contributed to the acceleration of wound healing by inducing early-phase neutrophil accumulation, whereas Dectin-2 was involved in prolonged neutrophilic responses and neutrophil extracellular trap formation, leading to delayed wound healing. Dectin-2 deficiency also improved collagen deposition and TGF-β1 expression. These results suggest that Dectin-1 and Dectin-2 have different roles in wound healing through their different effects on the neutrophilic response.
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Affiliation(s)
- Kenji Yamaguchi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Emi Kanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan.
| | - Hiromasa Tanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Ayako Sasaki
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yuki Kitai
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Takayuki Miura
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Naoyuki Takagi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Miki Shoji
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Jun Kasamatsu
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Ko Sato
- Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yuka Sato
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Momoko Niiyama
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yuka Goto
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Keiko Ishii
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Yoshimichi Imai
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Shinobu Saijo
- Department of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chuo-ku, Chiba, Japan
| | - Yoichiro Iwakura
- Division of Laboratory Animals, Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Chiba, Japan
| | - Masahiro Tachi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
| | - Kazuyoshi Kawakami
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan; Department of Intelligent Network for Infection Control, Tohoku University Graduate School of Medicine, Sendai, Miyagi, Japan
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17
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Autologous platelet-rich fibrin stimulates canine periodontal regeneration. Sci Rep 2020; 10:1850. [PMID: 32024893 PMCID: PMC7002419 DOI: 10.1038/s41598-020-58732-x] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2019] [Accepted: 01/19/2020] [Indexed: 12/18/2022] Open
Abstract
Platelet-rich fibrin (PRF) provides a scaffold for cell migration and growth factors for promoting wound healing and tissue regeneration. Here, we report using PRF in periodontal healing after open flap debridement (OFD) in canine periodontitis. A split-mouth design was performed in twenty dogs. Forty periodontitis surgical sites were randomly categorized into 2 groups; OFD alone and OFD with PRF treatment. Clinical parameters of periodontal pocket depth, gingival index, and the cemento-enamel junction-alveolar bone levels/root length ratio were improved in the OFD + PRF group. The OFD + PRF group also demonstrated a dramatically decreased inflammatory score compared with the OFD group. Collagen accumulation was improved in the OFD + PRF group at later time points compared with baseline. PRF application also significantly reduced inflammatory cytokine expression (TNFA and IL1B), and promoted the expression of collagen production-related genes (COL1A1, COL3A1, and TIMP1) and growth factors (PDGFB, TGFB1, and VEGFA). These findings suggest that PRF combined with OFD provides a new strategy to enhance the overall improvement of canine periodontitis treatment outcomes, especially in terms of inflammation and soft tissue healing. Therefore, PRF use in treating periodontitis could play an important role as a regenerative material to improve canine periodontitis treatment.
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18
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Shavandi A, Saeedi P, Gérard P, Jalalvandi E, Cannella D, Bekhit AED. The role of microbiota in tissue repair and regeneration. J Tissue Eng Regen Med 2020; 14:539-555. [PMID: 31845514 DOI: 10.1002/term.3009] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2019] [Revised: 09/15/2019] [Accepted: 10/28/2019] [Indexed: 12/22/2022]
Abstract
A comprehensive understanding of the human body endogenous microbiota is essential for acquiring an insight into the involvement of microbiota in tissue healing and regeneration process in order to enable development of biomaterials with a better integration with human body environment. Biomaterials used for biomedical applications are normally germ-free, and the human body as the host of the biomaterials is not germ-free. The complexity and role of the body microbiota in tissue healing/regeneration have been underestimated historically. Traditionally, studies aiming at the development of novel biomaterials had focused on the effects of environment within the target tissue, neglecting the signals generated from the microbiota and their impact on tissue regeneration. The significance of the human body microbiota in relation to metabolism, immune system, and consequently tissue regeneration has been recently realised and is a growing research field. This review summarises recent findings on the role of microbiota and mechanisms involved in tissue healing and regeneration, in particular skin, liver, bone, and nervous system regrowth and regeneration highlighting the potential new roles of microbiota for development of a new generation of biomaterials.
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Affiliation(s)
- Amin Shavandi
- BioMatter-BTL, École interfacultaire de Bioingénieurs (EIB), Université Libre de Brussels, Brussels, Belgium
| | - Pouya Saeedi
- Department of Human Nutrition, University of Otago, Dunedin, New Zealand
| | - Philippe Gérard
- Université Paris-Saclay, INRAE, AgroParisTech, Micalis Institute, 78350, Jouy-en-Josas, France
| | - Esmat Jalalvandi
- School of Engineering and Physical Sciences, Heriot-Watt University, Edinburgh, UK
| | - David Cannella
- PhotoBioCatalysis Unit - BTL - École interfacultaire de Bioingénieurs (EIB), Université Libre de Brussels, Brussels, Belgium
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19
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Mizuno Y, Taguchi T. A hydrophobic gelatin fiber sheet promotes secretion of endogenous vascular endothelial growth factor and stimulates angiogenesis. RSC Adv 2020; 10:24800-24807. [PMID: 35517459 PMCID: PMC9055140 DOI: 10.1039/d0ra03593a] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 06/20/2020] [Indexed: 01/24/2023] Open
Abstract
In tissue engineering and regenerative medicine, the formation of vascular beds is an effective method to supply oxygen and nutrients to implanted cells or tissues to improve their survival and promote normal cellular functions. Various types of angiogenic materials have been developed by incorporating growth factors, such as vascular endothelial growth factor, in biocompatible materials. However, these exogenous growth factors suffer from instability and inactivation under physiological conditions. In this study, we designed a novel angiogenic electrospun fiber sheet (C16-FS) composed of Alaska pollock-derived gelatin (ApGltn) modified with hexadecyl (C16) groups to induce localized and sustained angiogenesis without growth factors. C16-FS was thermally crosslinked to enhance its stability. We demonstrated that C16-FS swells in phosphate-buffered saline for over 24 h and resists degradation. Laser doppler perfusion imaging showed that C16-FS induced increased blood perfusion when implanted subcutaneously in rats compared with unmodified ApGltn-fiber sheets (Org-FS) and the sham control. Furthermore, angiogenesis was sustained for up to 7 days following implantation. Immunohistochemical studies revealed elevated nuclear factor-κB and CD31 levels around the C16-FS implantation site compared with the Org-FS implantation site and the control incision site. These results demonstrate that C16-FS is a promising angiogenic material to promote the formation of vascular beds for cell and tissue transplantation without the need for growth factors. In vivo long-term growth factor-free angiogenesis by LPS-mimicking C16-modified gelatin based electrospun fiber sheet.![]()
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Affiliation(s)
- Yosuke Mizuno
- Graduate School of Science and Technology
- University of Tsukuba
- Tsukuba
- Japan
- Polymers and Biomaterials Field
| | - Tetsushi Taguchi
- Graduate School of Science and Technology
- University of Tsukuba
- Tsukuba
- Japan
- Polymers and Biomaterials Field
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20
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Tomoda BT, Corazza FG, Beppu MM, Lopes PS, Moraes MA. Silk fibroin membranes with self‐assembled globular structures for controlled drug release. J Appl Polym Sci 2019. [DOI: 10.1002/app.48763] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Affiliation(s)
- Bruno Thorihara Tomoda
- Department of Chemical EngineeringInstitute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo Rua São Nicolau 210 Diadema Brazil
| | - Fulvio Gabriel Corazza
- Department of Pharmaceutical SciencesInstitute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo Rua São Nicolau 210 Diadema Brazil
| | - Marisa Masumi Beppu
- School of Chemical Engineering, University of Campinas Avenida Albert Einstein 500 Campinas Brazil
| | - Patricia Santos Lopes
- Department of Pharmaceutical SciencesInstitute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo Rua São Nicolau 210 Diadema Brazil
| | - Mariana Agostini Moraes
- Department of Chemical EngineeringInstitute of Environmental, Chemical and Pharmaceutical Sciences, Universidade Federal de São Paulo Rua São Nicolau 210 Diadema Brazil
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21
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Nicoletti G, Saler M, Tresoldi MM, Faga A, Benedet M, Cristofolini M. Regenerative effects of spring water-derived bacterial lysates on human skin fibroblast in in vitro culture: preliminary results. J Int Med Res 2019; 47:5777-5786. [PMID: 31601139 PMCID: PMC6862889 DOI: 10.1177/0300060519880371] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Objective: Previous studies have shown regenerative power of the skin with Comano (Trento, Italy) spring water and resident non-pathogenic microflora. This study investigated the action of bacterial lysates that were isolated from Comano spring water on in vitro culture of human skin fibroblasts. Methods: For this study, we selected the following four bacterial lysates: L1 (closest relative: Rudaea cellulosilytica), L2 (closest relative: Mesorhizobium erdmanii), L3 (closest relative: Herbiconiux ginsengi), and L4 (closest relative: Fictibacillus phosphorivorans). Human fibroblasts were cultured under Dulbecco’s modified Eagle’s medium (DMEM) with bacterial lysates added or DMEM (controls). Cell proliferation was evaluated by spectrophotometric absorbance analysis after the XTT-Microculture Tetrazolium Assay. Results: At 24 hours, cultures with L2, L3, and L4 showed a higher absorbance compared with controls. At 48 hours, cultures with L1, L2, and L3 showed slightly lower absorbance compared with controls, and culture with L4 showed a higher absorbance than in the other experimental conditions. At 72 hours, absorbance was lower in cultures with L1, L2, and L3 than in controls, and absorbance was higher in culture with L4 than in the other experimental conditions. Conclusions: Our study indicates a favorable action of Comano spring water microbiota on proliferation of human skin fibroblasts.
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Affiliation(s)
- Giovanni Nicoletti
- Plastic and Reconstructive Surgery, Department of Clinical Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.,Plastic and Reconstructive Surgery Unit, Department of Surgery, Istituti Clinici Scientifici Maugeri SB SpA IRCCS, Pavia, Italy.,Advanced Technologies for Regenerative Medicine and Inductive Surgery Research Center, University of Pavia, Pavia, Italy
| | - Marco Saler
- Plastic and Reconstructive Surgery, Department of Clinical Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy
| | - Marco Mario Tresoldi
- Plastic and Reconstructive Surgery, Department of Clinical Surgical, Diagnostic and Pediatric Sciences, University of Pavia, Pavia, Italy.,Plastic and Reconstructive Surgery Unit, Department of Surgery, Istituti Clinici Scientifici Maugeri SB SpA IRCCS, Pavia, Italy
| | - Angela Faga
- Advanced Technologies for Regenerative Medicine and Inductive Surgery Research Center, University of Pavia, Pavia, Italy
| | - Mattia Benedet
- Department of Cellular, Computational and Integrative Biology, University of Trento, Trento, Italy
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22
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Hansen TM, Targownik LE, Karimuddin A, Leung Y. Management of Biological Therapy Before Elective Inflammatory Bowel Disease Surgeries. Inflamm Bowel Dis 2019; 25:1613-1620. [PMID: 30794289 DOI: 10.1093/ibd/izz002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/17/2018] [Revised: 12/13/2018] [Accepted: 01/04/2019] [Indexed: 12/11/2022]
Abstract
Increasing uptake of biologic therapy has contributed to declining surgical rates for inflammatory bowel disease (IBD). However, a significant number of patients on biologic therapy will go on to require surgery. The literature is conflicted with regard to the preoperative management of biologic therapy before urgent or elective IBD surgery. This article reviews the available data on postoperative complications following preoperative treatment with anti-tumor necrosis factor alpha therapy, anti-integrin therapy, and anti-interleukin therapy.
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Affiliation(s)
- Tawnya M Hansen
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.,Section of Gastroenterology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Laura E Targownik
- Section of Gastroenterology, Department of Medicine, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Ahmer Karimuddin
- Division of General Surgery, University of British Columbia, Vancouver, British Columbia, Canada
| | - Yvette Leung
- Division of Gastroenterology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
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23
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Abstract
BACKGROUND The microbiome, collective microbial life in defined areas of the body, is of great importance. OBJECTIVE What is the significance of the wound microbiome in the treatment of chronic wounds? Which interactions exist with other microbiomes and which conclusions can be drawn for wound management? MATERIALS AND METHODS Swabs or debridement samples from wounds were analysed for microbial growth by culture or gene-based techniques. The genetic results are used to determine the wound microbiome. The pathogens were evaluated according to proportion of different species and related to different factors like type and location of wound, disease and underlying illnesses and to define the wound microbiome. RESULTS In comparison with conventional microbiological detection methods the wound microbiome comprises many more types and quantities of species. The wound microbiome is related to skin microbiome showing complex and time-dependent composition, as well as inter- and intraindividual differences. Diabetic wounds exhibit disease-related changes, e.g. staphylococcal species dominate whereas streptococcal species dominate in nondiabetic wounds. CONCLUSIONS The analysis of wound microbiome is still at an early stage; however it has already been shown that in hemodynamic disorders there are disease-specific relationships with the wound microbiome, which can also provide clues about the course of the disease. Phenomena from the skin microbiome should also be effective in wounds. In this context modern antimicrobial treatment options beyond conventional chemotherapy like colonization modulation become possible.
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Affiliation(s)
- Georg Daeschlein
- Klinik und Poliklinik für Hautkrankheiten, Universitätsmedizin Greifswald, Sauerbruchstr. 1-4, 17475, Greifswald, Deutschland.
| | - Peter Hinz
- Klinik für Unfall- und Wiederherstellungschirurgie, Universitätsmedizin Greifswald, Greifswald, Deutschland
| | - Thomas Kiefer
- Rehabilitationszentrum für Innere Medizin, Rüdersdorf b. Berlin, Deutschland
| | - Michael Jünger
- Klinik und Poliklinik für Hautkrankheiten, Universitätsmedizin Greifswald, Sauerbruchstr. 1-4, 17475, Greifswald, Deutschland
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24
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Brazil JC, Quiros M, Nusrat A, Parkos CA. Innate immune cell-epithelial crosstalk during wound repair. J Clin Invest 2019; 129:2983-2993. [PMID: 31329162 PMCID: PMC6668695 DOI: 10.1172/jci124618] [Citation(s) in RCA: 179] [Impact Index Per Article: 29.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Skin and intestinal epithelial barriers play a pivotal role in protecting underlying tissues from harsh external environments. The protective role of these epithelia is, in part, dependent on a remarkable capacity to restore barrier function and tissue homeostasis after injury. In response to damage, epithelial wounds repair by a series of events that integrate epithelial responses with those of resident and infiltrating immune cells including neutrophils and monocytes/macrophages. Compromise of this complex interplay predisposes to development of chronic nonhealing wounds, contributing to morbidity and mortality of many diseases. Improved understanding of crosstalk between epithelial and immune cells during wound repair is necessary for development of better pro-resolving strategies to treat debilitating complications of disorders ranging from inflammatory bowel disease to diabetes. In this Review we focus on epithelial and innate immune cell interactions that mediate wound healing and restoration of tissue homeostasis in the skin and intestine.
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25
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Koo JH, Jang HY, Lee Y, Moon YJ, Bae EJ, Yun SK, Park BH. Myeloid cell-specific sirtuin 6 deficiency delays wound healing in mice by modulating inflammation and macrophage phenotypes. Exp Mol Med 2019; 51:1-10. [PMID: 31028245 PMCID: PMC6486573 DOI: 10.1038/s12276-019-0248-9] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2018] [Revised: 12/27/2018] [Accepted: 01/16/2019] [Indexed: 12/18/2022] Open
Abstract
We recently reported that myeloid cell-expressed sirtuin 6 (Sirt6) plays a crucial role in M1 macrophage polarization and chemotaxis. Given the prominent role of macrophages during wound repair and macrophage heterogeneity, we hypothesized that a Sirt6 deficiency in myeloid cells would delay skin wound closure by affecting the phenotypes of macrophages in wounds. To address this question, a full-thickness excisional lesion was made in the dorsal skin of myeloid cell-specific Sirt6 knockout (KO) and wild-type mice. Wound closure was delayed in the KO mice, which exhibited less collagen deposition, suppressed angiogenesis, and reduced expression of wound healing-related genes compared to the wild-type mice. Using immunohistochemical, flow cytometric, and gene-expression analyses of macrophage subpopulations from wound tissue, we identified increased infiltration of M1 macrophages with a concomitant decrease in M2 macrophage numbers in the KO mice compared to the wild-type mice. Consistent with the in vivo wound closure defects observed in the KO mice, keratinocytes and fibroblasts treated with KO macrophage-derived conditioned medium migrated slower than those treated with wild-type macrophage-derived conditioned medium. An analysis of downstream signaling pathways indicated that impaired Akt signaling underlies the decreased M2 phenotypic switching in KO mice. These results suggest that a macrophage phenotypic switch induced by Sirt6 deficiency contributes to impaired wound healing in mice.
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Affiliation(s)
- Jeung-Hyun Koo
- Department of Biochemistry and Molecular Biology, Chonbuk National University Medical School, Jeonju, Jeonbuk, 54896, Republic of Korea
| | - Hyun-Young Jang
- Department of Biochemistry and Molecular Biology, Chonbuk National University Medical School, Jeonju, Jeonbuk, 54896, Republic of Korea
| | - Youngyi Lee
- Department of Biochemistry and Molecular Biology, Chonbuk National University Medical School, Jeonju, Jeonbuk, 54896, Republic of Korea
| | - Young Jae Moon
- Department of Biochemistry and Molecular Biology, Chonbuk National University Medical School, Jeonju, Jeonbuk, 54896, Republic of Korea
| | - Eun Ju Bae
- College of Pharmacy, Woosuk University, Wanju, Jeonbuk, 55338, Republic of Korea
| | - Seok-Kweon Yun
- Department of Dermatology and Research Institute of Clinical Medicine, Chonbuk National University Medical School, Jeonju, Jeonbuk, 54896, Republic of Korea.
- Biomedical Research Institute, Chonbuk National University Hospital, Jeonju, Jeonbuk, 54907, Republic of Korea.
| | - Byung-Hyun Park
- Department of Biochemistry and Molecular Biology, Chonbuk National University Medical School, Jeonju, Jeonbuk, 54896, Republic of Korea.
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26
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Miura T, Kawakami K, Kanno E, Tanno H, Tada H, Sato N, Masaki A, Yokoyama R, Kawamura K, Kitai Y, Takagi N, Yamaguchi K, Yamaguchi N, Kyo Y, Ishii K, Imai Y, Saijo S, Iwakura Y, Tachi M. Dectin-2-Mediated Signaling Leads to Delayed Skin Wound Healing through Enhanced Neutrophilic Inflammatory Response and Neutrophil Extracellular Trap Formation. J Invest Dermatol 2018; 139:702-711. [PMID: 30393083 DOI: 10.1016/j.jid.2018.10.015] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2017] [Revised: 10/03/2018] [Accepted: 10/04/2018] [Indexed: 01/13/2023]
Abstract
Dendritic cell-associated C-type lectin-2 (i.e., dectin-2) recognizes fungal polysaccharides, including α-mannan. Dectin-2-mediated recognition of fungi, such as Candida albicans, leads to NF-κB activation, which induces production of inflammatory cytokines. However, the role of dectin-2 in skin wound healing remains unclear. In this study, we sought to determine how dectin-2 deficiency and the administration of α-mannan affected the wound healing process. Full-thickness wounds were created on the backs of wild type C57BL/6 and dectin-2-deficient mice. We analyzed wound closure, histological findings, and re-epithelialization. We also examined the neutrophilic inflammatory responses and neutrophil extracellular trap (NET)-osis at the wound sites after administration of α-mannan. The percent wound closure and re-epithelialization was significantly accelerated in dectin-2-knockout mice compared with wild-type mice on days 3 and 5 after wounding. In contrast, administration of α-mannan delayed wound closure in wild-type mice, and these responses were canceled in dectin-2-knockout mice. Furthermore, mice administered α-mannan, neutrophil infiltration was prolonged, and the expression of citrullinated histone, an indicator of NETosis, at the wound sites was accelerated. Administration of a neutrophil elastase inhibitor significantly improved the delayed wound healing caused by α-mannan. These results suggest that dectin-2 may have a deep impact on the skin wound healing process through regulation of neutrophilic responses.
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Affiliation(s)
- Takayuki Miura
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuyoshi Kawakami
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Emi Kanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Japan.
| | - Hiromasa Tanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Hiroyuki Tada
- Division of Oral Microbiology, Tohoku University Graduate School of Dentistry, Sendai, Japan
| | - Noriko Sato
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Airi Masaki
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Rin Yokoyama
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kotone Kawamura
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yuki Kitai
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Naoyuki Takagi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kenji Yamaguchi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Natsuki Yamaguchi
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshika Kyo
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keiko Ishii
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Yoshimichi Imai
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shinobu Saijo
- Department of Molecular Immunology, Medical Mycology Research Center, Chiba University, Chiba, Japan
| | - Yoichiro Iwakura
- Division of Laboratory Animals, Research Institute for Biomedical Sciences, Tokyo University of Science, Chiba, Japan
| | - Masahiro Tachi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
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27
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Neutrophils in Tissue Trauma of the Skin, Bone, and Lung: Two Sides of the Same Coin. J Immunol Res 2018; 2018:8173983. [PMID: 29850639 PMCID: PMC5937416 DOI: 10.1155/2018/8173983] [Citation(s) in RCA: 89] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 03/21/2018] [Indexed: 12/12/2022] Open
Abstract
Following severe tissue injury, patients are exposed to various danger- and microbe-associated molecular patterns, which provoke a strong activation of the neutrophil defense system. Neutrophils trigger and modulate the initial posttraumatic inflammatory response and contribute critically to subsequent repair processes. However, severe trauma can affect central neutrophil functions, including circulation half-life, chemokinesis, phagocytosis, cytokine release, and respiratory burst. Alterations in neutrophil biology may contribute to trauma-associated complications, including immune suppression, sepsis, multiorgan dysfunction, and disturbed tissue regeneration. Furthermore, there is evidence that neutrophil actions depend on the quality of the initial stimulus, including trauma localization and severity, the micromilieu in the affected tissue, and the patient's overall inflammatory status. In the present review, we describe the effects of severe trauma on the neutrophil phenotype and dysfunction and the consequences for tissue repair. We particularly concentrate on the role of neutrophils in wound healing, lung injury, and bone fractures, because these are the most frequently affected tissues in severely injured patients.
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28
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Garcia M, Morello E, Garnier J, Barrault C, Garnier M, Burucoa C, Lecron JC, Si-Tahar M, Bernard FX, Bodet C. Pseudomonas aeruginosa flagellum is critical for invasion, cutaneous persistence and induction of inflammatory response of skin epidermis. Virulence 2018; 9:1163-1175. [PMID: 30070169 PMCID: PMC6086312 DOI: 10.1080/21505594.2018.1480830] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 05/21/2018] [Indexed: 12/22/2022] Open
Abstract
Pseudomonas aeruginosa, an opportunistic pathogen involved in skin and lung diseases, possesses numerous virulence factors, including type 2 and 3 secretion systems (T2SS and T3SS) and its flagellum, whose functions remain poorly known during cutaneous infection. Using isogenic mutants deleted from genes encoding each or all of these three virulence factors, we investigated their role in induction of inflammatory response and in tissue invasiveness in human primary keratinocytes and reconstructed epidermis. Our results showed that flagellum, but not T2SS and T3SS, is involved in induction of a large panel of cytokine, chemokine, and antimicrobial peptide (AMP) mRNA in the infected keratinocytes. Chemokine secretion and AMP tissular production were also dependent on the presence of the bacterial flagellum. This pro-inflammatory effect was significantly reduced in keratinocytes infected in presence of anti-toll-like receptor 5 (TLR5) neutralizing antibody. Bacterial invasion of human epidermis and persistence in a mouse model of sub-cutaneous infection were dependent on the P. aeruginosa flagellum. We demonstrated that flagellum constitutes the main virulence factor of P. aeruginosa involved not only in early induction of the epidermis inflammatory response but also in bacterial invasion and cutaneous persistence. P. aeruginosa is mainly sensed by TLR5 during the early innate immune response of human primary keratinocytes.
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Affiliation(s)
- Magali Garcia
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Laboratoire Inflammation Tissus Epithéliaux et Cytokines EA 4331, Université de Poitiers
, Poitiers, France
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Laboratoire de Virologie et Mycobactériologie, CHU de Poitiers
, Poitiers, France
| | - Eric Morello
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Centre d'Etude des Pathologies Respiratoires, INSERM UMR 1100, Université de Tours
, Tours, France
| | | | | | - Martine Garnier
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Laboratoire Inflammation Tissus Epithéliaux et Cytokines EA 4331, Université de Poitiers
, Poitiers, France
| | - Christophe Burucoa
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Laboratoire Inflammation Tissus Epithéliaux et Cytokines EA 4331, Université de Poitiers
, Poitiers, France
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Laboratoire de Bactériologie et Hygiène, CHU de Poitiers
, Poitiers, France
| | - Jean-Claude Lecron
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Laboratoire Inflammation Tissus Epithéliaux et Cytokines EA 4331, Université de Poitiers
, Poitiers, France
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Laboratoire d’Immunologie et Inflammation, CHU de Poitiers
, Poitiers, France
| | - Mustapha Si-Tahar
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Centre d'Etude des Pathologies Respiratoires, INSERM UMR 1100, Université de Tours
, Tours, France
| | | | - Charles Bodet
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Laboratoire Inflammation Tissus Epithéliaux et Cytokines EA 4331, Université de Poitiers
, Poitiers, France
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29
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Nicoletti G, Saler M, Pellegatta T, Tresoldi MM, Bonfanti V, Malovini A, Faga A, Riva F. Ex vivo regenerative effects of a spring water. Biomed Rep 2017; 7:508-514. [PMID: 29188053 PMCID: PMC5702968 DOI: 10.3892/br.2017.1002] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2017] [Accepted: 09/14/2017] [Indexed: 12/02/2022] Open
Abstract
Previous experiments by our group have indicated the regenerative effects of a spring water (Comano), which was possibly associated with the native non-pathogenic bacterial flora. The present study aimed to confirm these regenerative properties in a human ex vivo experimental model in the context of physiological wound healing. Human 6-mm punch skin biopsies harvested during plastic surgery sessions were injured in their central portion to induce skin loss and were cultured in either conventional medium (controls) or medium powder reconstituted with filtered Comano spring water (treated samples). At 24, 48 and 72 h the specimens were observed following staining with hematoxylin and eosin, Picrosirius Red, orcein and anti-proliferating cell nuclear antigen. Compared with the controls, the treated samples exhibited reduced overall cell infiltration, evidence of fibroblasts, stimulation of cell proliferation and collagen and elastic fiber regeneration. In the spring water, in addition to 12 resident non-pathogenic bacterial strains exhibiting favorable metabolic activities, more unknown non-pathogenic species are being identified by genomic analysis. In the present study, the efficacy of this ‘germ-free’, filtered spring water in wound regeneration was indicated. Thus, the Comano spring water microbiota should be acknowledged for its regenerative properties.
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Affiliation(s)
- Giovanni Nicoletti
- Plastic and Reconstructive Surgery, Department of Clinical-Surgical Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy.,Advanced Technologies for Regenerative Medicine and Inductive Surgery Research Center, University of Pavia, 27100 Pavia, Italy.,Plastic and Reconstructive Surgery Unit, Salvatore Maugeri Research and Care Institute, 27100 Pavia, Italy
| | - Marco Saler
- Plastic and Reconstructive Surgery, Department of Clinical-Surgical Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy
| | - Tommaso Pellegatta
- Plastic and Reconstructive Surgery, Department of Clinical-Surgical Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy
| | - Marco Mario Tresoldi
- Plastic and Reconstructive Surgery, Department of Clinical-Surgical Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy.,Plastic and Reconstructive Surgery Unit, Salvatore Maugeri Research and Care Institute, 27100 Pavia, Italy
| | - Viola Bonfanti
- Plastic and Reconstructive Surgery, Department of Clinical-Surgical Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy
| | - Alberto Malovini
- Laboratory of Informatics and Systems Engineering for Clinical Research, Istituti Clinici Scientifici Maugeri, 27100 Pavia, Italy
| | - Angela Faga
- Plastic and Reconstructive Surgery, Department of Clinical-Surgical Diagnostic and Pediatric Sciences, University of Pavia, 27100 Pavia, Italy.,Advanced Technologies for Regenerative Medicine and Inductive Surgery Research Center, University of Pavia, 27100 Pavia, Italy.,Plastic and Reconstructive Surgery Unit, Salvatore Maugeri Research and Care Institute, 27100 Pavia, Italy
| | - Federica Riva
- Advanced Technologies for Regenerative Medicine and Inductive Surgery Research Center, University of Pavia, 27100 Pavia, Italy.,Department of Public Health, Experimental and Forensic Medicine, Histology and Embryology Unit, University of Pavia, 27100 Pavia, Italy
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30
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Kanno E, Kawakami K, Tanno H, Suzuki A, Sato N, Masaki A, Imamura A, Takagi N, Miura T, Yamamoto H, Ishii K, Hara H, Imai Y, Maruyama R, Tachi M. Contribution of CARD9-mediated signalling to wound healing in skin. Exp Dermatol 2017. [PMID: 28620967 DOI: 10.1111/exd.13389] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
The inflammatory response after skin injury involves the secretion of a variety of cytokines and growth factors that are necessary for tissue repair. Caspase recruitment domain-containing protein 9 (CARD9) is an essential signalling adaptor molecule for NF-κB activation upon triggering through C-type lectin receptors (CLRs), which are expressed in macrophages and dendritic cells. However, the role of CARD9 in inflammatory responses at the wound site has not been elucidated. In this study, we analysed the role of CARD9 in the healing process of skin wounds. Wounds were created on the backs of wild-type (WT) C57BL/6 mice and CARD9 gene-disrupted (knockout [KO]) mice. We analysed per cent wound closure, and the wound tissues were harvested for analysis of leucocyte accumulation and cytokine and chemokine expressions. CARD9KO mice exhibited significant attenuation of wound closure compared with WT mice on days 5, 7 and 10 postwounding, which was associated with decreased macrophage accumulation and reduced TNF-α, IL-1β, CCL3 and CCL4 expressions. These results suggest that CARD9 may be involved in the wound-healing process through the regulation of macrophage-mediated inflammatory responses.
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Affiliation(s)
- Emi Kanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
| | - Kazuyoshi Kawakami
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
| | - Hiromasa Tanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
| | - Aiko Suzuki
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
| | - Noriko Sato
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
| | - Airi Masaki
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
| | - Ayano Imamura
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
| | - Naoyuki Takagi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
| | - Takayuki Miura
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
| | - Hideki Yamamoto
- Center for Transdisciplinary Research, Niigata University, Nishi-ku, Niigata, Japan
| | - Keiko Ishii
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
| | - Hiromitsu Hara
- Department of Immunology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan
| | - Yoshimichi Imai
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
| | - Ryoko Maruyama
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
| | - Masahiro Tachi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Aoba-ku, Sendai, Japan
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31
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Teunis AL, Popova TG, Espina V, Liotta LA, Popov SG. Immune-modulating Activity of Hydrogel Microparticles Contributes to the Host Defense in a Murine Model of Cutaneous Anthrax. Front Mol Biosci 2017; 4:62. [PMID: 28894739 PMCID: PMC5581330 DOI: 10.3389/fmolb.2017.00062] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2017] [Accepted: 08/14/2017] [Indexed: 11/17/2022] Open
Abstract
We recently reported that the open-mesh (0.7 μ) polyacrylamide microparticles (MPs) with internally-coupled Cibacron affinity dye demonstrate protective effect in mice challenged into footpads with high doses (200 LD50) of anthrax (Sterne) spores. A single injection of MPs before spore challenge reduces inflammatory response, delays onset of mortality and promotes survival. In this study, we show that the effect of MPs was substantially increased at the lower spore dose (7 LD50). The inflammation of footpads was reduced to the background level, and 60% of animals survived for 16 days while all untreated infected animals died within 6 days with strong inflammation. The effects of MPs were promoted when the MPs were loaded with a combination of neutrophil-attracting chemokines IL-8 and MIP-1α which delayed the onset of mortality in comparison with untreated mice for additional 8 days. The MPs were not inherently cytotoxic against the bacteria or cultured murine Raw 264.7 cells, but stimulated these cells to release G-CSF, MCP-1, MIP-1α, and TNF-α. Consistent with this finding the injection of MPs induced neutrophil influx into footpads, stimulated production of TNF-α associated with migration of pERK1/2-positive cells with the Langerhans phenotype from epidermis to regional lymph nodes. Our data support the mechanism of protection in which the immune defense induced by MPs along with the exogenous chemokines counterbalances the suppressive effect caused by anthrax infection.
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Affiliation(s)
- Allison L Teunis
- Department of Molecular Microbiology, National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason UniversityManassas, VA, United States
| | - Taissia G Popova
- Department of Molecular Microbiology, Center for Applied Proteomics and Molecular Medicine, School of Systems Biology, George Mason UniversityManassas, VA, United States
| | - Virginia Espina
- Department of Molecular Microbiology, Center for Applied Proteomics and Molecular Medicine, School of Systems Biology, George Mason UniversityManassas, VA, United States
| | - Lance A Liotta
- Department of Molecular Microbiology, Center for Applied Proteomics and Molecular Medicine, School of Systems Biology, George Mason UniversityManassas, VA, United States
| | - Serguei G Popov
- Department of Molecular Microbiology, National Center for Biodefense and Infectious Diseases, School of Systems Biology, George Mason UniversityManassas, VA, United States
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Gardiner M, Vicaretti M, Sparks J, Bansal S, Bush S, Liu M, Darling A, Harry E, Burke CM. A longitudinal study of the diabetic skin and wound microbiome. PeerJ 2017; 5:e3543. [PMID: 28740749 PMCID: PMC5522608 DOI: 10.7717/peerj.3543] [Citation(s) in RCA: 90] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2017] [Accepted: 06/14/2017] [Indexed: 12/28/2022] Open
Abstract
Background Type II diabetes is a chronic health condition which is associated with skin conditions including chronic foot ulcers and an increased incidence of skin infections. The skin microbiome is thought to play important roles in skin defence and immune functioning. Diabetes affects the skin environment, and this may perturb skin microbiome with possible implications for skin infections and wound healing. This study examines the skin and wound microbiome in type II diabetes. Methods Eight type II diabetic subjects with chronic foot ulcers were followed over a time course of 10 weeks, sampling from both foot skin (swabs) and wounds (swabs and debrided tissue) every two weeks. A control group of eight control subjects was also followed over 10 weeks, and skin swabs collected from the foot skin every two weeks. Samples were processed for DNA and subject to 16S rRNA gene PCR and sequencing of the V4 region. Results The diabetic skin microbiome was significantly less diverse than control skin. Community composition was also significantly different between diabetic and control skin, however the most abundant taxa were similar between groups, with differences driven by very low abundant members of the skin communities. Chronic wounds tended to be dominated by the most abundant skin Staphylococcus, while other abundant wound taxa differed by patient. No significant correlations were found between wound duration or healing status and the abundance of any particular taxa. Discussion The major difference observed in this study of the skin microbiome associated with diabetes was a significant reduction in diversity. The long-term effects of reduced diversity are not yet well understood, but are often associated with disease conditions.
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Affiliation(s)
- Melissa Gardiner
- The i3 institute, University of Technology Sydney, Sydney, New South Wales, Australia
| | - Mauro Vicaretti
- Medical School, University of Sydney, Sydney, New South Wales, Australia.,Westmead Hospital, Western Sydney Local Health District, Sydney, New South Wales, Australia
| | - Jill Sparks
- Community Nursing, Western Sydney Local Health District, Sydney, New South Wales, Australia
| | - Sunaina Bansal
- The i3 institute, University of Technology Sydney, Sydney, New South Wales, Australia
| | - Stephen Bush
- School of Mathematical and Physical Sciences, University of Technology Sydney, Sydney, New South Wales, Australia
| | - Michael Liu
- The i3 institute, University of Technology Sydney, Sydney, New South Wales, Australia
| | - Aaron Darling
- The i3 institute, University of Technology Sydney, Sydney, New South Wales, Australia
| | - Elizabeth Harry
- The i3 institute, University of Technology Sydney, Sydney, New South Wales, Australia
| | - Catherine M Burke
- The i3 institute, University of Technology Sydney, Sydney, New South Wales, Australia
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Bacterial load of conditioned pressure ulcers is not a predictor for early flap failure in spinal cord injury. Spinal Cord 2017; 55:535-539. [PMID: 28071687 DOI: 10.1038/sc.2016.186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Revised: 10/29/2016] [Accepted: 11/24/2016] [Indexed: 11/08/2022]
Abstract
OBJECTIVES Pressure ulcers impose a major lifetime medical problem to patients with high-grade spinal cord injury (SCI). For patients with stages 3-4 pressure ulcers, plastic surgery is often the only remaining treatment option. Despite considerable flap failure rates of around 30%, only sparse knowledge exists on predictors for flap failure. Hence, identification of predictors for flap failures is needed. METHODS We prospectively enrolled 38 SCI patients with stages 3-4 pressure ulcers scheduled for plastic surgery. Preoperative wound swabs, intraoperative tissue samples and postoperative drainage liquids were microbiologically analyzed. In multivariable logistic regression analyses, bacterial loads of deep tissue cultures of intraoperative samples as well as other clinical variables were analyzed with respect to the prediction of flap failures. RESULTS The flap failure rate was 27.5%. Bacterial loads of deep tissue cultures were not predictive for flap failure, neither was the colonization with a specific bacterial strain. We observed a considerable fluctuation of microbiological environment from initial swab cultures, intraoperative samples and postoperative drainage fluids. Antibioprophylaxis was sufficient in only 75% of deep tissue cultures and 69% of drainage fluids. Insufficient antibioprophylaxis was associated with a higher flap failure rates (odds ratio 6.3, confidence interval 1.2-41.0). CONCLUSION After inpatient wound conditioning, bacterial load analysis of intraoperative wound tissue cultures is ineffective in order to predict flap failure rates in SCI patients with stages 3-4 pressure ulcers after flap surgery. Instead, insufficient antibioprophylaxis might be a factor contributing to flap failure.
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Pellegatta T, Saler M, Bonfanti V, Nicoletti G, Faga A. Novel perspectives on the role of the human microbiota in regenerative medicine and surgery. Biomed Rep 2016; 5:519-524. [PMID: 27882211 PMCID: PMC5103662 DOI: 10.3892/br.2016.778] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2016] [Accepted: 09/21/2016] [Indexed: 12/19/2022] Open
Abstract
Plastic surgery is transitioning from a fine craftsmanship to a regenerative science. In wound healing, the role of microorganisms is no longer considered to be just counteracting, but also promoting. Furthermore, host-microbe interactions are essential for numerous aspects of normal mammalian physiology, from metabolic activity to immune homeostasis. Each area of the human body hosts a unique microbial community, and the composition of microbiota is dependent on the host, age and the anatomical area, and it changes according to the characteristics of the microenvironment. Every squared centimeter of skin contains ~1 billion bacteria. The majority of microorganisms of the skin are commensal or temporary passing members. Skin flora mechanisms interacting or influencing the human physical skin barrier are not well defined. Resident skin bacteria provide the first line of defence against potentially dangerous pathogens and produce small molecules that influence their microbial neighbours. Furthermore, the microbiota activates and assists innate immunity and influences adaptive immunity. Various types of immune and non-immune cells contribute to wound healing. The proliferative phase of wound healing is inversely proportional to the extent of the post-traumatic inflammatory reaction. Topical bacterial lipopolysaccharide application markedly affects wound healing by accelerating the resolution of inflammation, increasing macrophage infiltration, enhancing collagen synthesis and altering the secretion of mediators involved in skin regeneration. Various studies have investigated the biological contents of thermal spring waters, and their anti-inflammatory and immune protective roles. In addition, the regenerative properties of thermal spring waters were analysed in an experimental animal wound model. The areas treated with thermal water healed faster than the areas treated with conventional dressings, and exhibited a collagen and elastic fiber network comparable with the normal skin. Thus, the microbial environment may be considered as a potential tool in regenerative medicine and surgery.
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Affiliation(s)
- Tommaso Pellegatta
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, Plastic Surgery Unit, University of Pavia, Pavia, I-27100 Lombardy, Italy
| | - Marco Saler
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, Plastic Surgery Unit, University of Pavia, Pavia, I-27100 Lombardy, Italy
| | - Viola Bonfanti
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, Plastic Surgery Unit, University of Pavia, Pavia, I-27100 Lombardy, Italy
| | - Giovanni Nicoletti
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, Plastic Surgery Unit, University of Pavia, Pavia, I-27100 Lombardy, Italy
- Plastic and Reconstructive Surgery Unit, Salvatore Maugeri Research and Care Institute, Pavia, I-27100 Lombardy, Italy
| | - Angela Faga
- Department of Clinical-Surgical, Diagnostic and Pediatric Sciences, Plastic Surgery Unit, University of Pavia, Pavia, I-27100 Lombardy, Italy
- Plastic and Reconstructive Surgery Unit, Salvatore Maugeri Research and Care Institute, Pavia, I-27100 Lombardy, Italy
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Ma S, Lin Y, Deng B, Zheng Y, Hao C, He R, Ding F. Endothelial bioreactor system ameliorates multiple organ dysfunction in septic rats. Intensive Care Med Exp 2016; 4:23. [PMID: 27447715 PMCID: PMC4958089 DOI: 10.1186/s40635-016-0097-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 07/13/2016] [Indexed: 12/26/2022] Open
Abstract
BACKGROUND The endothelium is a potentially valuable target for sepsis therapy. We have previously studied an extracorporeal endothelial cell therapy system, called the endothelial bioreactor (EBR), which prolonged the survival time of endotoxemia sepsis in swine. To further study of the therapeutic effects and possible mechanisms, we established a miniature EBR system for septic rats induced by cecal ligation and puncture (CLP). METHODS In the miniature EBR system, the extracorporeal circulation first passed through a mini-hemofilter, and the ultrafiltrate (UF) was separated, then the UF passed through an EBR (a 1-mL cartridge containing approximately 2 × 10(6) endothelial cells grown on microcarriers) and interact with endothelial cells. Eighteen hours after CLP, the rats were treated for 4 h with this extracorporeal system containing either endothelial cells (EBR group) or no cells (sham EBR group). Physiologic and biochemical parameters, cytokines, endothelial functions, and 7-day survival time were monitored. In vitro, the pulmonary endothelial cells of the septic rats were treated with the EBR system and the resulting changes in their functions were monitored. RESULTS The EBR system ameliorated CLP-induced sepsis compared with the sham EBR system. After CLP, the 7-day survival rate of sham-treated rats was only 25.0 %, while in the EBR-treated group, it increased to 57.1 % (p = 0.04). The EBR system protected the liver and renal function and ameliorated the kidney and lung injury. Meanwhile, this therapy reduced pulmonary vascular leakage and alleviated the infiltration of inflammatory cells in the lungs, especially neutrophils. Furthermore, after the EBR treatment both in vivo and in vitro, the expression of intercellular adhesion molecule-1 and the secretion of CXCL1 and CXCL2 of pulmonary endothelium decreased, which helped to alleviate the adhesion and chemotaxis of neutrophils. In addition, the EBR system decreased CD11b expression and intracellular free calcium level of peripheral blood neutrophils, modulated the activation of these neutrophils. CONCLUSIONS The EBR system significantly ameliorated CLP-induced sepsis and improved survival and organ functions. Compared with the sham EBR system, this extracorporeal endothelial therapy may be involved in modulating the function of pulmonary endothelial cells, reducing the adhesion and chemotaxis of neutrophil, and modulating the activation of peripheral blood neutrophils.
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Affiliation(s)
- Shuai Ma
- Division of Nephrology & Unit of Critical Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, 639 Zhizaoju Road, Shanghai, 200011, China.,Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yuli Lin
- Department of Immunology, Shanghai Medical College, Fudan University, Shanghai, 200032, China
| | - Bo Deng
- Division of Nephrology & Unit of Critical Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, 639 Zhizaoju Road, Shanghai, 200011, China.,Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yin Zheng
- Division of Nephrology & Unit of Critical Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, 639 Zhizaoju Road, Shanghai, 200011, China.,Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Chuanming Hao
- Division of Nephrology, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Rui He
- Department of Immunology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Feng Ding
- Division of Nephrology & Unit of Critical Nephrology, Shanghai Ninth People's Hospital, School of Medicine, Shanghai Jiaotong University, 639 Zhizaoju Road, Shanghai, 200011, China.
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Kanno E, Kawakami K, Miyairi S, Tanno H, Suzuki A, Kamimatsuno R, Takagi N, Miyasaka T, Ishii K, Gotoh N, Maruyama R, Tachi M. Promotion of acute-phase skin wound healing by Pseudomonas aeruginosa C 4 -HSL. Int Wound J 2015; 13:1325-1335. [PMID: 26471357 DOI: 10.1111/iwj.12523] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 08/31/2015] [Accepted: 09/20/2015] [Indexed: 11/27/2022] Open
Abstract
A Pseudomonas aeruginosa quorum-sensing system, which produces N-(3-oxododecanoyl)-l-homoserine lactone (3-oxo-C12 -HSL) and N-butanoyl-l-homoserine lactone (C4 -HSL), regulates the virulence factors. In our previous study, 3-oxo-C12 -HSL, encoded by lasI gene, was shown to promote wound healing. However, the effect of C4 -HSL, encoded by rhlI gene, remains to be elucidated. We addressed the effect of C4 -HSL on wounds in P. aeruginosa infection. Wounds were created on the backs of Sprague-Dawley SD rats, and P. aeruginosa PAO1 (PAO1) or its rhlI deletion mutant (ΔrhlI) or lasI deletion mutant (ΔlasI) was inoculated onto the wound. Rats were injected intraperitoneally with anti-C4 -HSL antiserum or treated with C4 -HSL at the wound surface. PAO1 inoculation led to significant acceleration of wound healing, which was associated with neutrophil infiltration and TNF-α synthesis. These responses were reversed, except for TNF-α production, when ΔrhlI was inoculated instead of PAO1 or when rats were co-treated with PAO1 and anti-C4 -HSL antiserum. In contrast, the healing process and neutrophil infiltration, but not TNF-α synthesis, were accelerated when C4 -HSL was administered in the absence of PAO1. This acceleration was not affected by anti-TNF-α antibody. These results suggest that C4 -HSL may be involved in the acceleration of acute wound healing in P. aeruginosa infection by modifying the neutrophilic inflammation.
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Affiliation(s)
- Emi Kanno
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Kazuyoshi Kawakami
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Shinichi Miyairi
- Laboratory of Organic Chemistry, School of Pharmacy, Nihon University, Chiba, Japan
| | - Hiromasa Tanno
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Aiko Suzuki
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Rina Kamimatsuno
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Naoyuki Takagi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tomomitsu Miyasaka
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Keiko Ishii
- Department of Medical Microbiology, Mycology and Immunology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Naomasa Gotoh
- Department of Microbiology and Infection Control Sciences, Kyoto Pharmaceutical University, Kyoto, Japan
| | - Ryoko Maruyama
- Department of Science of Nursing Practice, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Masahiro Tachi
- Department of Plastic and Reconstructive Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
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Roy DC, Tomblyn S, Burmeister DM, Wrice NL, Becerra SC, Burnett LR, Saul JM, Christy RJ. Ciprofloxacin-Loaded Keratin Hydrogels Prevent Pseudomonas aeruginosa Infection and Support Healing in a Porcine Full-Thickness Excisional Wound. Adv Wound Care (New Rochelle) 2015; 4:457-468. [PMID: 26244102 DOI: 10.1089/wound.2014.0576] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2014] [Accepted: 09/19/2014] [Indexed: 12/19/2022] Open
Abstract
Objective: Cutaneous wound infection can lead to impaired healing, multiple surgical procedures, and increased hospitalization time. We tested the effectiveness of keratin-based hydrogels (termed "keratose") loaded with ciprofloxacin to inhibit infection and support healing when topically administered to porcine excision wounds infected with Pseudomonas aeruginosa. Approach: Using a porcine excisional wound model, 10 mm full-thickness wounds were inoculated with 106 colony-forming units of P. aeruginosa and treated on days 1 and 3 postinoculation with ciprofloxacin-loaded keratose hydrogels. Bacteria enumeration and wound healing were assessed on days 3, 7, and 11 postinjury. Results: Ciprofloxacin-loaded keratose hydrogels reduced the amount of P. aeruginosa in the wound bed by 99.9% compared with untreated wounds on days 3, 7, and 11 postinjury. Ciprofloxacin-loaded keratose hydrogels displayed decreased wound contraction and reepithelialization at day 7 postinjury. By day 11, wounds treated with ciprofloxacin-keratose hydrogels contained collagen-rich granulation tissue and myofibroblasts. Wounds treated with ciprofloxacin-loaded keratose hydrogels exhibited a transient increase in macrophages in the wound bed at day 7 postinjury that subsided by day 11. Innovation: Current therapies for wound infection include systemic antibiotics, which could lead to antibiotic resistance, and topical antimicrobial treatments, which require multiple applications and can delay healing. Here, we show that ciprofloxacin-loaded keratose hydrogels inhibit cutaneous wound infection without interfering with key aspects of the healing process including granulation tissue deposition and remodeling. Conclusions: Ciprofloxacin-loaded keratose hydrogels have the potential to serve as a point-of-injury antibiotic therapy that prevents infection and supports healing following cutaneous injury.
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Affiliation(s)
- Daniel C. Roy
- United States Army Institute of Surgical Research, Fort Sam Houston, Texas
- KeraNetics, LLC, Winston-Salem, North Carolina
| | | | | | - Nicole L. Wrice
- United States Army Institute of Surgical Research, Fort Sam Houston, Texas
| | - Sandra C. Becerra
- United States Army Institute of Surgical Research, Fort Sam Houston, Texas
| | | | | | - Robert J. Christy
- United States Army Institute of Surgical Research, Fort Sam Houston, Texas
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Nakagami G, Minematsu T, Morohoshi T, Yamane T, Kanazawa T, Huang L, Asada M, Nagase T, Ikeda SI, Ikeda T, Sanada H. Pseudomonas aeruginosa quorum-sensing signaling molecule N-3-oxododecanoyl homoserine lactone induces matrix metalloproteinase 9 expression via the AP1 pathway in rat fibroblasts. Biosci Biotechnol Biochem 2015; 79:1719-24. [PMID: 26096293 DOI: 10.1080/09168451.2015.1056509] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Quorum sensing is a cell-to-cell communication mechanism, which is responsible for regulating a number of bacterial virulence factors and biofilm maturation and therefore plays an important role for establishing wound infection. Quorum-sensing signals may induce inflammation and predispose wounds to infection by Pseudomonas aeruginosa; however, the interaction has not been well investigated. We examined the effects of the P. aeruginosa las quorum-sensing signal, N-3-oxo-dodecanoyl homoserine lactone (3OC12-HSL), on matrix metalloproteinase (MMP) 9 expression in Rat-1 fibroblasts. 3OC12-HSL upregulated the expression of the MMP9 gene bearing an activator protein-1 (AP-1) binding site in the promoter region. We further investigated the mechanism underlying this effect. c-Fos gene expression increased rapidly after exposure to 3OC12-HSL, and nuclear translocation of c-Fos protein was observed; both effects were reduced by pretreatment with an AP-1 inhibitor. These results suggest that 3OC12-HSL can alter MMP9 gene expression in fibroblasts via the AP-1 signaling pathway.
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Affiliation(s)
- Gojiro Nakagami
- a Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine , The University of Tokyo , Tokyo , Japan
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Holmes CJ, Plichta JK, Gamelli RL, Radek KA. Dynamic Role of Host Stress Responses in Modulating the Cutaneous Microbiome: Implications for Wound Healing and Infection. Adv Wound Care (New Rochelle) 2015; 4:24-37. [PMID: 25566412 DOI: 10.1089/wound.2014.0546] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2014] [Accepted: 06/01/2014] [Indexed: 01/06/2023] Open
Abstract
Significance: Humans are under constant bombardment by various stressors, including psychological anxiety and physiologic injury. Understanding how these stress responses influence the innate immune system and the skin microbiome remains elusive due to the complexity of the neuroimmune and stress response pathways. Both animal and human studies have provided critical information upon which to further elucidate the mechanisms by which mammalian stressors impair normal wound healing and/or promote chronic wound progression. Recent Advances: Development of high-throughput genomic and bioinformatic approaches has led to the discovery of both an epidermal and dermal microbiome with distinct characteristics. This technology is now being used to identify statistical correlations between specific microbiota profiles and clinical outcomes related to cutaneous wound healing and the response to pathogenic infection. Studies have also identified more prominent roles for typical skin commensal organisms in maintaining homeostasis and modulating inflammatory responses. Critical Issues: It is well-established that stress-induced factors, including catecholamines, acetylcholine, and glucocorticoids, increase the risk of impaired wound healing and susceptibility to infection. Despite the characterization of the cutaneous microbiome, little is known regarding the impact of these stress-induced molecules on the development and evolution of the cutaneous microbiome during wound healing. Future Directions: Further characterization of the mechanisms by which stress-induced molecules influence microbial proliferation and metabolism in wounds is necessary to identify altered microbial phenotypes that differentially influence host innate immune responses required for optimal healing. These mechanisms may yield beneficial as targets for manipulation of the microbiome to further benefit the host after cutaneous injury.
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Affiliation(s)
- Casey J. Holmes
- Department of Surgery, Loyola University Chicago, Health Sciences Division, Maywood, Illinois
- Burn Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, Illinois
| | - Jennifer K. Plichta
- Department of Surgery, Loyola University Chicago, Health Sciences Division, Maywood, Illinois
| | - Richard L. Gamelli
- Department of Surgery, Loyola University Chicago, Health Sciences Division, Maywood, Illinois
- Burn Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, Illinois
| | - Katherine A. Radek
- Department of Surgery, Loyola University Chicago, Health Sciences Division, Maywood, Illinois
- Burn Shock Trauma Research Institute, Loyola University Chicago, Health Sciences Division, Maywood, Illinois
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Eslani M, Movahedan A, Afsharkhamseh N, Sroussi H, Djalilian AR. The role of toll-like receptor 4 in corneal epithelial wound healing. Invest Ophthalmol Vis Sci 2014; 55:6108-15. [PMID: 25183764 DOI: 10.1167/iovs.14-14736] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
PURPOSE We evaluated the role of Toll-like receptor 4 (TLR4) in corneal epithelial wound healing. METHODS The expression of TLR4 during in vivo corneal epithelial wound healing was examined by immunostaining in mice. The expression and activation of TLR4 was studied in primary or telomerase-immortalized human corneal epithelial cells (HCEC). Scratch assay was performed to evaluate in vitro wound closure using live time-lapse microscopy. Transwell migration assay and Ki67 immunostaining were done to evaluate migration and proliferation, respectively. Lipopolysaccharide (LPS) was used to activate TLR4, whereas CLI-095 was used for its inhibition. The expression of inflammatory cytokines was determined by RT-PCR and ELISA. The activation of p42/44 and p38 was determined by immunoblotting. RESULTS In the murine model, TLR4 immunostaining was noted prominently in the epithelium 8 hours after wounding. There was a 4-fold increase in the expression of TLR4 6 hours after in vitro scratch wounding (P < 0.001). Confocal microscopy confirmed the membrane localization of TLR4/MD2 complex. There was a significant increase in migration, proliferation, and wound closure in HCEC treated with LPS (P < 0.05), while there was significant decrease with TLR4 inhibition (P < 0.05). Addition of LPS to wounded HCEC resulted in a significant increase in the expression of IL-6, TNF-α, CXCL8/IL8, and CCL5/RANTES at the mRNA and protein levels. Likewise, LPS increased the activation of p42/44 and p38 in wounded HCEC. CONCLUSIONS These results suggest that epithelial wounding induces the expression of functional TLR4. Toll-like receptor 4 signaling appears to contribute to early corneal epithelial wound repair by enhancing migration and proliferation.
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Affiliation(s)
- Medi Eslani
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Asadolah Movahedan
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Neda Afsharkhamseh
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Herve Sroussi
- Oral Medicine and Diagnostic Sciences, College of Dentistry, University of Illinois at Chicago, Chicago, Illinois, United States
| | - Ali R Djalilian
- Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, Chicago, Illinois, United States
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Sommer K, Sander AL, Albig M, Weber R, Henrich D, Frank J, Marzi I, Jakob H. Delayed wound repair in sepsis is associated with reduced local pro-inflammatory cytokine expression. PLoS One 2013; 8:e73992. [PMID: 24086305 PMCID: PMC3783436 DOI: 10.1371/journal.pone.0073992] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2013] [Accepted: 07/26/2013] [Indexed: 11/18/2022] Open
Abstract
Sepsis is one of the main causes for morbidity and mortality in hospitalized patients. Moreover, sepsis associated complications involving impaired wound healing are common. Septic patients often require surgical interventions that in-turn may lead to further complications caused by impaired wound healing. We established a mouse model to the study delayed wound healing during sepsis distant to the septic focus point. For this reason cecal ligation and puncture (CLP) was combined with the creation of a superficial wound on the mouse ear. Control animals received the same procedure without CPL. Epithelialization was measured every second day by direct microscopic visualization up to complete closure of the wound. As interplay of TNF-α, TGF-β, matrix metalloproteinases (MMP), and tissue inhibitors of metalloproteinases (TIMP) is important in wound healing in general, TNF-α, TGF-β, MMP7, and TIMP1 were assessed immunohistochemical in samples of wounded ears harvested on days 2, 6, 10 and 16 after wounding. After induction of sepsis, animals showed a significant delay in wound epithelialization from day 2 to 12 compared to control animals. Complete wound healing was attained after mean 12.2± standard deviation (SD) 3.0 days in septic animals compared to 8.7± SD 1.7 days in the control group. Septic animals showed a significant reduction in local pro-inflammatory cytokine level of TNF-α on day 2 and day 6 as well as a reduced expression of TGF-β on day 2 in wounds. A significant lower expression of MMP7 as well as TIMP1 was also observed on day 2 after wounding. The induction of sepsis impairs wound healing distant to the septic focus point. We could demonstrate that expression of important cytokines for wound repair is deregulated after induction of sepsis. Thus restoring normal cytokine response locally in wounds could be a good strategy to enhance wound repair in sepsis.
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Affiliation(s)
- Katharina Sommer
- Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
- * E-mail:
| | - Anna Lena Sander
- Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
| | - Michael Albig
- Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
| | - Roxane Weber
- Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
| | - Dirk Henrich
- Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
| | - Johannes Frank
- Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
| | - Ingo Marzi
- Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
| | - Heike Jakob
- Department of Trauma, Hand and Reconstructive Surgery, Hospital of the Johann Wolfgang Goethe-University, Frankfurt am Main, Germany
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Kostarnoy AV, Gancheva PG, Logunov DY, Verkhovskaya LV, Bobrov MA, Scheblyakov DV, Tukhvatulin AI, Filippova NE, Naroditsky BS, Gintsburg AL. Topical Bacterial Lipopolysaccharide Application Affects Inflammatory Response and Promotes Wound Healing. J Interferon Cytokine Res 2013; 33:514-22. [DOI: 10.1089/jir.2012.0108] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Affiliation(s)
- Alexey V. Kostarnoy
- Laboratory of Molecular Biotechnology, NF Gamaleya Research Institute for Epidemiology and Microbiology, Moscow, Russia
| | - Petya G. Gancheva
- Laboratory of Molecular Biotechnology, NF Gamaleya Research Institute for Epidemiology and Microbiology, Moscow, Russia
| | - Denis Y. Logunov
- Laboratory of Cellular Microbiology, NF Gamaleya Research Institute for Epidemiology and Microbiology, Moscow, Russia
| | - Lyudmila V. Verkhovskaya
- Laboratory of Molecular Biotechnology, NF Gamaleya Research Institute for Epidemiology and Microbiology, Moscow, Russia
| | - Maxim A. Bobrov
- Laboratory of Molecular Biotechnology, NF Gamaleya Research Institute for Epidemiology and Microbiology, Moscow, Russia
| | - Dmitry V. Scheblyakov
- Laboratory of Molecular Biotechnology, NF Gamaleya Research Institute for Epidemiology and Microbiology, Moscow, Russia
| | - Amir I. Tukhvatulin
- Laboratory of Cellular Microbiology, NF Gamaleya Research Institute for Epidemiology and Microbiology, Moscow, Russia
| | - Natalia E. Filippova
- Laboratory of Molecular Biotechnology, NF Gamaleya Research Institute for Epidemiology and Microbiology, Moscow, Russia
| | - Boris S. Naroditsky
- Laboratory of Molecular Biotechnology, NF Gamaleya Research Institute for Epidemiology and Microbiology, Moscow, Russia
| | - Alexandr L. Gintsburg
- Laboratory of Gene Engineering of Pathogenic Microorganisms, NF Gamaleya Research Institute for Epidemiology and Microbiology, Moscow, Russia
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Klein S, Schreml S, Dolderer J, Gehmert S, Niederbichler A, Landthaler M, Prantl L. Evidence-based topical management of chronic wounds according to the T.I.M.E. principle. J Dtsch Dermatol Ges 2013; 11:819-29. [PMID: 23848976 DOI: 10.1111/ddg.12138] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2012] [Accepted: 04/24/2013] [Indexed: 01/19/2023]
Abstract
The number of patients suffering from chronic wound healing disorders in Germany alone is estimated to be 2.5-4 million. Therapy related expenses reach 5-8 billion Euros annually. This number is partially caused by costly dressing changes due to non-standardized approaches and the application of non-evidence-based topical wound therapies. The purpose of this paper is to elucidate a straightforward principle for the management of chronic wounds, and to review the available evidence for the particular therapy options. The T.I.M.E.-principle (Tissue management, Inflammation and infection control, Moisture balance, Epithelial [edge] advancement) was chosen as a systematic strategy for wound bed preparation. Literature was retrieved from the PubMed and Cochrane Library databases and subjected to selective analysis. Topical wound management should be carried out according to a standardized principle and should further be synchronized to the phases of wound healing. Despite the broad implementation of these products in clinical practice, often no benefit exists in the rate of healing, when evaluated in meta-analyses or systematic reviews. This insufficient evidence is additionally limited by varying study designs. In case of non-superiority, the results suggest to prefer relatively inexpensive wound dressings over expensive alternatives. Arbitrary endpoints to prove the effectiveness of wound dressings, contribute to the random use of such therapies. Defining rational endpoints for future studies as well as the deployment of structured therapy strategies will be essential for the economical and evidence-based management of chronic wounds.
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Affiliation(s)
- Silvan Klein
- Center for Plastic, Hand and Reconstructive Surgery, University Hospital Regensburg, Germany
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44
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Kanno E, Kawakami K, Miyairi S, Tanno H, Otomaru H, Hatanaka A, Sato S, Ishii K, Hayashi D, Shibuya N, Imai Y, Gotoh N, Maruyama R, Tachi M. Neutrophil-derived tumor necrosis factor-α contributes to acute wound healing promoted by N-(3-oxododecanoyl)-l-homoserine lactone from Pseudomonas aeruginosa. J Dermatol Sci 2013; 70:130-8. [DOI: 10.1016/j.jdermsci.2013.01.004] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2012] [Revised: 12/29/2012] [Accepted: 01/18/2013] [Indexed: 11/25/2022]
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Scales BS, Huffnagle GB. The microbiome in wound repair and tissue fibrosis. J Pathol 2013; 229:323-31. [PMID: 23042513 PMCID: PMC3631561 DOI: 10.1002/path.4118] [Citation(s) in RCA: 100] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2012] [Revised: 09/22/2012] [Accepted: 09/24/2012] [Indexed: 02/06/2023]
Abstract
Bacterial colonization occurs in all wounds, chronic or acute, and the break in epithelium integrity that defines a wound impairs the forces that shape and constrain the microbiome at that site. This review highlights the interactions between bacterial communities in the wound and the ultimate resolution of the wound or development of fibrotic lesions. Chronic wounds support complex microbial communities comprising a wide variety of bacterial phyla, genera, and species, including some fastidious anaerobic bacteria not identified using culture-based methods. Thus, the complexity of bacterial communities in wounds has historically been underestimated. There are a number of intriguing possibilities to explain these results that may also provide novel insights into changes and adaptation of bacterial metabolic networks in inflamed and wounded mucosa, including the critical role of biofilm formation. It is well accepted that the heightened state of activation of host cells in a wound that is driven by the microbiota can certainly lead to detrimental effects on wound regeneration, but the microbiota of the wound may also have beneficial effects on wound healing. Studies in experimental systems have clearly demonstrated a beneficial effect for members of the gut microbiota on regulation of systemic inflammation, which could also impact wound healing at sites outside the gastrointestinal tract. The utilization of culture-independent microbiology to characterize the microbiome of wounds and surrounding mucosa has raised many intriguing questions regarding previously held notions about the cause and effect relationships between bacterial colonization and wound repair and mechanisms involved in this symbiotic relationship.
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Affiliation(s)
- Brittan S. Scales
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan
| | - Gary B. Huffnagle
- Department of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, Michigan
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan
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46
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Paes C, Nakagami G, Minematsu T, Nagase T, Huang L, Sari Y, Sanada H. The Pseudomonas aeruginosa quorum sensing signal molecule N-(3-oxododecanoyl) homoserine lactone enhances keratinocyte migration and induces Mmp13 gene expression in vitro. Biochem Biophys Res Commun 2012; 427:273-9. [PMID: 22989746 DOI: 10.1016/j.bbrc.2012.09.037] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2012] [Accepted: 09/07/2012] [Indexed: 12/31/2022]
Abstract
Re-epithelialization is an essential step of wound healing involving three overlapping keratinocyte functions: migration, proliferation and differentiation. While quorum sensing (QS) is a cell density-dependent signaling system that enables bacteria to regulate the expression of certain genes, the QS molecule N-(3-oxododecanoyl) homoserine lactone (AHL) exerts effects also on mammalian cells in a process called inter-kingdom signaling. Recent studies have shown that AHL improves epithelialization in in vivo wound healing models but detailed understanding of the molecular and cellular mechanisms are needed. The present study focused on the AHL as a candidate reagent to improve wound healing through direct modulation of keratinocyte's activity in the re-epithelialization process. Results indicated that AHL enhances the keratinocyte's ability to migrate in an in vitro scratch wound healing model probably due to the high Mmp13 gene expression analysis after AHL treatment that was revealed by real-time RT-PCR. Inhibition of activator protein 1 (AP-1) signaling pathway completely prevented the migration of keratinocytes, and also resulted in a diminished Mmp13 gene expression, suggesting that AP-1 might be essential in the AHL-induced migration. Taken together, these results imply that AHL is a promising candidate molecule to improve re-epithelialization through the induction of migration of keratinocytes. Further investigation is needed to clarify the mechanism of action and molecular pathway of AHL on the keratinocyte migration process.
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Affiliation(s)
- Camila Paes
- University of Tokyo, Department of Gerontological Nursing/Wound Care Management, Graduate School of Medicine, 7-3-1 Hongo, Tokyo 113-0033, Japan.
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Dulmovits BM, Herman IM. Microvascular remodeling and wound healing: a role for pericytes. Int J Biochem Cell Biol 2012; 44:1800-12. [PMID: 22750474 DOI: 10.1016/j.biocel.2012.06.031] [Citation(s) in RCA: 132] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2012] [Revised: 06/18/2012] [Accepted: 06/19/2012] [Indexed: 12/20/2022]
Abstract
Physiologic wound healing is highly dependent on the coordinated functions of vascular and non-vascular cells. Resolution of tissue injury involves coagulation, inflammation, formation of granulation tissue, remodeling and scarring. Angiogenesis, the growth of microvessels the size of capillaries, is crucial for these processes, delivering blood-borne cells, nutrients and oxygen to actively remodeling areas. Central to angiogenic induction and regulation is microvascular remodeling, which is dependent upon capillary endothelial cell and pericyte interactions. Despite our growing knowledge of pericyte-endothelial cell crosstalk, it is unclear how the interplay among pericytes, inflammatory cells, glia and connective tissue elements shape microvascular injury response. Here, we consider the relationships that pericytes form with the cellular effectors of healing in normal and diabetic environments, including repair following injury and vascular complications of diabetes, such as diabetic macular edema and proliferative diabetic retinopathy. In addition, pericytes and stem cells possessing "pericyte-like" characteristics are gaining considerable attention in experimental and clinical efforts aimed at promoting healing or eradicating ocular vascular proliferative disorders. As the origin, identification and characterization of microvascular pericyte progenitor populations remains somewhat ambiguous, the molecular markers, structural and functional characteristics of pericytes will be briefly reviewed.
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Affiliation(s)
- Brian M Dulmovits
- Sackler School of Graduate Biomedical Sciences Program in Cellular and Molecular Physiology, Department of Molecular Physiology and Pharmacology and the Center for Innovation in Wound Healing Research, Tufts University, 150 Harrison Avenue, Boston, MA 02111, USA
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48
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Cima RR. Surgical Outcomes in Inflammatory Bowel Disease Patients and the Potential Impact of Biologic Therapies. SEMINARS IN COLON AND RECTAL SURGERY 2012. [DOI: 10.1053/j.scrs.2012.02.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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Sahu K, Sharma M, Bansal H, Dube A, Gupta PK. Topical photodynamic treatment with poly-L-lysine-chlorin p6 conjugate improves wound healing by reducing hyperinflammatory response in Pseudomonas aeruginosa-infected wounds of mice. Lasers Med Sci 2012; 28:465-71. [PMID: 22454129 DOI: 10.1007/s10103-012-1083-6] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2012] [Accepted: 03/13/2012] [Indexed: 11/30/2022]
Abstract
We report the results of our investigations on the effect of antimicrobial photodynamic treatment (APDT) with poly-lysine-conjugated chlorin p6 (pl-cp6) on proinflammatory cytokine expression and wound healing in a murine excisional wound model infected with Pseudomonas aeruginosa. Treatment of infected wounds with pl-cp6 and light doses of 60 and 120 J/cm(2) reduced the bacterial load by ~1.5 and 2.0 log, respectively, after 24 h. The treated wounds healed ~5 days earlier as compared to untreated control and wound closure was not dependent on light dose. Interestingly, at 96 h post-treatment, drug-treated wounds irradiated at 60 J/cm(2) showed considerable reduction of proinflammatory cytokines IL-6 (approximately five times) and TNF-α (approximately four times) compared to untreated control. Further, exposure of culture supernatants to similar light dose and pl-cp6 concentration under in vitro conditions reduced the protease activity by ~50 % as compared to the untreated control, suggesting inactivation of extracellular virulent factors. Additionally, histological analysis of treated infected wounds showed complete reepithelialization, ordered collagen fibers, and considerable decrease in inflammatory cell infiltration compared to untreated wounds. These results imply that pl-cp6-mediated PDT reduces hyperinflammatory response of infected wounds, leading to acceleration of wound healing.
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Affiliation(s)
- Khageswar Sahu
- Laser Biomedical Applications and Instrumentation Division, Raja Ramanna Centre for Advanced Technology, Indore, 452013, India
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