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Rong B, Jiang H, Zhu W, Yang G, Zhou X, Lyu Z, Li X, Zhang J. Unraveling the role of macrophages in diabetes: Impaired phagocytic function and therapeutic prospects. Medicine (Baltimore) 2025; 104:e41613. [PMID: 39993124 PMCID: PMC11856964 DOI: 10.1097/md.0000000000041613] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2024] [Revised: 11/28/2024] [Accepted: 02/03/2025] [Indexed: 02/26/2025] Open
Abstract
The rising aging population and changing lifestyles have led to a global increase in diabetes and its complications, making it one of the most prevalent diseases worldwide. Chronic inflammation is a key pathogenic feature of diabetes and its complications, yet the precise mechanisms remain unclear, impeding the development of targeted therapies. Recent studies have highlighted the β cell-macrophage crosstalk pathway as a crucial factor in chronic low-grade inflammation and glucose homeostasis imbalance in both type 1 and type 2 diabetes. Furthermore, impaired macrophage phagocytic functions, including pathogen phagocytosis, efferocytosis, and autophagy, play a significant role in diabetes complications. Given their high plasticity, macrophages represent a promising research target. This review summarizes recent findings on macrophage phagocytic dysfunction in diabetes and its complications, and explores emerging therapies targeting macrophage phagocytic function. We also discuss the current challenges in translating basic research to clinical practice, aiming to guide researchers in developing targeted treatments to regulate macrophage status and phagocytic function, thus preventing and treating metabolic inflammatory diseases.
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Affiliation(s)
- Bing Rong
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Hailun Jiang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Weiming Zhu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Guanhu Yang
- Department of Specialty Medicine, Ohio University, Athens, OH
| | - Xuancheng Zhou
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Zhongxi Lyu
- School of Acupuncture & Moxibustion and Tuina, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiangyi Li
- Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jieying Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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2
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Kelly JH. A single injection of CM1021, a long half-life hepatocyte growth factor mimetic, increases liver mass in mice. Biochem Biophys Rep 2021; 28:101186. [PMID: 34977363 PMCID: PMC8683692 DOI: 10.1016/j.bbrep.2021.101186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 11/01/2022] Open
Abstract
Despite years of positive animal data, hepatocyte growth factor (HGF) has never been developed into a useful pharmaceutical, primarily due to its poor pharmacological properties. CM1021 is a fusion protein containing the K1 loop of HGF and the human IgG1 Fc region. The experiments described here demonstrate that CM1021 has the biological properties of HGF and the pharmacological properties of a monoclonal antibody. CM1021 stimulates scattering and branching morphogenesis in MDCK cells and stimulates liver growth in vivo. Unlike HGF, it is available via intraperitoneal injection and has an estimated half-life similar to an antibody.
Fusion of the K1 loop of HGF to the Fc region of IgG creates CM1021, a long half-life HGF mimetic. CM1021 has the biological properties of HGF without the pharmacological liabilities. CM1021 stimulates hepatocyte division in vivo. CM1021 can realize the potential of HGF in regenerative medicine.
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Aspal M, Zemans RL. Mechanisms of ATII-to-ATI Cell Differentiation during Lung Regeneration. Int J Mol Sci 2020; 21:E3188. [PMID: 32366033 PMCID: PMC7246911 DOI: 10.3390/ijms21093188] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2020] [Revised: 04/22/2020] [Accepted: 04/24/2020] [Indexed: 12/12/2022] Open
Abstract
The alveolar epithelium consists of (ATI) and type II (ATII) cells. ATI cells cover the majority of the alveolar surface due to their thin, elongated shape and are largely responsible for barrier function and gas exchange. During lung injury, ATI cells are susceptible to injury, including cell death. Under some circumstances, ATII cells also die. To regenerate lost epithelial cells, ATII cells serve as progenitor cells. They proliferate to create new ATII cells and then differentiate into ATI cells [1,2,3]. Regeneration of ATI cells is critical to restore normal barrier and gas exchange function. Although the signaling pathways by which ATII cells proliferate have been explored [4,5,6,7,8,9,10,11,12], the mechanisms of ATII-to-ATI cell differentiation have not been well studied until recently. New studies have uncovered signaling pathways that mediate ATII-to-ATI differentiation. Bone morphogenetic protein (BMP) signaling inhibits ATII proliferation and promotes differentiation. Wnt/β-catenin and ETS variant transcription factor 5 (Etv5) signaling promote proliferation and inhibit differentiation. Delta-like 1 homolog (Dlk1) leads to a precisely timed inhibition of Notch signaling in later stages of alveolar repair, activating differentiation. Yes-associated protein/Transcriptional coactivator with PDZ-binding motif (YAP/TAZ) signaling appears to promote both proliferation and differentiation. We recently identified a novel transitional cell state through which ATII cells pass as they differentiate into ATI cells, and this has been validated by others in various models of lung injury. This intermediate cell state is characterized by the activation of Transforming growth factor beta (TGFβ) and other pathways, and some evidence suggests that TGFβ signaling induces and maintains this state. While the abovementioned signaling pathways have all been shown to be involved in ATII-to-ATI cell differentiation during lung regeneration, there is much that remains to be understood. The up- and down-stream signaling events by which these pathways are activated and by which they induce ATI cell differentiation are unknown. In addition, it is still unknown how the various mechanistic steps from each pathway interact with one another to control differentiation. Based on these recent studies that identified major signaling pathways driving ATII-to-ATI differentiation during alveolar regeneration, additional studies can be devised to understand the interaction between these pathways as they work in a coordinated manner to regulate differentiation. Moreover, the knowledge from these studies may eventually be used to develop new clinical treatments that accelerate epithelial cell regeneration in individuals with excessive lung damage, such as patients with the Acute Respiratory Distress Syndrome (ARDS), pulmonary fibrosis, and emphysema.
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Affiliation(s)
- Mohit Aspal
- College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI 48109, USA
| | - Rachel L Zemans
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA
- Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI 48109, USA
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Wang L, Zhao Y, Yang F, Feng M, Zhao Y, Chen X, Mi J, Yao Y, Guan D, Xiao Z, Chen B, Dai J. Biomimetic collagen biomaterial induces in situ lung regeneration by forming functional alveolar. Biomaterials 2020; 236:119825. [PMID: 32044576 DOI: 10.1016/j.biomaterials.2020.119825] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Revised: 01/07/2020] [Accepted: 01/25/2020] [Indexed: 01/02/2023]
Abstract
In situ restoration of severely damaged lung remains difficult due to its limited regeneration capacity after injury. Artificial lung scaffolds are emerging as potential substitutes, but it is still a challenge to reconstruct lung regeneration microenvironment in scaffold after lung resection injury. Here, a 3D biomimetic porous collagen scaffold with similar structure characteristics as lung is fabricated, and a novel collagen binding hepatocyte growth factor (CBD-HGF) is tethered on the collagen scaffold for maintaining the biomimetic function of HGF to improve the lung regeneration microenvironment. The biomimetic scaffold was implanted into the operative region of a rat partial lung resection model. The results revealed that vascular endothelial cells and endogenous alveolar stem cells entered the scaffold at the early stage of regeneration. At the later stage, inflammation and fibrosis were attenuated, the microvascular and functional alveolar-like structures were formed, and the general morphology of the injured lung was restored. Taken together, the functional 3D biomimetic collagen scaffold facilitates recovery of the injured lung, alveolar regeneration, and angiogenesis after acute lung injury. Particularly, this is the first study of lung regeneration in vivo guided by biomimetic collagen scaffold materials, which supports the concept that tissue engineering is an effective strategy for alveolar regeneration.
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Affiliation(s)
- Linjie Wang
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Yannan Zhao
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Feng Yang
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Meng Feng
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Yazhen Zhao
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Xi Chen
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Junwei Mi
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Yuanjiang Yao
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Dongwei Guan
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Zhifeng Xiao
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China
| | - Bing Chen
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
| | - Jianwu Dai
- Institute of Combined Injury, State Key Laboratory of Trauma, Burns and Combined Injury, Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Chongqing Engineering Research Center for Biomaterials and Regenerative Medicine, Army Medical University (Third Military Medical University), Chongqing, 400038, China; State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, 100101, China.
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Raredon MSB, Adams TS, Suhail Y, Schupp JC, Poli S, Neumark N, Leiby KL, Greaney AM, Yuan Y, Horien C, Linderman G, Engler AJ, Boffa DJ, Kluger Y, Rosas IO, Levchenko A, Kaminski N, Niklason LE. Single-cell connectomic analysis of adult mammalian lungs. SCIENCE ADVANCES 2019; 5:eaaw3851. [PMID: 31840053 PMCID: PMC6892628 DOI: 10.1126/sciadv.aaw3851] [Citation(s) in RCA: 150] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Accepted: 09/18/2019] [Indexed: 05/17/2023]
Abstract
Efforts to decipher chronic lung disease and to reconstitute functional lung tissue through regenerative medicine have been hampered by an incomplete understanding of cell-cell interactions governing tissue homeostasis. Because the structure of mammalian lungs is highly conserved at the histologic level, we hypothesized that there are evolutionarily conserved homeostatic mechanisms that keep the fine architecture of the lung in balance. We have leveraged single-cell RNA sequencing techniques to identify conserved patterns of cell-cell cross-talk in adult mammalian lungs, analyzing mouse, rat, pig, and human pulmonary tissues. Specific stereotyped functional roles for each cell type in the distal lung are observed, with alveolar type I cells having a major role in the regulation of tissue homeostasis. This paper provides a systems-level portrait of signaling between alveolar cell populations. These methods may be applicable to other organs, providing a roadmap for identifying key pathways governing pathophysiology and informing regenerative efforts.
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Affiliation(s)
- Micha Sam Brickman Raredon
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
- Vascular Biology and Therapeutics, Yale University, New Haven, CT 06520, USA
- Medical Scientist Training Program, Yale School of Medicine, New Haven, CT 06510, USA
| | - Taylor Sterling Adams
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University, New Haven, CT 06520, USA
| | - Yasir Suhail
- Yale Systems Biology Institute, Yale University, West Haven, CT 06516, USA
| | - Jonas Christian Schupp
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University, New Haven, CT 06520, USA
| | - Sergio Poli
- Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Nir Neumark
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University, New Haven, CT 06520, USA
- Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA
| | - Katherine L. Leiby
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
- Vascular Biology and Therapeutics, Yale University, New Haven, CT 06520, USA
- Medical Scientist Training Program, Yale School of Medicine, New Haven, CT 06510, USA
| | - Allison Marie Greaney
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
- Vascular Biology and Therapeutics, Yale University, New Haven, CT 06520, USA
| | - Yifan Yuan
- Department of Anesthesiology, Yale University, New Haven, CT 06510, USA
| | - Corey Horien
- Medical Scientist Training Program, Yale School of Medicine, New Haven, CT 06510, USA
- Interdepartmental Neuroscience Program, Yale University, New Haven, CT 06510, USA
| | - George Linderman
- Medical Scientist Training Program, Yale School of Medicine, New Haven, CT 06510, USA
- Applied Mathematics Program, Yale University, New Haven, CT 06511, USA
| | - Alexander J. Engler
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
- Vascular Biology and Therapeutics, Yale University, New Haven, CT 06520, USA
| | - Daniel J. Boffa
- Thoracic Surgery, Yale School of Medicine, New Haven, CT 06510, USA
| | - Yuval Kluger
- Interdepartmental Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA
- Applied Mathematics Program, Yale University, New Haven, CT 06511, USA
- Department of Pathology, Yale University, New Haven, CT 06520, USA
| | - Ivan O. Rosas
- Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Andre Levchenko
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
- Yale Systems Biology Institute, Yale University, West Haven, CT 06516, USA
| | - Naftali Kaminski
- Section of Pulmonary, Critical Care and Sleep Medicine, Yale University, New Haven, CT 06520, USA
| | - Laura E. Niklason
- Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA
- Vascular Biology and Therapeutics, Yale University, New Haven, CT 06520, USA
- Department of Anesthesiology, Yale University, New Haven, CT 06510, USA
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6
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Yamashita Y, Kuroki R, Takaki M, Tanaka T, Senba M, Morimoto K, Amano H. Impairment of tissue repair in pneumonia due to β-cell deficiency: role of endoplasmic reticulum stress in alveolar macrophages. BMC Res Notes 2019; 12:160. [PMID: 30902065 PMCID: PMC6431046 DOI: 10.1186/s13104-019-4209-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 03/18/2019] [Indexed: 12/16/2022] Open
Abstract
Objective Diabetes mellitus (DM) patients are susceptible to delayed resolution of pneumonia. However, the pathogenesis of the impaired tissue repair in inflamed lungs in diabetic patients is unknown. We evaluated phagocytosis of apoptotic cells (efferocytosis), hepatocyte growth factor (HGF) production in bronchoalveolar lavage fluid (BALF), and lung histology in the resolution phase following acute lung injury in streptozotocin (STZ)-induced β-cell-depleted hyperglycemic mice. We also investigated efferocytosis and HGF production by macrophages under β-cell depletion condition ex vivo. Results In β-cell-depleted mice, efferocytosis was not significantly different from that in control mice; however, the concentration of HGF in BALF was decreased. In addition, diminished HGF production by alveolar macrophages and DNA synthesis in the alveolar epithelium was observed by immunohistochemistry. Ex vivo experiments confirmed that HGF production by macrophages was impaired under β-cell depletion probably because of endoplasmic reticulum stress. Electronic supplementary material The online version of this article (10.1186/s13104-019-4209-0) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yoshiro Yamashita
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Sakamoto 1-12-4, Nagasaki, Nagasaki, 852-8523, Japan
| | - Reiki Kuroki
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Sakamoto 1-12-4, Nagasaki, Nagasaki, 852-8523, Japan
| | - Masahiro Takaki
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Sakamoto 1-12-4, Nagasaki, Nagasaki, 852-8523, Japan
| | - Takeshi Tanaka
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Sakamoto 1-12-4, Nagasaki, Nagasaki, 852-8523, Japan
| | - Masachika Senba
- Department of Pathology, Institute of Tropical Medicine, Nagasaki University, Sakamoto 1-12-4, Nagasaki, Nagasaki, 852-8523, Japan
| | - Konosuke Morimoto
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Sakamoto 1-12-4, Nagasaki, Nagasaki, 852-8523, Japan.
| | - Hideaki Amano
- Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Sakamoto 1-12-4, Nagasaki, Nagasaki, 852-8523, Japan
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7
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Lung Mesenchymal Stem Cells Ameliorate Elastase-Induced Damage in an Animal Model of Emphysema. Stem Cells Int 2018; 2018:9492038. [PMID: 29731780 PMCID: PMC5872595 DOI: 10.1155/2018/9492038] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2017] [Revised: 11/15/2017] [Accepted: 12/21/2017] [Indexed: 12/28/2022] Open
Abstract
Pulmonary emphysema is a respiratory condition characterized by alveolar destruction that leads to airflow limitation and reduced lung function. Although with extensive research, the pathophysiology of emphysema is poorly understood and effective treatments are still missing. Evidence suggests that mesenchymal stem cells (MSCs) possess the ability to engraft the injured tissues and induce repair via a paracrine effect. Thus, the aim of this study was to test the effects of the intratracheal administration of lung-derived mouse MSCs in a model of elastase-induced emphysema. Pulmonary function (static lung compliance) showed an increased stiffness induced by elastase, while morphometric findings (mean linear intercept and tissue/alveolar area) confirmed the severity of alveolar disruption. Contrarily, MSC administration partially restored lung elasticity and alveolar architecture. In the absence of evidence that MSCs acquired epithelial phenotype, we detected an increased proliferative activity of aquaporin 5- and surfactant protein C-positive lung cells, suggesting MSC-driven paracrine mechanisms. The data indicate the mediation of hepatocyte growth factor in amplifying MSC-driven tissue response after injury. Our study shed light on supportive properties of lung-derived MSCs, although the full identification of mechanisms orchestrated by MSCs and responsible for epithelial repair after injury is a critical aspect yet to be achieved.
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McClendon J, Jansing NL, Redente EF, Gandjeva A, Ito Y, Colgan SP, Ahmad A, Riches DWH, Chapman HA, Mason RJ, Tuder RM, Zemans RL. Hypoxia-Inducible Factor 1α Signaling Promotes Repair of the Alveolar Epithelium after Acute Lung Injury. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 187:1772-1786. [PMID: 28618253 PMCID: PMC5530913 DOI: 10.1016/j.ajpath.2017.04.012] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 04/20/2017] [Indexed: 01/09/2023]
Abstract
During the acute respiratory distress syndrome, epithelial cells, primarily alveolar type (AT) I cells, die and slough off, resulting in enhanced permeability. ATII cells proliferate and spread onto the denuded basement membrane to reseal the barrier. Repair of the alveolar epithelium is critical for clinical recovery; however, mechanisms underlying ATII cell proliferation and spreading are not well understood. We hypothesized that hypoxia-inducible factor (HIF)1α promotes proliferation and spreading of ATII cells during repair after lung injury. Mice were treated with lipopolysaccharide or hydrochloric acid. HIF activation in ATII cells after injury was demonstrated by increased luciferase activity in oxygen degradation domain-Luc (HIF reporter) mice and expression of the HIF1α target gene GLUT1. ATII cell proliferation during repair was attenuated in ATII cell-specific HIF1α knockout (SftpcCreERT2+/-;HIF1αf/f) mice. The HIF target vascular endothelial growth factor promoted ATII cell proliferation in vitro and after lung injury in vivo. In the scratch wound assay of cell spreading, HIF stabilization accelerated, whereas HIF1α shRNA delayed wound closure. SDF1 and its receptor, CXCR4, were found to be HIF1α-regulated genes in ATII cells and were up-regulated during lung injury. Stromal cell-derived factor 1/CXCR4 inhibition impaired cell spreading and delayed the resolution of permeability after lung injury. We conclude that HIF1α is activated in ATII cells after lung injury and promotes proliferation and spreading during repair.
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Affiliation(s)
- Jazalle McClendon
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Nicole L Jansing
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Elizabeth F Redente
- Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado; Department of Research, Denver Veterans Affairs Medical Center, Denver, Colorado
| | - Aneta Gandjeva
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado
| | - Yoko Ito
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado
| | - Sean P Colgan
- Mucosal Inflammation Program, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado; Integrated Department of Immunology, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado
| | - Aftab Ahmad
- Department of Anesthesiology and Perioperative Medicine, University of Alabama at Birmingham, Birmingham, Alabama
| | - David W H Riches
- Program in Cell Biology, Department of Pediatrics, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado
| | - Harold A Chapman
- Division of Pulmonary and Critical Care Medicine, University of California San Francisco, San Francisco, California
| | - Robert J Mason
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado
| | - Rubin M Tuder
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado; Program in Translational Lung Research, Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado
| | - Rachel L Zemans
- Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, National Jewish Health, Denver, Colorado; Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Aurora, Colorado.
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9
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Oh DK, Kim YS, Oh YM. Lung Regeneration Therapy for Chronic Obstructive Pulmonary Disease. Tuberc Respir Dis (Seoul) 2016; 80:1-10. [PMID: 28119741 PMCID: PMC5256352 DOI: 10.4046/trd.2017.80.1.1] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2016] [Revised: 01/13/2016] [Accepted: 07/05/2016] [Indexed: 12/16/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is a critical condition with high morbidity and mortality. Although several medications are available, there are no definite treatments. However, recent advances in the understanding of stem and progenitor cells in the lung, and molecular changes during re-alveolization after pneumonectomy, have made it possible to envisage the regeneration of damaged lungs. With this background, numerous studies of stem cells and various stimulatory molecules have been undertaken, to try and regenerate destroyed lungs in animal models of COPD. Both the cell and drug therapies show promising results. However, in contrast to the successes in laboratories, no clinical trials have exhibited satisfactory efficacy, although they were generally safe and tolerable. In this article, we review the previous experimental and clinical trials, and summarize the recent advances in lung regeneration therapy for COPD. Furthermore, we discuss the current limitations and future perspectives of this emerging field.
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Affiliation(s)
- Dong Kyu Oh
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, Seoul, Korea
| | - You-Sun Kim
- Asan Institute for Life Sciences, Seoul, Korea.; University of Ulsan College of Medicine, Seoul, Korea
| | - Yeon-Mok Oh
- Department of Pulmonary and Critical Care Medicine, Asan Medical Center, Seoul, Korea.; Asan Institute for Life Sciences, Seoul, Korea.; University of Ulsan College of Medicine, Seoul, Korea
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10
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Knudsen L, Ruppert C, Ochs M. Tissue remodelling in pulmonary fibrosis. Cell Tissue Res 2016; 367:607-626. [PMID: 27981380 DOI: 10.1007/s00441-016-2543-2] [Citation(s) in RCA: 87] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2016] [Accepted: 11/19/2016] [Indexed: 12/16/2022]
Abstract
Many lung diseases result in fibrotic remodelling. Fibrotic lung disorders can be divided into diseases with known and unknown aetiology. Among those with unknown aetiology, idiopathic pulmonary fibrosis (IPF) is a common diagnosis. Because of its progressive character leading to a rapid decline in lung function, it is a fatal disease with poor prognosis and limited therapeutic options. Thus, IPF has motivated many studies in the last few decades in order to increase our mechanistic understanding of the pathogenesis of the disease. The current concept suggests an ongoing injury of the alveolar epithelium, an impaired regeneration capacity, alveolar collapse and, finally, a fibroproliferative response. The origin of lung injury remains elusive but a diversity of factors, which will be discussed in this article, has been shown to be associated with IPF. Alveolar epithelial type II (AE2) cells play a key role in lung fibrosis and their crucial role for epithelial regeneration, stabilisation of alveoli and interaction with fibroblasts, all known to be responsible for collagen deposition, will be illustrated. Whereas mechanisms of collagen deposition and fibroproliferation are the focus of many studies in the field, the awareness of other mechanisms in this disease is currently limited to biochemical and imaging studies including quantitative assessments of lung structure in IPF and animal models assigning alveolar collapse and collapse induration crucial roles for the degradation of the lung resulting in de-aeration and loss of surface area. Dysfunctional AE2 cells, instable alveoli and mechanical stress trigger remodelling that consists of collapsed alveoli absorbed by fibrotic tissue (i.e., collapse induration).
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Affiliation(s)
- Lars Knudsen
- Institute of Functional and Applied Anatomy, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany. .,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany. .,REBIRTH, Cluster of Excellence, Hannover Medical School, Hannover, Germany.
| | - Clemens Ruppert
- Department of Internal Medicine, Justus-Liebig-University Giessen, Giessen, Germany.,Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Universities of Giessen and Marburg, Giessen, Germany
| | - Matthias Ochs
- Institute of Functional and Applied Anatomy, Hannover Medical School, Carl-Neuberg Strasse 1, 30625, Hannover, Germany.,Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover Medical School, Hannover, Germany.,REBIRTH, Cluster of Excellence, Hannover Medical School, Hannover, Germany
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11
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Ohnishi S, Ichiba H, Saito M, Hamazaki T, Matsumura H, Shintaku H. Glucocorticoids and erythropoietin in chronic lung disease of prematurity: Proliferative potential in lung fibroblast and epithelial cells exposed to tracheal aspirates. Pediatr Int 2016; 58:1163-1170. [PMID: 27076443 DOI: 10.1111/ped.13009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2015] [Revised: 03/03/2016] [Accepted: 04/01/2016] [Indexed: 11/27/2022]
Abstract
BACKGROUND We investigated the effects of glucocorticoids, erythropoietin (EPO) and spironolactone (SPL) n human fetal lung fibroblasts and human alveolar epithelial cells exposed to tracheal aspirate fluid (TAF) from extremely premature infants with chronic lung disease (CLD), characterized by fibrosis and changes in the alveolar epithelium. METHODS Fibroblasts and epithelial cells (FHs 738Lu and A549, respectively) were treated with different concentrations of hydrocortisone (HDC), dexamethasone (DEX), betamethasone (BET), SPL, and EPO in the absence or presence of TAF from infants with CLD (gestational age, 25.3 ± 0.8 weeks; birthweight, 658 ± 77 g; postnatal age, 0-28 days) and assayed for proliferation. RESULTS Exposure to TAF resulted in a concentration-dependent proliferation of fibroblasts and epithelial cells. Proliferation of TAF-exposed fibroblasts was suppressed most significantly by 100 μmol/L DEX (21%, P = 0.046) and 300 mIU/mL EPO (18%, P = 0.02) and promoted most significantly by 0.4 μmol/L HDC (10%, P = 0.04). Epithelial proliferation was promoted by 4 μmol/L HDC (15%, P = 0.04), 10 μmol/L DEX (53%, P < 0.01), 0.2 μmol/L BET (56%, P < 0.01), and 300 mIU/mL EPO (35%, P < 0.01) in the presence of TAF. Treatment with glucocorticoids alone did not significantly affect fibroblast proliferation. CONCLUSIONS Glucocorticoids and EPO reduced fibroproliferation while promoting epithelial cell growth in vitro within certain dose ranges. Appropriate doses of glucocorticoids and EPO may be useful in the prevention and resolution of CLD in extremely premature infants.
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Affiliation(s)
- Satoshi Ohnishi
- Department of Pediatrics Osaka City University Graduate School of Medicine, Osaka, Japan.,Department of Neonatology Osaka City General Hospital, Osaka, Japan
| | - Hiroyuki Ichiba
- Department of Neonatology Osaka City General Hospital, Osaka, Japan
| | - Mika Saito
- Department of Pediatrics Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Takashi Hamazaki
- Department of Pediatrics Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Hisako Matsumura
- Department of Pediatrics Osaka City University Graduate School of Medicine, Osaka, Japan.,Department of Neonatology Osaka City General Hospital, Osaka, Japan
| | - Haruo Shintaku
- Department of Pediatrics Osaka City University Graduate School of Medicine, Osaka, Japan
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12
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Laube M, Stolzing A, Thome UH, Fabian C. Therapeutic potential of mesenchymal stem cells for pulmonary complications associated with preterm birth. Int J Biochem Cell Biol 2016; 74:18-32. [PMID: 26928452 DOI: 10.1016/j.biocel.2016.02.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2015] [Revised: 02/23/2016] [Accepted: 02/25/2016] [Indexed: 12/22/2022]
Abstract
Preterm infants frequently suffer from pulmonary complications resulting in significant morbidity and mortality. Physiological and structural lung immaturity impairs perinatal lung transition to air breathing resulting in respiratory distress. Mechanical ventilation and oxygen supplementation ensure sufficient oxygen supply but enhance inflammatory processes which might lead to the establishment of a chronic lung disease called bronchopulmonary dysplasia (BPD). Current therapeutic options to prevent or treat BPD are limited and have salient side effects, highlighting the need for new therapeutic approaches. Mesenchymal stem cells (MSCs) have demonstrated therapeutic potential in animal models of BPD. This review focuses on MSC-based therapeutic approaches to treat pulmonary complications and critically compares results obtained in BPD models. Thereby bottlenecks in the translational systems are identified that are preventing progress in combating BPD. Notably, current animal models closely resemble the so-called "old" BPD with profound inflammation and injury, whereas clinical improvements shifted disease pathology towards a "new" BPD in which arrest of lung maturation predominates. Future studies need to evaluate the utility of MSC-based therapies in animal models resembling the "new" BPD though promising in vitro evidence suggests that MSCs do possess the potential to stimulate lung maturation. Furthermore, we address the mode-of-action of MSC-based therapies with regard to lung development and inflammation/fibrosis. Their therapeutic efficacy is mainly attributed to an enhancement of regeneration and immunomodulation due to paracrine effects. In addition, we discuss current improvement strategies by genetic modifications or precondition of MSCs to enhance their therapeutic efficacy which could also prove beneficial for BPD therapies.
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Affiliation(s)
- Mandy Laube
- Center for Pediatric Research Leipzig, Hospital for Children & Adolescents, Division of Neonatology, University of Leipzig, Leipzig, Germany.
| | - Alexandra Stolzing
- Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany; Loughborough University, Wolfson School of Mechanical and Manufacturing Engineering, Centre for Biological Engineering, Loughborough, UK.
| | - Ulrich H Thome
- Center for Pediatric Research Leipzig, Hospital for Children & Adolescents, Division of Neonatology, University of Leipzig, Leipzig, Germany.
| | - Claire Fabian
- Fraunhofer Institute for Cell Therapy and Immunology, Leipzig, Germany; Interdisciplinary Centre for Bioinformatics, University of Leipzig, Leipzig, Germany.
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13
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Standiford TJ, Ward PA. Therapeutic targeting of acute lung injury and acute respiratory distress syndrome. Transl Res 2016; 167:183-91. [PMID: 26003524 PMCID: PMC4635065 DOI: 10.1016/j.trsl.2015.04.015] [Citation(s) in RCA: 138] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2015] [Revised: 04/27/2015] [Accepted: 04/29/2015] [Indexed: 12/12/2022]
Abstract
There is no Food and Drug Administration-approved treatment for acute respiratory distress syndrome (ARDS), in spite of the relatively large number of patients with the diagnosis. In this report, we provide an overview of preclinical studies and a description of completed and future clinical trials in humans with ARDS. Preclinical studies dealing with acute lung injury have suggested roles for complement and complement receptors, as well as the evolving role of histones, but details of these pathways are inadequately understood. Anti-inflammatory interventions have not been convincingly effective. Various cell growth factors are being considered for clinical study. Interventions to block complement activation or its products are under consideration. Stem cell therapies have shown efficacy in preclinical studies, which have motivated phase I/II trials in humans with ARDS.
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Affiliation(s)
- Theodore J Standiford
- Department of Internal Medicine, Pulmonary and Critical Care, University of Michigan Medical School, Ann Arbor, Mich
| | - Peter A Ward
- Department of Pathology, University of Michigan Medical School, Ann Arbor, Mich.
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14
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Ito Y, Correll K, Zemans RL, Leslie CC, Murphy RC, Mason RJ. Influenza induces IL-8 and GM-CSF secretion by human alveolar epithelial cells through HGF/c-Met and TGF-α/EGFR signaling. Am J Physiol Lung Cell Mol Physiol 2015; 308:L1178-88. [PMID: 26033355 PMCID: PMC4451400 DOI: 10.1152/ajplung.00290.2014] [Citation(s) in RCA: 65] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 04/07/2015] [Indexed: 11/22/2022] Open
Abstract
The most severe complication of influenza is viral pneumonia, which can lead to the acute respiratory distress syndrome. Alveolar epithelial cells (AECs) are the first cells that influenza virus encounters upon entering the alveolus. Infected epithelial cells produce cytokines that attract and activate neutrophils and macrophages, which in turn induce damage to the epithelial-endothelial barrier. Hepatocyte growth factor (HGF)/c-Met and transforming growth factor-α (TGF-α)/epidermal growth factor receptor (EGFR) are well known to regulate repair of damaged alveolar epithelium by stimulating cell migration and proliferation. Recently, TGF-α/EGFR signaling has also been shown to regulate innate immune responses in bronchial epithelial cells. However, little is known about whether HGF/c-Met signaling alters the innate immune responses and whether the innate immune responses in AECs are regulated by HGF/c-Met and TGF-α/EGFR. We hypothesized that HGF/c-Met and TGF-α/EGFR would regulate innate immune responses to influenza A virus infection in human AECs. We found that recombinant human HGF (rhHGF) and rhTGF-α stimulated primary human AECs to secrete IL-8 and granulocyte macrophage colony-stimulating factor (GM-CSF) strongly and IL-6 and monocyte chemotactic protein 1 moderately. Influenza infection stimulated the secretion of IL-8 and GM-CSF by AECs plated on rat-tail collagen through EGFR activation likely by TGF-α released from AECs and through c-Met activated by HGF secreted from lung fibroblasts. HGF secretion by fibroblasts was stimulated by AEC production of prostaglandin E2 during influenza infection. We conclude that HGF/c-Met and TGF-α/EGFR signaling enhances the innate immune responses by human AECs during influenza infections.
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Affiliation(s)
- Yoko Ito
- Department of Medicine, National Jewish Health, Denver, Colorado;
| | - Kelly Correll
- Department of Medicine, National Jewish Health, Denver, Colorado
| | - Rachel L Zemans
- Department of Medicine, National Jewish Health, Denver, Colorado; Department of Medicine, University of Colorado, Aurora, Colorado
| | | | - Robert C Murphy
- Department of Pharmacology, University of Colorado, Aurora, Colorado
| | - Robert J Mason
- Department of Medicine, National Jewish Health, Denver, Colorado; Department of Medicine, University of Colorado, Aurora, Colorado
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15
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Fujita M. New therapies for chronic obstructive pulmonary disease, lung regeneration. World J Respirol 2015; 5:34-39. [DOI: 10.5320/wjr.v5.i1.34] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/19/2014] [Revised: 12/15/2014] [Accepted: 01/19/2015] [Indexed: 02/06/2023] Open
Abstract
Chronic obstructive pulmonary disease (COPD) is characterized by the presence of airflow limitations that are not fully reversible and is a major cause of chronic morbidity and mortality worldwide. Although there has been extensive research examining the molecular mechanisms underlying the development of COPD, there is no proven clinically effective treatment for promoting recovery from established COPD. At present, regeneration is the only hope for a cure in patients with COPD. In this article, we review current treatments for COPD, focusing particularly on recent advances in lung regeneration based on two major approaches: regeneration-promoting agents and cell therapy. Retinoic acids are the major focus among regeneration-promoting agents, while mesenchymal stem cells are the main topic in the field of cell-based therapy. This article aims to provide valuable information for developing new therapies for COPD.
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16
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Herold S, Becker C, Ridge KM, Budinger GRS. Influenza virus-induced lung injury: pathogenesis and implications for treatment. Eur Respir J 2015; 45:1463-78. [PMID: 25792631 DOI: 10.1183/09031936.00186214] [Citation(s) in RCA: 341] [Impact Index Per Article: 34.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2014] [Accepted: 01/07/2015] [Indexed: 01/21/2023]
Abstract
The influenza viruses are some of the most important human pathogens, causing substantial seasonal and pandemic morbidity and mortality. In humans, infection of the lower respiratory tract of can result in flooding of the alveolar compartment, development of acute respiratory distress syndrome and death from respiratory failure. Influenza-mediated damage of the airway, alveolar epithelium and alveolar endothelium results from a combination of: 1) intrinsic viral pathogenicity, attributable to its tropism for host airway and alveolar epithelial cells; and 2) a robust host innate immune response, which, while contributing to viral clearance, can worsen the severity of lung injury. In this review, we summarise the molecular events at the virus-host interface during influenza virus infection, highlighting some of the important cellular responses. We discuss immune-mediated viral clearance, the mechanisms promoting or perpetuating lung injury, lung regeneration after influenza-induced injury, and recent advances in influenza prevention and therapy.
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Affiliation(s)
- Susanne Herold
- Dept of Internal Medicine II, Universities Giessen and Marburg Lung Center (UGMLC), Justus-Liebig University, Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Christin Becker
- Dept of Internal Medicine II, Universities Giessen and Marburg Lung Center (UGMLC), Justus-Liebig University, Member of the German Center for Lung Research (DZL), Giessen, Germany
| | - Karen M Ridge
- Pulmonary and Critical Care Medicine, Northwestern University, Chicago, IL, USA
| | - G R Scott Budinger
- Pulmonary and Critical Care Medicine, Northwestern University, Chicago, IL, USA
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17
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Ito Y, Correll K, Schiel JA, Finigan JH, Prekeris R, Mason RJ. Lung fibroblasts accelerate wound closure in human alveolar epithelial cells through hepatocyte growth factor/c-Met signaling. Am J Physiol Lung Cell Mol Physiol 2014; 307:L94-105. [PMID: 24748602 DOI: 10.1152/ajplung.00233.2013] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
There are 190,600 cases of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) each year in the United States, and the incidence and mortality of ALI/ARDS increase dramatically with age. Patients with ALI/ARDS have alveolar epithelial injury, which may be worsened by high-pressure mechanical ventilation. Alveolar type II (ATII) cells are the progenitor cells for the alveolar epithelium and are required to reestablish the alveolar epithelium during the recovery process from ALI/ARDS. Lung fibroblasts (FBs) migrate and proliferate early after lung injury and likely are an important source of growth factors for epithelial repair. However, how lung FBs affect epithelial wound healing in the human adult lung has not been investigated in detail. Hepatocyte growth factor (HGF) is known to be released mainly from FBs and to stimulate both migration and proliferation of primary rat ATII cells. HGF is also increased in lung tissue, bronchoalveolar lavage fluid, and serum in patients with ALI/ARDS. Therefore, we hypothesized that HGF secreted by FBs would enhance wound closure in alveolar epithelial cells (AECs). Wound closure was measured using a scratch wound-healing assay in primary human AEC monolayers and in a coculture system with FBs. We found that wound closure was accelerated by FBs mainly through HGF/c-Met signaling. HGF also restored impaired wound healing in AECs from the elderly subjects and after exposure to cyclic stretch. We conclude that HGF is the critical factor released from FBs to close wounds in human AEC monolayers and suggest that HGF is a potential strategy for hastening alveolar repair in patients with ALI/ARDS.
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Affiliation(s)
- Yoko Ito
- Department of Medicine, National Jewish Health, Denver, Colorado;
| | - Kelly Correll
- Department of Medicine, National Jewish Health, Denver, Colorado
| | - John A Schiel
- Department of Cell and Developmental Biology, University of Colorado, Aurora, Colorado
| | - Jay H Finigan
- Department of Medicine, National Jewish Health, Denver, Colorado
| | - Rytis Prekeris
- Department of Cell and Developmental Biology, University of Colorado, Aurora, Colorado
| | - Robert J Mason
- Department of Medicine, National Jewish Health, Denver, Colorado
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18
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Aggarwal NR, King LS, D'Alessio FR. Diverse macrophage populations mediate acute lung inflammation and resolution. Am J Physiol Lung Cell Mol Physiol 2014; 306:L709-25. [PMID: 24508730 PMCID: PMC3989724 DOI: 10.1152/ajplung.00341.2013] [Citation(s) in RCA: 450] [Impact Index Per Article: 40.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Accepted: 02/05/2014] [Indexed: 12/14/2022] Open
Abstract
Acute respiratory distress syndrome (ARDS) is a devastating disease with distinct pathological stages. Fundamental to ARDS is the acute onset of lung inflammation as a part of the body's immune response to a variety of local and systemic stimuli. In patients surviving the inflammatory and subsequent fibroproliferative stages, transition from injury to resolution and recovery is an active process dependent on a series of highly coordinated events regulated by the immune system. Experimental animal models of acute lung injury (ALI) reproduce key components of the injury and resolution phases of human ARDS and provide a methodology to explore mechanisms and potential new therapies. Macrophages are essential to innate immunity and host defense, playing a featured role in the lung and alveolar space. Key aspects of their biological response, including differentiation, phenotype, function, and cellular interactions, are determined in large part by the presence, severity, and chronicity of local inflammation. Studies support the importance of macrophages to initiate and maintain the inflammatory response, as well as a determinant of resolution of lung inflammation and repair. We will discuss distinct roles for lung macrophages during early inflammatory and late resolution phases of ARDS using experimental animal models. In addition, each section will highlight human studies that relate to the diverse role of macrophages in initiation and resolution of ALI and ARDS.
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Affiliation(s)
- Neil R Aggarwal
- Johns Hopkins Univ. School of Medicine, Pulmonary and Critical Care Medicine, Johns Hopkins Asthma & Allergy Center, Rm. 4B.68, 5501 Hopkins Bayview Circle, Baltimore, MD 21224.
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19
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Takahashi K, Moyo P, Chigweshe L, Chang WC, White MR, Hartshorn KL. Efficacy of recombinant chimeric lectins, consisting of mannose binding lectin and L-ficolin, against influenza A viral infection in mouse model study. Virus Res 2013; 178:495-501. [PMID: 24140629 PMCID: PMC3885334 DOI: 10.1016/j.virusres.2013.10.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2013] [Revised: 09/23/2013] [Accepted: 10/02/2013] [Indexed: 12/22/2022]
Abstract
Influenza A virus infection could result in fatal complications. Although immunization is the most effective prevention it is not effective to pandemic infection and is less effective or not approved for certain age groups. Some influenza virus strains have developed resistance to antiviral agents. Thus, new therapeutic agents are urgently needed. We focused on innate immune molecules, including mannose-binding lectin (MBL). In order to optimize its antiviral activities, we have previously generated three recombinant chimeric lectins (RCL), by introducing portions of L-ficolin, another innate immune lectin. Our in vitro characterizations previously selected RCL2 and RCL3 for further investigations against viruses, including influenza viruses. Here, we examined efficacy of these lectins against infection with PR8 (H1N1) influenza A virus using mouse model studies and a human tracheal epithelial cell system. Our results provide in vivo evidence that RCL3 is effective agent against influenza virus infection. The therapeutic mechanisms are in part by providing host protective responses mediated by cytokines. We conclude that RCL3 is a potential new innate immune anti-influenza virus therapeutic agent.
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Affiliation(s)
- Kazue Takahashi
- Program of Developmental Immunology, Department of Pediatrics, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
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20
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Abstract
Cytokines and growth factors play an integral role in the maintenance of immune homeostasis, the generation of protective immunity, and lung reparative processes. However, the dysregulated expression of cytokines and growth factors in response to infectious or noxious insults can initiate and perpetuate deleterious lung inflammation and fibroproliferation. In this article, we will comprehensively review the contribution of individual cytokines and growth factors and cytokine networks to key pathophysiological events in human and experimental acute lung injury (ALI), including inflammatory cell recruitment and activation, alveolar epithelial injury and repair, angiogenesis, and matrix deposition and remodeling. The application of cytokines/growth factors as prognostic indicators and therapeutic targets in human ALI is explored.
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Affiliation(s)
- Jane C Deng
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, UCLA Medical Center, Los Angeles, CA, USA
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21
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Gazdhar A, Temuri A, Knudsen L, Gugger M, Schmid RA, Ochs M, Geiser T. Targeted gene transfer of hepatocyte growth factor to alveolar type II epithelial cells reduces lung fibrosis in rats. Hum Gene Ther 2013; 24:105-16. [PMID: 23134111 DOI: 10.1089/hum.2012.098] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Inefficient alveolar wound repair contributes to the development of pulmonary fibrosis. Hepatocyte growth factor (HGF) is a potent growth factor for alveolar type II epithelial cells (AECII) and may improve repair and reduce fibrosis. We studied whether targeted gene transfer of HGF specifically to AECII improves lung fibrosis in bleomycin-induced lung fibrosis. A plasmid encoding human HGF expressed from the human surfactant protein C promoter (pSpC-hHGF) was designed, and extracorporeal electroporation-mediated gene transfer of HGF specifically to AECII was performed 7 days after bleomycin-induced lung injury in the rat. Animals were killed 7 days after hHGF gene transfer. Electroporation-mediated HGF gene transfer resulted in HGF expression specifically in AECII at biologically relevant levels. HGF gene transfer reduced pulmonary fibrosis as assessed by histology, hydroxyproline determination, and design-based stereology compared with controls. Our results indicate that the antifibrotic effect of HGF is due in part to a reduction of transforming growth factor-β(1), modulation of the epithelial-mesenchymal transition, and reduction of extravascular fibrin deposition. We conclude that targeted HGF gene transfer specifically to AECII decreases bleomycin-induced lung fibrosis and may therefore represent a novel cell-specific gene transfer technology to treat pulmonary fibrosis.
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Affiliation(s)
- Amiq Gazdhar
- Department of Pulmonary Medicine, University Hospital Bern, 3010 Bern, Switzerland
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22
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Hepatocyte growth factor, a determinant of airspace homeostasis in the murine lung. PLoS Genet 2013; 9:e1003228. [PMID: 23459311 PMCID: PMC3573081 DOI: 10.1371/journal.pgen.1003228] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2012] [Accepted: 11/23/2012] [Indexed: 12/02/2022] Open
Abstract
The alveolar compartment, the fundamental gas exchange unit in the lung, is critical for tissue oxygenation and viability. We explored hepatocyte growth factor (HGF), a pleiotrophic cytokine that promotes epithelial proliferation, morphogenesis, migration, and resistance to apoptosis, as a candidate mediator of alveolar formation and regeneration. Mice deficient in the expression of the HGF receptor Met in lung epithelial cells demonstrated impaired airspace formation marked by a reduction in alveolar epithelial cell abundance and survival, truncation of the pulmonary vascular bed, and enhanced oxidative stress. Administration of recombinant HGF to tight-skin mice, an established genetic emphysema model, attenuated airspace enlargement and reduced oxidative stress. Repair in the TSK/+ mouse was punctuated by enhanced akt and stat3 activation. HGF treatment of an alveolar epithelial cell line not only induced proliferation and scattering of the cells but also conferred protection against staurosporine-induced apoptosis, properties critical for alveolar septation. HGF promoted cell survival was attenuated by akt inhibition. Primary alveolar epithelial cells treated with HGF showed improved survival and enhanced antioxidant production. In conclusion, using both loss-of-function and gain-of-function maneuvers, we show that HGF signaling is necessary for alveolar homeostasis in the developing lung and that augmentation of HGF signaling can improve airspace morphology in murine emphysema. Our studies converge on prosurvival signaling and antioxidant protection as critical pathways in HGF–mediated airspace maintenance or repair. These findings support the exploration of HGF signaling enhancement for diseases of the airspace. The airspace compartment of the mammalian lung, comprised of spherical sacs termed alveoli, harbors the architecture, cellular composition, and molecular armamentarium to perform the critical function of gas exchange or oxygen uptake. Despite the necessity of this alveolar compartment for organismal viability, the mechanism by which alveoli are formed and maintained is obscure. Furthermore, no treatments are currently available that can regenerate the airspace once damaged. In this manuscript, we sought to determine whether hepatocyte growth factor, a cytokine with a functional armamentarium that subserves the critical events of alveolar formation (epithelial proliferation, migration, resistance from apoptosis and angiogenesis), could be an important mediator of alveolar formation and airspace maintenance. Our simple paradigm was that critical homeostatic pathways for the lung should operate both in lung formation and in lung maintenance/regeneration. Using an informative battery of mouse models and cell lines, we show that hepatocyte growth factor is a determinant of alveolar formation and that the enhancement of hepatocyte growth factor signaling can both protect and repair the airspace from pathologic airspace enlargement or emphysema.
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23
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Analysis of gene expression profiles in alveolar epithelial type II-like cells differentiated from human alveolar epithelial progenitor cells. Respir Investig 2012; 50:110-6. [PMID: 23021770 DOI: 10.1016/j.resinv.2012.07.002] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2012] [Revised: 07/24/2012] [Accepted: 07/25/2012] [Indexed: 01/01/2023]
Abstract
BACKGROUND Damage to lung epithelial cells through chronic injury and abnormal repair and remodeling lead to lung destruction and fibrosis. We isolated lung progenitor cells that could potentially contribute to lung diseases. The progenitor cells can differentiate into alveolar type II (ATII)-like cells in vitro, and are increased in number and localized within the region of alveolar epithelial cell proliferation that is involved in the reparative response to injury. However, global gene expression patterns in the ATII-like cells derived from the progenitor cells and in mature ATII cells isolated from lung tissue have not yet been evaluated. METHODS We performed gene expression array and directly compared the gene expression patterns in ATII-like cells derived from the progenitor cells with those in mature ATII cells isolated from human lung tissues. RESULTS ATII-like cells and mature ATII cells expressed certain common genes, such as CEPBD and FOXP1, which determine the phenotypes of ATII cells. However, many genes were differentially expressed between the 2 cell types. As compared to mature ATII cells, ATII-like cells showed decreased expression of the genes associated with surfactant protein production and epithelial phenotypes. Pathway analysis indicated changes in several pathways, including those involved in epithelial-to-mesenchymal transition and receptor tyrosine kinase signaling, which could contribute to the observed differences in gene expression patterns. CONCLUSIONS In this study, we identified genes commonly or differentially expressed by ATII-like cells differentiated from progenitor cells and mature ATII cells isolated from human lung tissues.
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Leuenberger A, Gazdhar A, Herrmann G, Ochs M, Geiser T, Knudsen L. Cell-specific expression of human HGF by alveolar type II cells induces remodeling of septal wall tissue in the lung: a morphometric study. J Appl Physiol (1985) 2012; 113:799-807. [PMID: 22744972 DOI: 10.1152/japplphysiol.00411.2012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Hepatocyte growth factor (HGF) is involved in development and regeneration of the lungs. Human HGF, which was expressed specifically by alveolar epithelial type II cells after gene transfer, attenuated the bleomycin-induced pulmonary fibrosis in an animal model. As there are also regions that appear morphologically unaffected in fibrosis, the effects of this gene transfer to normal lungs is of interest. In vitro studies showed that HGF inhibits the formation of the basal lamina by cultured alveolar epithelial cells. Thus we hypothesized that, in the healthy lung, cell-specific expression of HGF induces a remodeling within septal walls. Electroporation of a plasmid of human HGF gene controlled by the surfactant protein C promoter was applied for targeted gene transfer. Using design-based stereology at light and electron microscopic level, structural alterations were analyzed and compared with a control group. HGF gene transfer increased the volume of distal air spaces, as well as the surface area of the alveolar epithelium. The volume of septal walls, as well as the number of alveoli, was unchanged. Volumes per lung of collagen and elastic fibers were unaltered, but a marked reduction of the volume of residual extracellular matrix (all components other than collagen and elastic fibers) and interstitial cells was found. A correlation between the volumes of residual extracellular matrix and distal air spaces, as well as total surface area of alveolar epithelium, could be established. Cell-specific expression of HGF leads to a remodeling of the connective tissue within the septal walls in the healthy lung, which is associated with more pronounced stretching of distal air spaces at a given hydrostatic pressure during instillation fixation.
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Hiruma H, Hikawa S, Kawakami T. Immunocytochemical colocalization of fibroblast growth factor-1 with neurotrophin-3 in mouse alveolar macrophages. Acta Histochem Cytochem 2012; 45:131-7. [PMID: 22685355 PMCID: PMC3365304 DOI: 10.1267/ahc.11055] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2011] [Accepted: 02/02/2012] [Indexed: 12/02/2022] Open
Abstract
Alveolar macrophages are known to express a variety of growth factors and neurotrophins. Fibroblast growth factor-1 (FGF-1) is abundantly present in the lung and has mitogenic and neurotrophic activities similarly to neurotrophins. In order to determine whether FGF-1 associates with neurotrophins in alveolar macrophages, we investigated the immunocytochemical colocalization of FGF-1 with neurotrophins, nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3), in mouse alveolar macrophages. The results showed that 34% of macrophages were immunoreactive for FGF-1, 10% for NGF, 9% for BDNF, and 17% for NT-3. Of FGF-1-immunoreactive (IR) macrophages, 16% were immunoreactive for NT-3, but only small percentages were immunoreactive for NGF (0.8%) and for BDNF (0.3%). FGF-1 and neurotrophins were all localized in the intracellular vesicles. In the vesicles, FGF-1 and NT-3 were frequently colocalized. All macrophages expressed lysosome-associated protein-2 (LAMP-2), a late endosomal and lysosomal marker, and early endosomes antigen 1 (EEA1), an early endosomal marker. FGF-1 and NT-3 were predominantly colocalized with LAMP-2 rather than with EEA1, whereas NGF and BDNF were colocalized with EEA1 rather than with LAMP-2. These results indicate that FGF-1 and NT-3 are substantially expressed in mouse alveolar macrophages and colocalized in vesicles, predominantly in late endosomes and lysosomes.
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Affiliation(s)
- Hiromi Hiruma
- Department of Physiology, Kitasato University School of Medicine
| | - Shiori Hikawa
- Department of Medicine, Kitasato University School of Medicine
| | - Tadashi Kawakami
- Department of Physiology, Kitasato University School of Medicine
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Hoshino K, Satoh T, Kawaguchi Y, Kuwana M. Association of hepatocyte growth factor promoter polymorphism with severity of interstitial lung disease in Japanese patients with systemic sclerosis. ACTA ACUST UNITED AC 2011; 63:2465-72. [PMID: 21520010 DOI: 10.1002/art.30415] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
OBJECTIVE To examine associations of single-nucleotide polymorphisms (SNPs) within genes for hepatocyte growth factor (HGF) and its receptor c-met with disease susceptibility and organ involvement in Japanese patients with systemic sclerosis (SSc). METHODS Four SNPs (HGF -1652 C/T, +44222 C/T, and +63555 G/T, and c-met -980 T/A) were analyzed in 159 SSc patients and 103 healthy control subjects with the use of a polymerase chain reaction-based assay. The influence of the HGF -1652 SNP on transcription activity was evaluated with a luciferase reporter assay and an electrophoretic mobility shift assay (EMSA). RESULTS There was no difference in the distribution of HGF/c-met SNPs between SSc patients and controls. HGF -1652 TT was found much more frequently in SSc patients with end-stage lung disease (ESLD) than in those without (41% versus 8%; P = 0.0004). This association was confirmed by a replication study involving a separate cohort of 155 SSc patients. Kaplan-Meyer analysis revealed that HGF -1652 TT carriers had a higher probability of developing ESLD than did CT or CC carriers. The HGF promoter carrying the HGF -1652 T allele had lower transcription activity than did the promoter carrying the C allele. EMSA showed the presence of a potential negative transcription regulator that binds specifically to the HGF promoter carrying a T allele at position -1652. Finally, TT carriers had a relative inability to increase circulating HGF levels even in the presence of advanced interstitial lung disease. CONCLUSION A SNP in the HGF promoter region may modulate the severity of interstitial lung disease by controlling the transcriptional efficiency of the HGF gene.
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Affiliation(s)
- Kana Hoshino
- Keio University School of Medicine, Shinjuku-ku, Tokyo, Japan
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Huh JW, Kim SY, Lee JH, Lee JS, Van Ta Q, Kim M, Oh YM, Lee YS, Lee SD. Bone marrow cells repair cigarette smoke-induced emphysema in rats. Am J Physiol Lung Cell Mol Physiol 2011; 301:L255-66. [PMID: 21622846 DOI: 10.1152/ajplung.00253.2010] [Citation(s) in RCA: 103] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The therapeutic potential of stem cells in chronic obstructive pulmonary disease is not well known although stem cell therapy is effective in models of other pulmonary diseases. We tested the capacities of bone marrow cells (BMCs), mesenchymal stem cells (MSCs), and conditioned media of MSCs (MSC-CM) to repair cigarette smoke-induced emphysema. Inbred female Lewis rats were exposed to cigarette smoke for 6 mo and then received BMCs, MSCs, or MSC-CM from male Lewis rats. For 2 mo after injection, the BMC treatment gradually alleviated the cigarette smoke-induced emphysema and restored the increased mean linear intercept. The BMC treatment significantly increased cell proliferation and the number of small pulmonary vessels, reduced apoptotic cell death, attenuated the mean pulmonary arterial pressure, and inhibited muscularization in small pulmonary vessels. However, only a few male donor cells were detected from 1 day to 1 mo after BMC administration. The MSCs and cell-free MSC-CM also induced the repair of emphysema and increased the number of small pulmonary vessels. Our data show that BMC, MSCs, and MSC-CM treatment repaired cigarette smoke-induced emphysema. The repair activity of these treatments is consistent with a paracrine effect rather than stem cell engraftment because most of the donor cells disappeared and because cell-free MSC-CM also induced the repair.
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Affiliation(s)
- Jin Won Huh
- Dept. of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan Univ. School of Medicine, Suwon 440-746, South Korea
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Hind M, Maden M. Is a regenerative approach viable for the treatment of COPD? Br J Pharmacol 2011; 163:106-15. [PMID: 21265829 PMCID: PMC3085872 DOI: 10.1111/j.1476-5381.2011.01246.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2010] [Revised: 01/03/2011] [Accepted: 01/06/2011] [Indexed: 12/23/2022] Open
Abstract
Degenerative lung diseases such as chronic obstructive pulmonary disease (COPD) are common with huge worldwide morbidity. Anti-inflammatory drug development strategies have proved disappointing and current treatment is aimed at symptomatic relief. Only lung transplantation with all its attendant difficulties offers hope of cure and the outlook for affected patients is bleak. Lung regeneration therapies aim to reverse the structural and functional deficits in COPD either by delivery of exogenous lung cells to replace lost tissue, delivery of exogenous stem cells to induce a local paracrine effect probably through an anti-inflammatory action or by the administration of small molecules to stimulate the endogenous regenerative ability of lung cells. In animal models of emphysema and disrupted alveolar development each of these strategies has shown some success but there are potential tumour-inducing dangers with a cellular approach. Small molecules such as all-trans retinoic acid have been successful in animal models although the mechanism is not completely understood. There are currently two Pharma-sponsored trials in progress concerning patients with COPD, one of a specific retinoic acid receptor gamma agonist and another using mesenchymal stem cells.
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Affiliation(s)
- Matthew Hind
- Royal Brompton Hospital, National Heart and Lung Institute, Imperial College, London, UK.
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Molecular basis of lung tissue regeneration. Gen Thorac Cardiovasc Surg 2011; 59:231-44. [PMID: 21484549 DOI: 10.1007/s11748-010-0757-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2010] [Accepted: 12/05/2010] [Indexed: 12/29/2022]
Abstract
Recent advances have expanded our understanding of lung endogenous stem cells, and this knowledge provides us with new ideas for future regenerative therapy for lung diseases. In studies using animal models for lung regeneration, compensatory lung growth, and lung repair, promising reagents for lung regeneration have been discovered. Stem or progenitor cells are needed for alveolar regeneration, lung growth, and lung repair after injury. Endogenous progenitor cells mainly participate in alveologenesis. However, human lung endogenous progenitor cells have not yet been clearly defined. Recently discovered human alveolar epithelial progenitor cells may give us a new perspective for understanding the pathogenesis of lung diseases. In parallel with such basic research, projects geared toward clinical application are proceeding. Cell therapy using mesenchymal stem cells to treat acute lung injury is one of the promising areas for this research. The creation of bioartificial lungs, which are based on decellularized lungs, is another interesting approach for future clinical applications. Although lungs are the most challenging organ for regenerative medicine, our cumulative knowledge of lung regeneration and of endogenous progenitor cells makes clear the possibilities and limitations of regenerative medicine for lung diseases.
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Park HJ, Choi YH, Cho YJ, Henson PM, Kang JL. RhoA-mediated signaling up-regulates hepatocyte growth factor gene and protein expression in response to apoptotic cells. J Leukoc Biol 2010; 89:399-411. [PMID: 21148681 DOI: 10.1189/jlb.0710414] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Clearance of apoptotic cells by macrophages induces HGF secretion. We examined the regulatory mechanisms of HGF mRNA and protein expression in macrophages upon exposure to apoptotic cells. The interaction of RAW 264.7 macrophages with apoptotic Jurkat cells, but not with viable cells, resulted in expression of HGF mRNA and protein. Exposure of RAW 264.7 cells to apoptotic cells induced activation of RhoA, the PI3K/Akt pathway, and MAPKs, including p38 MAPK, ERK, and JNK. Down-regulation of the RhoA/Rho kinase pathway by pharmacological inhibitors or a RhoA-specific siRNA suppressed HGF mRNA and protein expression by macrophages in response to apoptotic cells through the phosphorylation of Akt and the MAPKs. Inhibition of PI3K decreased phosphorylation of Akt and the MAPKs. Inhibition of JNK, but not p38 MAPK and ERK, reduced Akt phosphorylation. The pharmacological inhibitor of PI3K and the MAPKs blocked HGF mRNA and protein expression. Other types of apoptotic cells, such as HeLa cells and murine thymocytes, could also induce HGF mRNA through the RhoA-dependent pathway. Likely, the RhoA-dependent signaling pathway was required for HGF mRNA induction in primary cells of peritoneal macrophages in response to apoptotic cells. An HGFR-blocking antibody did not alter apoptotic cell-induced activation of RhoA, Akt, and the MAPKs, as well as HGF production. Overall, the data provide evidence that activation of the RhoA/Rho kinase pathway up-regulates transcriptional HGF production in response to apoptotic cells.
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Affiliation(s)
- Hyun-Jung Park
- Department of Physiology, Tissue Injury Defense Research Center, School of Medicine, Ewha Womans University, Seoul, Korea
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Crosby LM, Waters CM. Epithelial repair mechanisms in the lung. Am J Physiol Lung Cell Mol Physiol 2010; 298:L715-31. [PMID: 20363851 DOI: 10.1152/ajplung.00361.2009] [Citation(s) in RCA: 524] [Impact Index Per Article: 34.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The recovery of an intact epithelium following lung injury is critical for restoration of lung homeostasis. The initial processes following injury include an acute inflammatory response, recruitment of immune cells, and epithelial cell spreading and migration upon an autologously secreted provisional matrix. Injury causes the release of factors that contribute to repair mechanisms including members of the epidermal growth factor and fibroblast growth factor families (TGF-alpha, KGF, HGF), chemokines (MCP-1), interleukins (IL-1beta, IL-2, IL-4, IL-13), and prostaglandins (PGE(2)), for example. These factors coordinate processes involving integrins, matrix materials (fibronectin, collagen, laminin), matrix metalloproteinases (MMP-1, MMP-7, MMP-9), focal adhesions, and cytoskeletal structures to promote cell spreading and migration. Several key signaling pathways are important in regulating these processes, including sonic hedgehog, Rho GTPases, MAP kinase pathways, STAT3, and Wnt. Changes in mechanical forces may also affect these pathways. Both localized and distal progenitor stem cells are recruited into the injured area, and proliferation and phenotypic differentiation of these cells leads to recovery of epithelial function. Persistent injury may contribute to the pathology of diseases such as asthma, chronic obstructive pulmonary disease, and pulmonary fibrosis. For example, dysregulated repair processes involving TGF-beta and epithelial-mesenchymal transition may lead to fibrosis. This review focuses on the processes of epithelial restitution, the localization and role of epithelial progenitor stem cells, the initiating factors involved in repair, and the signaling pathways involved in these processes.
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Affiliation(s)
- Lynn M Crosby
- Departments of 1Physiology, University of Tennessee Health Science Center, Memphis, TN 38163-0001, USA
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Narasaraju T, Ng HH, Phoon MC, Chow VTK. MCP-1 antibody treatment enhances damage and impedes repair of the alveolar epithelium in influenza pneumonitis. Am J Respir Cell Mol Biol 2009; 42:732-43. [PMID: 19617401 DOI: 10.1165/rcmb.2008-0423oc] [Citation(s) in RCA: 82] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Recent studies have demonstrated an essential role of alveolar macrophages during influenza virus infection. Enhanced mortalities were observed in macrophage-depleted mice and pigs after influenza virus infection, but the basis for the enhanced pathogenesis is unclear. This study revealed that blocking macrophage recruitment into the lungs in a mouse model of influenza pneumonitis resulted in enhanced alveolar epithelial damage and apoptosis, as evaluated by histopathology, immunohistochemistry, Western blot, RT-PCR, and TUNEL assays. Abrogation of macrophage recruitment was achieved by treatment with monoclonal antibody against monocyte chemoattractant protein-1 (MCP-1) after sub-lethal challenge with mouse-adapted human influenza A/Aichi/2/68 virus. Interestingly, elevated levels of hepatocyte growth factor (HGF), a mitogen for alveolar epithelium, were detected in bronchoalveolar lavage samples and in lung homogenates of control untreated and nonimmune immunoglobulin (Ig)G-treated mice after infection compared with anti-MCP-1-treated infected mice. The lungs of control animals also displayed strongly positive HGF staining in alveolar macrophages as well as alveolar epithelial cell hyperplasia. Co-culture of influenza virus-infected alveolar epithelial cells with freshly isolated alveolar macrophages induced HGF production and phagocytic activity of macrophages. Recombinant HGF added to mouse lung explants after influenza virus infection resulted in enhanced BrdU labeling of alveolar type II epithelial cells, indicating their proliferation, in contrast with anti-HGF treatment showing significantly reduced epithelial regeneration. Our data indicate that inhibition of macrophage recruitment augmented alveolar epithelial damage and apoptosis during influenza pneumonitis, and that HGF produced by macrophages in response to influenza participates in the resolution of alveolar epithelium.
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Affiliation(s)
- T Narasaraju
- Infectious Diseases Program, Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, 5 Science Drive 2, Kent Ridge 117597, Singapore.
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Intranasal HGF administration ameliorates the physiologic and morphologic changes in lung emphysema. Mol Ther 2008; 16:1417-26. [PMID: 18560414 DOI: 10.1038/mt.2008.137] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Hepatocyte growth factor (HGF) has multiple biological effects on stem cells, epithelial proliferation, and wound healing. In this study, we investigated a possible therapeutic benefit of intranasal HGF on elastase-induced emphysema, and assessed the role of stem/progenitor cells in this process. HGF was given twice a week for 1-4 weeks after the establishment of emphysema in mice. HGF inhalation significantly ameliorated the enlargement of airspaces and alveolar wall destruction. Also, elevated static lung compliance returned to control levels within 2 weeks of HGF treatment. The expressions of stem-cell markers, c-kit, stem-cell antigen 1 (Sca-1), and CD34 were also significantly influenced by HGF. Most of the c-kit(+) cells were bone marrow derived, while most Sca-1(+) were lung endogenous cells. CD34(+) cells were from both sources, and a portion of the endogenous CD34(+) cells was also Sca-1(+). Further, HGF increased the expression levels of proliferating cell nuclear antigen (PCNA) and cytokeratin-19. Also, their immunohistochemical staining patterns were colocalized, indicative of epithelial multiplication. The results of the study show that intranasal treatment with HGF reverses both the physiological and morphometric changes of lung emphysema, possibly through stem-cell mobilization and alveolar regeneration, providing a nonsurgical treatment and suggesting the possibility of achieving a similar effect in humans.
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Abstract
Lung epithelium is the primary site of lung damage in interstitial lung diseases. Although there are various initiating factors, the terminal stages are characterized by pulmonary fibrosis. Conventional therapy consisting of glucocorticoids or immunosuppressive drugs is usually ineffective. Epithelial cell apoptosis have been considered to be initial events in interstitial lung diseases. The death receptor-mediated signaling pathway directly induces caspase activation and apoptosis. Other stresses induce the release of cytochrome from mitochondria and caspase activation. Endoplasmic reticulum stress also induces apoptosis. Epithelial cell death is followed by remodeling processes, which consist of epithelial and fibroblast activation, cytokine production, activation of the coagulation pathway, neoangiogenesis, re-epithelialization and fibrosis. Epithelial and mesenchymal interaction plays important roles in these processes. Further understanding of apoptosis signaling may lead to effective strategies against devastating lung diseases. We review the role of epithelial cell apoptosis in the molecular mechanisms of pulmonary fibrosis.
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Affiliation(s)
- Kazuyoshi Kuwano
- Division of Respiratory Diseases, Department of Internal Medicine, Jikei University School of Medicine, Tokyo.
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Gazdhar A, Fachinger P, van Leer C, Pierog J, Gugger M, Friis R, Schmid RA, Geiser T. Gene transfer of hepatocyte growth factor by electroporation reduces bleomycin-induced lung fibrosis. Am J Physiol Lung Cell Mol Physiol 2006; 292:L529-36. [PMID: 17056705 DOI: 10.1152/ajplung.00082.2006] [Citation(s) in RCA: 68] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Abnormal alveolar wound repair contributes to the development of pulmonary fibrosis after lung injury. Hepatocyte growth factor (HGF) is a potent mitogenic factor for alveolar epithelial cells and may therefore improve alveolar epithelial repair in vitro and in vivo. We hypothesized that HGF could increase alveolar epithelial repair in vitro and improve pulmonary fibrosis in vivo. Alveolar wound repair in vitro was determined using an epithelial wound repair model with HGF-transfected A549 alveolar epithelial cells. Electroporation-mediated, nonviral gene transfer of HGF in vivo was performed 7 days after bleomycin-induced lung injury in the rat. Alveolar epithelial repair in vitro was increased after transfection of wounded epithelial monolayers with a plasmid encoding human HGF, pCikhHGF [human HGF (hHGF) gene expressed from the cytomegalovirus (CMV) immediate-early promoter and enhancer] compared with medium control. Electroporation-mediated in vivo HGF gene transfer using pCikhHGF 7 days after intratracheal bleomycin reduced pulmonary fibrosis as assessed by histology and hydroxyproline determination 14 days after bleomycin compared with controls treated with the same vector not containing the HGF sequence (pCik). Lung epithelial cell proliferation was increased and apoptosis reduced in hHGF-treated lungs compared with controls, suggesting increased alveolar epithelial repair in vivo. In addition, profibrotic transforming growth factor-beta1 (TGF-beta1) was decreased in hHGF-treated lungs, indicating an involvement of TGF-beta1 in hHGF-induced reduction of lung fibrosis. In conclusion, electroporation-mediated gene transfer of hHGF decreases bleomycin-induced pulmonary fibrosis, possibly by increasing alveolar epithelial cell proliferation and reducing apoptosis, resulting in improved alveolar wound repair.
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Affiliation(s)
- Amiq Gazdhar
- Division of Thoracic Surgery, University Hospital, CH-3010 Bern, Switzerland
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Cohen M, Marchand-Adam S, Lecon-Malas V, Marchal-Somme J, Boutten A, Durand G, Crestani B, Dehoux M. HGF synthesis in human lung fibroblasts is regulated by oncostatin M. Am J Physiol Lung Cell Mol Physiol 2006; 290:L1097-103. [PMID: 16684952 DOI: 10.1152/ajplung.00166.2005] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
Oncostatin M (OSM) is a IL-6 family cytokine locally produced in acute lung injury. Its profibrotic properties suggest a role in lung wound repair. Hepatocyte growth factor (HGF), produced by fibroblasts, is involved in pulmonary epithelial repair. We investigated the role of OSM in HGF synthesis by human lung fibroblasts. We showed that OSM upregulated HGF mRNA in MRC5 cells and in human lung fibroblasts, whereas IL-6 and leukemia inhibitory factor did not. OSM induced HGF secretion to a similar extent as IL-1beta in both a time- and dose-dependent manner. HGF was released in its cleaved mature form, and its secretion was completely inhibited in the presence of cycloheximide, indicating a de novo protein synthesis. OSM in combination with prostaglandin E(2), a powerful HGF inductor, led to an additive effect. OSM and indomethacin in combination further increased HGF secretion. This could be explained, at least in part, by a moderate upregulation of specific OSM receptor beta mRNA expression through cyclooxygenase inhibition. These results demonstrate that OSM-induced HGF synthesis did not involve a PGE(2) pathway. OSM-induced HGF secretion was inhibited by PD-98059 (a specific pharmacological inhibitor of ERK1/2), SB-203580 (a p38 MAPK inhibitor), and SP-600125 (a JNK inhibitor) by 70, 82, and 100%, respectively, whereas basal HGF secretion was only inhibited by SP-600125 by 30%. Our results demonstrate a specific upregulation of HGF synthesis by OSM, most likely through a MAPK pathway, and support the suggestion that OSM may participate in lung repair through HGF production.
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Affiliation(s)
- Murielle Cohen
- Service de Biochimie A, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, 46 rue Henri Huchard, 75877 Paris cedex 18, France
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Chen JT, Lin TS, Chow KC, Huang HH, Chiou SH, Chiang SF, Chen HC, Chuang TL, Lin TY, Chen CY. Cigarette Smoking Induces Overexpression of Hepatocyte Growth Factor in Type II Pneumocytes and Lung Cancer Cells. Am J Respir Cell Mol Biol 2006; 34:264-73. [PMID: 16254251 DOI: 10.1165/rcmb.2005-0117oc] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
We examined gene expression of hepatocyte growth factor (HGF) and HGF receptor (HGFR), or product of proto-oncogene c-met (c-met), in smokers and nonsmokers with adenocarcinoma (ADC) by suppression subtractive hybridization and microarray techniques. Expression of HGF and c-met was confirmed by RT-PCR. HGF content in the respective tumor mass and nontumor lung tissue was measured by ELISA. HGF in pathologic samples was localized by immunohistochemistry and in situ hybridization. Our results indicate that overexpression of HGFR was frequently detected in ADC cells, whereas overexpression of HGF was detected in alveolar type II (ATII) cells. Overexpression of HGF was correlated with cigarette smoking and tumor stages. In vitro, HGF expression was evaluated in isolated murine ATII cells and in 12 ADC cell lines, and we found that nicotine activated HGF expression in ATII cells and lung cancer cells.
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Ishida Y, Takayasu T, Kimura A, Hayashi T, Kakimoto N, Miyashita T, Kondo T. Gene expression of cytokines and growth factors in the lungs after paraquat administration in mice. Leg Med (Tokyo) 2006; 8:102-9. [PMID: 16324872 DOI: 10.1016/j.legalmed.2005.08.010] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2005] [Revised: 08/17/2005] [Accepted: 08/18/2005] [Indexed: 11/17/2022]
Abstract
It is well known that the intake of paraquat (PQ), an herbicide, causes severe lung injury at chronic phases. We examined the intrapulmonary gene expression of cytokines and growth factors after PQ administration. To induce lung injury, C57BL/6 mice were intraperitoneally injected twice a week with 20 mg/kg of PQ. Histopathologically, at the early phase, lots of alveolar spaces contained edematous fluid. At 3 weeks after PQ challenge, a marked thickening of the alveolar walls with the accumulation of macrophages and T cells was found. Azan staining revealed the patchy distribution of collagen accumulation, indicating pulmonary fibrosis. Consistently, intrapulmonary hydroxyproline contents were significantly elevated, compared with the controls. Semi-quantitative RT-PCR analysis demonstrated that the gene expression of tumor necrosis factor-alpha and monocyte chemoattractant protein-1 were significantly increased at 3 weeks after PQ challenge compared with the controls. The mRNA expression of macrophage inflammatory protein (MIP)-1alpha and MIP-2 was significantly enhanced at 1 and 2 weeks after PQ treatment, respectively. Moreover, PQ-treated mice showed enhanced gene expression of fibrogenic growth factors such as transforming growth factor-beta, platelet-derived growth factor-A, acidic fibroblast growth factor, and hepatoctyte growth factor at 2 and/or 3 weeks after PQ challenge. The synergistic effects of these molecules are presumed to cause pulmonary fibrosis due to PQ challenge.
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Affiliation(s)
- Yuko Ishida
- Department of Forensic Medicine, Wakayama Medical University, 811-1 Kimiidera, Wakayama 641-8509, Japan.
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Bonay M, Boutten A, Leçon-Malas V, Marchal J, Soler P, Fournier M, Leseche G, Dehoux M, Crestani B. Hepatocyte and keratinocyte growth factors and their receptors in human lung emphysema. BMC Pulm Med 2005; 5:13. [PMID: 16216128 PMCID: PMC1283976 DOI: 10.1186/1471-2466-5-13] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2005] [Accepted: 10/10/2005] [Indexed: 11/13/2022] Open
Abstract
Background Hepatocyte and keratinocyte growth factors are key growth factors in the process of alveolar repair. We hypothesized that excessive alveolar destruction observed in lung emphysema involves impaired expression of hepatocyte and keratinocyte growth factors or their respective receptors, c-met and keratinocyte growth factor receptor. The aim of our study was to compare the expression of hepatocyte and keratinocyte growth factors and their receptors in lung samples from 3 groups of patients: emphysema; smokers without emphysema and non-smokers without emphysema. Methods Hepatocyte and keratinocyte growth factor proteins were analysed by immunoassay and western blot; mRNA expression was measured by real time quantitative polymerase chain reaction. Results Hepatocyte and keratinocyte growth factors, c-met and keratinocyte growth factor receptor mRNA levels were similar in emphysema and non-emphysema patients. Hepatocyte growth factor mRNA correlated negatively with FEV1 and the FEV1/FVC ratio both in emphysema patients and in smokers with or without emphysema. Hepatocyte and keratinocyte growth factor protein concentrations were similar in all patients' groups. Conclusion The expression of hepatocyte and keratinocyte growth factors and their receptors is preserved in patients with lung emphysema as compared to patients without emphysema. Hepatocyte growth factor mRNA correlates with the severity of airflow obstruction in smokers.
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Affiliation(s)
- Marcel Bonay
- INSERM U 700, Faculté Xavier Bichat, Paris, France
- Service de Physiologie-Explorations Fonctionnelles, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris, France
| | - Anne Boutten
- INSERM U 700, Faculté Xavier Bichat, Paris, France
- Service de Biochimie A, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris, France
| | - Véronique Leçon-Malas
- Service de Biochimie A, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris, France
| | | | - Paul Soler
- INSERM U 700, Faculté Xavier Bichat, Paris, France
| | - Michel Fournier
- Service de Pneumologie, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris, France
| | - Guy Leseche
- Service de Chirurgie Thoracique, Hôpital Beaujon, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris, France
| | - Monique Dehoux
- INSERM U 700, Faculté Xavier Bichat, Paris, France
- Service de Biochimie A, Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris, France
| | - Bruno Crestani
- INSERM U 700, Faculté Xavier Bichat, Paris, France
- Service de Pneumologie Hôpital Bichat-Claude Bernard, Assistance Publique-Hôpitaux de Paris, Université Paris 7, Paris, France
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40
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Padela S, Cabacungan J, Shek S, Belcastro R, Yi M, Jankov RP, Tanswell AK. Hepatocyte growth factor is required for alveologenesis in the neonatal rat. Am J Respir Crit Care Med 2005; 172:907-14. [PMID: 15994466 DOI: 10.1164/rccm.200504-567oc] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
RATIONALE Our core hypothesis is that growth factors that have dysregulated expression during experimental neonatal lung injury are likely to be involved in normal postnatal lung growth and alveologenesis. OBJECTIVES To determine if hepatocyte growth factor (HGF) is upregulated in neonatal lung injury and is essential for postnatal alveologenesis. METHODS A neonatal lung injury, in which there were patchy areas of interstitial thickening with a relative increase in the proportion of epithelial cells, was induced in newborn rats by exposing them to 60% oxygen for 14 days. Air-exposed pups had binding of endogenous HGF to its natural receptor, c-Met, inhibited by the intraperitoneal injection of either neutralizing antibody to HGF, or a truncated soluble c-Met receptor. MEASUREMENTS AND MAIN RESULTS The 60% oxygen-mediated lung injury was associated with increased lung mRNAs for hepatocyte growth factor and c-Met, relative to air-exposed control lungs, at Day 7 after birth. After exposure to 60% oxygen, immunoreactive HGF was increased at Days 4 and 7, and immunoreactive c-Met was increased at Day 14. In air-exposed pups, intraperitoneal injections of neutralizing antibody to HGF inhibited DNA synthesis in alveoli-forming secondary crests, and reduced the number of alveoli in 6-day-old pups. Intraperitoneal injections of a truncated soluble c-Met receptor inhibited DNA synthesis in secondary crests in 4-day-old air-exposed rat pups. CONCLUSIONS HGF and its c-Met receptor are required for normal postnatal alveolar formation from secondary crests, and are upregulated during 60% oxygen-induced neonatal lung injury.
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Affiliation(s)
- Sanna Padela
- Canadian Institutes of Health Research Group in Lung Development, Hospital for Sick Children Research Institute, University of Toronto, Ontario, Canada
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41
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Abstract
The mode of cell death termed apoptosis, sometimes referred to as programmed cell death, is as critical a determinant of cell population size as is cell proliferation. Although best characterized in cells of the immune system, apoptosis is now known to be a key factor in the maintenance of normal cell turnover within structural cells in the parenchyma of virtually every organ. Recent interest in apoptosis in the lung has sparked a surge of investigations designed to determine the roles of apoptosis in lung development, injury, and remodeling. Of particular recent interest are the roles of apoptosis in disease pathogenesis and resolution, in which the concept of apoptosis as a "programmed" cell death, i.e., genetically determined, is often more accurately viewed as "inappropriate cell suicide" with regard to its extent and/or timing. Data accumulating over the past decade have made clear the complexity of the control of lung cell apoptosis; concepts of the regulation of apoptosis originally determined in classical cell culture models are often, but not always, applicable to structural cells. For this reason, each of the many cell types of the lung must be studied as a potentially new subject with its own idiosyncrasies yet to be discovered. In light of the large volume of literature now available, this article focuses on the roles of apoptosis in three pathophysiological contexts: acute respiratory distress syndrome, chronic obstructive pulmonary disease, and pulmonary fibrosis. Each section presents key data describing the evidence for apoptosis in the lung, its possible relevance to disease pathogenesis, and proposed mechanisms that might suggest potential avenues for therapeutic intervention.
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Affiliation(s)
- Xiaopeng Li
- Dept. of Physiology, Michigan State University, 3185 Biomedical and Physical Sciences Bldg., East Lansing, MI 48824, USA
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42
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Shigemura N, Sawa Y, Mizuno S, Ono M, Minami M, Okumura M, Nakamura T, Kaneda Y, Matsuda H. Induction of compensatory lung growth in pulmonary emphysema improves surgical outcomes in rats. Am J Respir Crit Care Med 2005; 171:1237-45. [PMID: 15764723 DOI: 10.1164/rccm.200411-1518oc] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
RATIONALE AND OBJECTIVES Although lung volume reduction surgery (LVRS) has been widely used as a therapeutic strategy for pulmonary emphysema, the procedure carries significant disadvantages, including significant operative mortality and a limited duration of effective response. Pulmonary resection is known to elicit compensatory growth in remnant lung tissues; however, it remains unclear whether and how compensatory growth occurs and contributes to clinical outcomes after LVRS. The goal of the present study was to characterize the role of hepatocyte growth factor (HGF) in compensatory lung growth after LVRS in a rat model of elastase-induced emphysema, since HGF is a potent pulmotrophic factor responsible for the regeneration of lung parenchyma in damaged lungs, including after a pulmonary resection. METHODS AND MAIN RESULTS Unexpectedly, LVRS did not cause apparent increases in the endogenous HGF profiles of emphysematous lungs. Further, the lowered HGF production reflected a histologically inferior regenerative capacity in remnant lungs and was linked with impaired pulmonary functional recoveries after LVRS. When HGF was exogenously supplemented by gene transfection into emphysematous lungs simultaneously with LVRS, compensatory lung growth (as evidenced by increased lobe weight and alveolar regeneration and angiogenesis) was significantly enhanced as compared with rats that underwent LVRS alone. Consequently, pulmonary function and gas exchange were also significantly improved. CONCLUSIONS We concluded that the induction of compensatory growth by growth factors after LVRS may be a new strategy to further improve clinical outcomes of LVRS in patients with pulmonary emphysema.
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Affiliation(s)
- Norihisa Shigemura
- Department of Surgery, Division of Molecular Regenerative Medicine, Osaka University Graduate School of Medicine, E1, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
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43
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Liu J, Nethery D, Kern JA. Neuregulin-1 induces branching morphogenesis in the developing lung through a P13K signal pathway. Exp Lung Res 2005; 30:465-78. [PMID: 15524405 DOI: 10.1080/01902140490476454] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Neuregulin-1 (NRG-1) induces signal transduction through the activation of its receptor, a heterodimer of human epidermal growth factor receptors 2 and 3 (HER2/HER3). Signal transduction through this receptor/ligand system plays a critical role in the developing heart, mammary gland, and nervous systems. Previous studies showed that NRG-1-induced HER2 activation resulted in pulmonary epithelial cell proliferation in the human fetal lung. The authors hypothesized that NRG-1 further contributes to lung development and maturation by inducing branching morphogenesis. In the present study, the authors show that NRG-1, HER2, and HER3, but not HER4, are expressed in the developing mouse lung. Addition of NRG-1 to fetal lung explants increased lung branching morphogenesis by 32% (P < .05). This increase in branching was blocked by 2C4, an antibody directed against HER2 that inhibits its dimerization and subsequent NRG-1-induced signal transduction. To gain an understanding of the intracellular signaling pathways involved in NRG-1-induced branching morphogenesis, the authors specifically blocked the phosphatidylinositol-3 kinase (PI3K) and mitogen activation protein kinase (MAPK) pathways. Inhibition of PI3K signaling significantly decreased NRG-1-induced branching morphogenesis (P < .05). Inhibition of NRG-1-induced MAPK activation had no effect on explant branching morphogenesis. These data suggest that NRG-1, binding to the HER2/HER3 heterodimer receptor complex, induces pulmonary branching morphogenesis through HER2 activation of the PI3K pathway.
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Affiliation(s)
- Jinbo Liu
- Department of Internal Medicine, Pulmonary and Critical Care Division, University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio 44106, USA
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Saito M, Ichiba H, Yokoi T, Hirai C, Yamano T, Kusuda S. Mitogenic activity of tracheal effluents from premature infants with chronic lung disease. Pediatr Res 2004; 55:960-5. [PMID: 15028841 DOI: 10.1203/01.pdr.0000125257.55596.97] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Lung injury alters the expression and release of growth factors that disrupt postnatal pulmonary development in newborns and causes chronic lung disease (CLD). The effect of these factors, released into the airways of newborns with CLD, on cell proliferation and collagen production was characterized in vitro. Human fetal lung fibroblast and alveolar-epithelial-like cell lines (FHs 738Lu and A549, respectively) were exposed to tracheal effluents from infants with CLD (mean gestation, 24.7 +/- 0.9 wk; birth weight, 666 +/- 85 g; postnatal age, 0-62 d). In both cell types, proliferation was assessed by measuring [(3)H]-thymidine uptake; in fibroblasts, collagen production was analyzed by measuring [(3)H]-proline incorporation. The activity of specific growth factors in effluents was determined using anti-growth factor antibodies and the growth factors themselves. Growth factors in tracheal effluents promoted proliferation in a dose-dependent manner and caused up to a 10.2- and 3.1-fold increase in thymidine uptake by fibroblasts and epithelial cells, respectively. Collagen production by fibroblasts increased dose dependently, peaking at 177% of baseline. Antibody against transforming growth factor beta-1 (TGF-beta(1)) inhibited proliferation and the increase in collagen production by 31% (p = 0.01) and 14% (p = 0.045), respectively. Antibody against hepatocyte growth factor (HGF) inhibited proliferation of epithelial cells (25%, p = 0.039). The effects of exogenous TGF-beta(1) on fibroblasts and HGF on epithelial cells resembled those of tracheal effluents. Potent mitogenic and differentiating substances are released into the tracheal effluents of newborns with CLD. TGF-beta(1) may worsen CLD by inducing fibrosis whereas HGF may favor resolution by promoting epithelialization.
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Affiliation(s)
- Mika Saito
- Department of Pediatrics, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abenoku, Osaka 545-8585, Japan
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45
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Gollamudi M, Nethery D, Liu J, Kern JA. Autocrine activation of ErbB2/ErbB3 receptor complex by NRG-1 in non-small cell lung cancer cell lines. Lung Cancer 2004; 43:135-43. [PMID: 14739033 DOI: 10.1016/j.lungcan.2003.08.027] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Our prior studies identified co-expression of the human epidermal growth factor-like receptors 2 (ErbB2) and 3 (ErbB3), as well as the growth factor neuregulin-1 (NRG-1) in normal lung epithelium and lung cancers. As ErbB2 and ErbB3 dimerize to produce a high affinity receptor for NRG-1, we postulated that an autocrine growth loop was present in transformed and non-transformed pulmonary epithelial cells. To test this hypothesis, we examined four cell lines derived from human non-small cell carcinomas for: (1) ErbB2 and ErbB3 expression and endogenous activation; (2) NRG-1 expression and secretion/shedding; and (3) the effect of receptor blockade on autocrine receptor activation. Our studies found that ErbB2 and ErbB3 were expressed by each of these cell lines. In addition, the NRG-1 gene was also expressed with both major isoforms of NRG-1 (NRG-1alpha and NRG-1beta) found intracellularly. Only the NRG-1alpha isoform, however, was found secreted/shed into the culture medium. The secreted/shed NRG-1alpha was capable of activating the ErbB2/ErbB3 receptor complex expressed on the breast adenocarcinoma cell line MCF-7. Basal ErbB2 phosphorylation was identified in all lung cancer cell lines and was inhibited with an antibody that blocked the NRG-1 binding site on ErbB3. Taken together, these data show that secreted NRG-1alpha can activate the ErbB2/ErbB3 heterodimer in an autocrine fashion. The identification of a NRG-1alpha/ErbB2/ErbB3 autocrine loop raises the possibility that interruption of this loop may have therapeutic potential in lung cancer.
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Affiliation(s)
- Murthy Gollamudi
- Department of Internal Medicine, Pulmonary and Critical Care Division, University Hospitals of Cleveland, Case Western Reserve University, Wearn 610, 11100 Euclid Avenue, Cleveland, OH 44106, USA
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46
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Affiliation(s)
- Robert P Jankov
- Canadian Institutes of Health Research (CIHR) Group in Lung Development and Lung Biology Programme, The Hospital for Sick Children Research Institute, Toronto, Ontario M5G 1X8, Canada
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Furuyama A, Mochitate K. Hepatocyte growth factor inhibits the formation of the basement membrane of alveolar epithelial cells in vitro. Am J Physiol Lung Cell Mol Physiol 2004; 286:L939-46. [PMID: 14672920 DOI: 10.1152/ajplung.00238.2002] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Hepatocyte growth factor (HGF) is a pulmotrophic factor for the regeneration of injured pulmonary tissue. We investigated the role of HGF in basement membrane formation during wound healing by immortalized alveolar type II epithelial cells that could form a continuous basement membrane when they were cultured on collagen fibrils in the presence of entactin-contaminated laminin-1. Cells cultured with 5.0 ng/ml HGF neither formed a continuous basement membrane on collagen fibrils nor maintained a continuous basement membrane architecture on a basement membrane substratum. The cells showed increased secretion of matrix metalloproteinase-9 and urokinase-type plasminogen activator, and the HGF-induced inhibition of basement membrane formation was attenuated by addition of 200 ng/ml tissue inhibitor of matrix metalloproteinase-1. Cells sequentially exposed to HGF and 1.0 ng/ml transforming growth factor-β1 had enhanced basement membrane formation compared with those receiving these reagents in the reverse order or concurrently. HGF simultaneously stimulated proliferation and migration of the cells so that it advanced wound closure on the basement membrane substratum. The present results indicate that the role of HGF in wound healing is the stimulation of reepithelization, but this factor may also contribute to the degradation of the basement membrane.
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Affiliation(s)
- Akiko Furuyama
- Inhalation Toxicology Team, PM2.5 & DEP Research Project, National Institute for Environmental Studies, 16-2 Onogawa, Tsukuba, Ibaraki 305-8506, Japan.
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48
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Amano H, Morimoto K, Senba M, Wang H, Ishida Y, Kumatori A, Yoshimine H, Oishi K, Mukaida N, Nagatake T. Essential contribution of monocyte chemoattractant protein-1/C-C chemokine ligand-2 to resolution and repair processes in acute bacterial pneumonia. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2004; 172:398-409. [PMID: 14688348 DOI: 10.4049/jimmunol.172.1.398] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Neutrophil infiltration is the first step in eradication of bacterial infection, but neutrophils rapidly die after killing bacteria. Subsequent accumulation of macrophage lineage cells, such as alveolar macrophages (AMs), is essential to remove dying neutrophils, which are a source of injurious substances. Macrophage lineage cells can promote tissue repair, by producing potential growth factors including hepatocyte growth factor (HGF). However, it remains elusive which factor activates macrophage in these processes. Intratracheal instillation of Pseudomonas aeruginosa caused neutrophil infiltration in the airspace; subsequently, the numbers of total AMs and neutrophil ingested AMs were increased. Bronchoalveolar lavage (BAL) fluid levels of monocyte chemoattractant protein (MCP)-1/CC chemokine ligand-2 (CCL2), a potent macrophage-activating factor, were increased before the increases in the number of AM ingesting neutrophils and HGF levels in BAL fluid. Immunoreactive MCP-1 proteins were detected in alveolar type II epithelial cells and AMs only after P. aeruginosa infection. The administration of anti-MCP-1/CCL2 Abs reduced the increases in the number of AM-ingesting neutrophils and HGF levels in BAL fluid, and eventually aggravated lung tissue injury. In contrast, the administration of MCP-1/CCL2 enhanced the increases in the number of AM ingesting neutrophils and HGF levels in BAL fluid, and eventually attenuated lung tissue injury. Furthermore, MCP-1/CCL2 enhanced the ingestion of apoptotic neutrophils and HGF production by a mouse macrophage cell line, RAW 267.4, in a dose-dependent manner. Collectively, MCP-1/CCL2 has a crucial role in the resolution and repair processes of acute bacterial pneumonia by enhancing the removal of dying neutrophils and HGF production by AMs.
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MESH Headings
- Acute Disease
- Animals
- Apoptosis/immunology
- Cell Line
- Cells, Cultured
- Chemokine CCL2/administration & dosage
- Chemokine CCL2/immunology
- Chemokine CCL2/physiology
- Coculture Techniques
- Hepatocyte Growth Factor/biosynthesis
- Immune Sera/administration & dosage
- Ligands
- Macrophages, Alveolar/immunology
- Macrophages, Alveolar/metabolism
- Macrophages, Alveolar/pathology
- Male
- Mice
- Mice, Inbred ICR
- Neutrophil Infiltration/immunology
- Neutrophils/immunology
- Neutrophils/pathology
- Phosphatidylserines/metabolism
- Pneumonia, Bacterial/immunology
- Pneumonia, Bacterial/pathology
- Pneumonia, Bacterial/prevention & control
- Pseudomonas Infections/immunology
- Pseudomonas Infections/pathology
- Pseudomonas Infections/prevention & control
- Receptors, CCR2
- Receptors, Cell Surface/biosynthesis
- Receptors, Chemokine/physiology
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Affiliation(s)
- Hideaki Amano
- Department of Respiratory Medicine, Nijigaoka Hospital, 1-1 Nijigaoka, Nagasaki City, Nagasaki 852-8055, Japan.
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Umeda Y, Marui T, Matsuno Y, Shirahashi K, Iwata H, Takagi H, Matsumoto K, Nakamura T, Kosugi A, Mori Y, Takemura H. Skeletal muscle targeting in vivo electroporation-mediated HGF gene therapy of bleomycin-induced pulmonary fibrosis in mice. J Transl Med 2004; 84:836-44. [PMID: 15197407 PMCID: PMC7102183 DOI: 10.1038/labinvest.3700098] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
Lung fibrosis is a common feature of interstitial lung diseases, and apoptosis and fibrinogenesis play critical roles in its formation and progression. Hepatocyte growth factor (HGF) is one of the ideal therapeutic agents for prevention of lung fibrosis because of its antiapoptotic and fibrinolytic effects. The aim of this study is to establish nonviral HGF gene therapy of bleomycin-induced lung fibrosis avoiding the viral vector-related side effects. C57BL/6 mice were injected with 3.0 mg/kg body weight of bleomycin intratracheally. Following bleomycin injection, 50 microl of pUC-HGF (1 mg/ml) was injected into each of the quadriceps muscle. Immediately after plasmid injection, in vivo electroporation was performed with pulse generator. Skeletal muscle-targeting electroporation induced transgene expression on day 1 and persisted for 4 weeks, and human HGF was also detected in the lung. In mice transferred with HGF, pathological score (1.0+/-0.3 vs 3.2+/-0.6), TUNEL-positive cell index (4.5+/-1.1 vs 14.2+/-3.1), and hydroxyproline content (9.0+/-1.3 vs 14.4+/-5.1 micromol/g) were significantly reduced compared with the control. Furthermore, survival rate of HGF mice was significantly improved compared with the control. Our data indicate that HGF gene therapy with a single skeletal muscle-targeting electroporation has a therapeutic potential for bleomycin-induced lung fibrosis and this strategy can be applied as a practical gene therapy protocol for various organs.
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Affiliation(s)
- Yukio Umeda
- Advanced Surgery, Department of Organ Pathobiology, Gifu University School of Medicine, 40 Tsukasa-machi, Gifu 500-8705, Japan.
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50
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Marchand-Adam S, Marchal J, Cohen M, Soler P, Gerard B, Castier Y, Lesèche G, Valeyre D, Mal H, Aubier M, Dehoux M, Crestani B. Defect of hepatocyte growth factor secretion by fibroblasts in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003; 168:1156-61. [PMID: 12947024 DOI: 10.1164/rccm.200212-1514oc] [Citation(s) in RCA: 58] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Hepatocyte growth factor (HGF) is a growth factor that protects alveolar epithelial cells from pulmonary fibrosis in various animal models. We compared in vitro HGF production by human lung fibroblasts from patients with idiopathic pulmonary fibrosis (IPF, n = 8) and from control subjects (n = 6). Basal HGF secretion by IPF fibroblasts was decreased by 50% when compared with control fibroblasts (p < 0.05). HGF was secreted mainly in the cleaved mature form, both in IPF and control fibroblasts. HGF messenger RNA levels were reduced in IPF fibroblasts. Prostaglandin (PG) E2 secretion by IPF fibroblasts was low when compared with control subjects (p < 0.05). After the addition of PGE2 (10-6 M) or dibutyryl cyclic AMP (10-3 M), HGF secretion by IPF fibroblasts reached the level of control subjects. Inhibition of PGE2 synthesis with indomethacin reduced HGF secretion by control fibroblasts but had no effect on IPF fibroblasts. HGF secretion by control fibroblasts was also slightly inhibited by transforming growth factor (TGF)-beta1 and stimulated by anti-TGF-beta antibody, whereas both agents had no effect on IPF fibroblasts. Our results demonstrate a defect in HGF production by IPF fibroblasts that seems secondary to a defect in PGE2 secretion.
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Affiliation(s)
- Sylvain Marchand-Adam
- INSERM unit 408, Faculté Xavier Bichat, Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, 16 rue Henri Huchard, 75877 Paris Cedex 18, France
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