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Cell Death in Acute Organ Injury and Fibrosis
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Cell Death in Acute Organ Injury and Fibrosis

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (5 August 2023) | Viewed by 17762

Special Issue Editors

Prof. Dr. Esteban C. Gabazza

E-Mail Website
Guest Editor
Professor and Chairman, Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu city, Mie 514-8507, Japan
Interests: cancer; tissue fibrosis; microbiome
Special Issues, Collections and Topics in MDPI journals
Dr. Taro Yasuma

E-Mail Website
Guest Editor
Department of Immunology, Faculty and Graduate School of Medicine, Mie University, Edobashi 2-174, Tsu city, Mie 514-8507, Japan
Interests: diabetes; fibrosis; T cells; apoptosis; microbiome

Special Issue Information

Dear Colleagues,

Tissue fibrosis is defined as excessive extracellular matrix deposition in any organ, including the lungs, liver, skin, kidneys, pancreas, and heart, which generally ends in organ failure. The process of fibrosis occurs due to tissue injury caused by different mechanisms, such as infection, trauma, metabolic disorders, wound, acute or chronic inflammation, autoimmune disorders, and cancer. Injury is followed by an abnormal tissue repair process characterized by the enhanced organ accumulation of fibroblasts and myofibroblasts that produce excessive extracellular matrix proteins. A variety of cells participate in the mechanism of fibrosis, including parenchymal epithelial cells, vascular endothelial cells, and cells from the innate or acquired immune systems that secrete factors that contribute to the recruitment and activation of extracellular matrix protein-producing fibroblasts. Importantly, during tissue injury and fibrosis, parenchymal cells undergo cell death, leading to the replacement of parenchymal cells by collagen-producing cells, further enhancing the fibrotic process. Cell death may occur by several mechanisms: apoptosis, necrosis, necroptosis, pyroptosis, ferroptosis, or autophagy. This Special Issue welcomes any study that evaluates the role of cell death in the pathogenesis of organ injury and fibrosis.

Prof. Dr. Esteban C. Gabazza
Dr. Taro Yasuma
Guest Editors

Manuscript Submission Information

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Keywords

  • fibrosis
  • apoptosis
  • inflammation
  • organ injury
  • cell death

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Published Papers (8 papers)

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Editorial

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3 pages, 164 KiB  
Editorial
Cell Death in Acute Organ Injury and Fibrosis
by Taro Yasuma and Esteban C. Gabazza
Int. J. Mol. Sci. 2024, 25(7), 3930; https://doi.org/10.3390/ijms25073930 - 1 Apr 2024
Cited by 1 | Viewed by 1022
Abstract
Tissue fibrosis is characterized by the excessive accumulation of extracellular matrix in various organs, including the lungs, liver, skin, kidneys, pancreas, and heart, ultimately leading to organ failure [...] Full article
(This article belongs to the Special Issue Cell Death in Acute Organ Injury and Fibrosis)

Research

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16 pages, 7924 KiB  
Article
Inhibition of the NF-κB Signaling Pathway Alleviates Pyroptosis in Bladder Epithelial Cells and Neurogenic Bladder Fibrosis
by Jing Chen, Qi Li, Yifan Hong, Xiazhu Zhou, Chengjun Yu, Xiaomao Tian, Jie Zhao, Chunlan Long, Lianju Shen, Shengde Wu and Guanghui Wei
Int. J. Mol. Sci. 2023, 24(13), 11160; https://doi.org/10.3390/ijms241311160 - 6 Jul 2023
Cited by 5 | Viewed by 2067
Abstract
Most children with a neurogenic bladder (NB) have bladder fibrosis, which causes irreversible bladder dysfunction and damage to the upper urinary tract. However, the mechanism of bladder fibrosis remains unclear. This study aimed to investigate the underlying causes of bladder fibrosis. Here, the [...] Read more.
Most children with a neurogenic bladder (NB) have bladder fibrosis, which causes irreversible bladder dysfunction and damage to the upper urinary tract. However, the mechanism of bladder fibrosis remains unclear. This study aimed to investigate the underlying causes of bladder fibrosis. Here, the lumbar 6 (L6) and sacral 1 (S1) spinal nerves of Sprague Dawley rats were severed bilaterally to establish NB models. Using RNA-seq, we discovered that the NF-κB signaling pathway and inflammation were upregulated in spinal cord injury (SCI)-induced bladder fibrosis. Subsequent Western blotting, enzyme-linked immunosorbent assays, immunohistochemical staining, and immunofluorescence staining verified the RNA-seq findings. To further clarify whether the NF-κB signaling pathway and pyroptosis were involved in bladder fibrosis, a TGF-β1-treated urinary epithelial cell line (SV-HUC-1 cells) was used as an in vitro model. Based on the results of RNA-seq, we consistently found that the NF-κB signaling pathway and pyroptosis might play important roles in TGF-β1-treated cells. Further experiments also confirmed the RNA-seq findings in vitro. Moreover, using the NLRP3 inhibitor MCC950 rescued TGF-β1-induced fibrosis, and the NF-κB signaling pathway inhibitor BAY 11-7082 effectively rescued TGF-β1-induced pyroptosis and the deposition of extracellular matrix by SV-HUC-1 cells. In summary, our research demonstrated for the first time that the NF-κB signaling pathway inhibition rescued bladder epithelial cells pyroptosis and fibrosis in neurogenic bladders. Full article
(This article belongs to the Special Issue Cell Death in Acute Organ Injury and Fibrosis)
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24 pages, 58044 KiB  
Article
Amelioration of Pulmonary Fibrosis by Matrix Metalloproteinase-2 Overexpression
by Ryo Inoue, Taro Yasuma, Valeria Fridman D’Alessandro, Masaaki Toda, Toshiyuki Ito, Atsushi Tomaru, Corina N. D’Alessandro-Gabazza, Tatsuki Tsuruga, Tomohito Okano, Atsuro Takeshita, Kota Nishihama, Hajime Fujimoto, Tetsu Kobayashi and Esteban C. Gabazza
Int. J. Mol. Sci. 2023, 24(7), 6695; https://doi.org/10.3390/ijms24076695 - 3 Apr 2023
Cited by 10 | Viewed by 2229
Abstract
Idiopathic pulmonary fibrosis is a progressive and fatal disease with a poor prognosis. Matrix metalloproteinase-2 is involved in the pathogenesis of organ fibrosis. The role of matrix metalloproteinase-2 in lung fibrosis is unclear. This study evaluated whether overexpression of matrix metalloproteinase-2 affects the [...] Read more.
Idiopathic pulmonary fibrosis is a progressive and fatal disease with a poor prognosis. Matrix metalloproteinase-2 is involved in the pathogenesis of organ fibrosis. The role of matrix metalloproteinase-2 in lung fibrosis is unclear. This study evaluated whether overexpression of matrix metalloproteinase-2 affects the development of pulmonary fibrosis. Lung fibrosis was induced by bleomycin in wild-type mice and transgenic mice overexpressing human matrix metalloproteinase-2. Mice expressing human matrix metalloproteinase-2 showed significantly decreased infiltration of inflammatory cells and inflammatory and fibrotic cytokines in the lungs compared to wild-type mice after induction of lung injury and fibrosis with bleomycin. The computed tomography score, Ashcroft score of fibrosis, and lung collagen deposition were significantly reduced in human matrix metalloproteinase transgenic mice compared to wild-type mice. The expression of anti-apoptotic genes was significantly increased, while caspase-3 activity was significantly reduced in the lungs of matrix metalloproteinase-2 transgenic mice compared to wild-type mice. Active matrix metalloproteinase-2 significantly decreased bleomycin-induced apoptosis in alveolar epithelial cells. Matrix metalloproteinase-2 appears to protect against pulmonary fibrosis by inhibiting apoptosis of lung epithelial cells. Full article
(This article belongs to the Special Issue Cell Death in Acute Organ Injury and Fibrosis)
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19 pages, 4533 KiB  
Article
Selective CB2 Receptor Agonist, HU-308, Reduces Systemic Inflammation in Endotoxin Model of Pneumonia-Induced Acute Lung Injury
by Stefan Hall, Sufyan Faridi, Purvi Trivedi, Saki Sultana, Bithika Ray, Tanya Myers, Irene Euodia, David Vlatten, Mathieu Castonguay, Juan Zhou, Melanie Kelly and Christian Lehmann
Int. J. Mol. Sci. 2022, 23(24), 15857; https://doi.org/10.3390/ijms232415857 - 13 Dec 2022
Cited by 7 | Viewed by 2685
Abstract
Acute respiratory distress syndrome (ARDS) and sepsis are risk factors contributing to mortality in patients with pneumonia. In ARDS, also termed acute lung injury (ALI), pulmonary immune responses lead to excessive pro-inflammatory cytokine release and aberrant alveolar neutrophil infiltration. Systemic spread of cytokines [...] Read more.
Acute respiratory distress syndrome (ARDS) and sepsis are risk factors contributing to mortality in patients with pneumonia. In ARDS, also termed acute lung injury (ALI), pulmonary immune responses lead to excessive pro-inflammatory cytokine release and aberrant alveolar neutrophil infiltration. Systemic spread of cytokines is associated with systemic complications including sepsis, multi-organ failure, and death. Thus, dampening pro-inflammatory cytokine release is a viable strategy to improve outcome. Activation of cannabinoid type II receptor (CB2) has been shown to reduce cytokine release in various in vivo and in vitro studies. Herein, we investigated the effect of HU-308, a specific CB2 agonist, on systemic and pulmonary inflammation in a model of pneumonia-induced ALI. C57Bl/6 mice received intranasal endotoxin or saline, followed by intravenous HU-308, dexamethasone, or vehicle. ALI was scored by histology and plasma levels of select inflammatory mediators were assessed by Luminex assay. Intravital microscopy (IVM) was performed to assess leukocyte adhesion and capillary perfusion in intestinal and pulmonary microcirculation. HU-308 and dexamethasone attenuated LPS-induced cytokine release and intestinal microcirculatory impairment. HU-308 modestly reduced ALI score, while dexamethasone abolished it. These results suggest administration of HU-308 can reduce systemic inflammation without suppressing pulmonary immune response in pneumonia-induced ALI and systemic inflammation. Full article
(This article belongs to the Special Issue Cell Death in Acute Organ Injury and Fibrosis)
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11 pages, 2728 KiB  
Article
Reduced Elastin Fibers and Melanocyte Loss in Vitiliginous Skin Are Restored after Repigmentation by Phototherapy and/or Autologous Minigraft Transplantation
by Tomohisa Hirobe and Hisao Enami
Int. J. Mol. Sci. 2022, 23(23), 15361; https://doi.org/10.3390/ijms232315361 - 6 Dec 2022
Cited by 6 | Viewed by 1894
Abstract
Vitiligo is a hypopigmentation disease characterized by melanocyte death in the human epidermis. However, the mechanism of vitiligo development and repigmentation is largely unknown. Dermal fiber components might play an important role in vitiligo development and repigmentation. Indeed, our preliminary study demonstrated that [...] Read more.
Vitiligo is a hypopigmentation disease characterized by melanocyte death in the human epidermis. However, the mechanism of vitiligo development and repigmentation is largely unknown. Dermal fiber components might play an important role in vitiligo development and repigmentation. Indeed, our preliminary study demonstrated that elastin fibers were decreased in vitiliginous skin, suggesting that the elastin fiber is one of the factors involved in vitiligo development and repigmentation. To confirm our hypothesis, we investigated whether elastin fibers can be restored after treatment using phototherapy and/or autologous skin transplantation. Punch biopsies from 14 patients of stable nonsegmental vitiligo vulgaris were collected from nonlesional, lesional, and repigmented skin, and processed to dopa and combined dopa–premelanin reactions. Melanocytes positive to the dopa reaction and melanoblasts/melanocytes positive to the combined dopa–premelanin reaction were surveyed. Moreover, elastin fibers were detected by Victoria blue staining. Numerous melanocytes and melanoblasts were observed in the epidermis of repigmented skin after the treatment. Moreover, in the dermis of repigmented skin, elastin fibers were completely recovered or even upregulated. These results suggest that melanocyte loss in the vitiliginous skin, as well as melanocyte differentiation in repigmented skin, may be at least in part regulated by elastin fibers in the dermis. Full article
(This article belongs to the Special Issue Cell Death in Acute Organ Injury and Fibrosis)
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19 pages, 4016 KiB  
Communication
Transforming Growth Factorβ1 Overexpression Is Associated with Insulin Resistance and Rapidly Progressive Kidney Fibrosis under Diabetic Conditions
by Valeria Fridman D’Alessandro, Atsuro Takeshita, Taro Yasuma, Masaaki Toda, Corina N. D’Alessandro-Gabazza, Yuko Okano, Suphachai Tharavecharak, Chisa Inoue, Kota Nishihama, Hajime Fujimoto, Tetsu Kobayashi, Yutaka Yano and Esteban C. Gabazza
Int. J. Mol. Sci. 2022, 23(22), 14265; https://doi.org/10.3390/ijms232214265 - 17 Nov 2022
Cited by 2 | Viewed by 1627
Abstract
Diabetes mellitus is a global health problem. Diabetic nephropathy is a common complication of diabetes mellitus and the leading cause of end-stage renal disease. The clinical course, response to therapy, and prognosis of nephropathy are worse in diabetic than in non-diabetic patients. The [...] Read more.
Diabetes mellitus is a global health problem. Diabetic nephropathy is a common complication of diabetes mellitus and the leading cause of end-stage renal disease. The clinical course, response to therapy, and prognosis of nephropathy are worse in diabetic than in non-diabetic patients. The role of transforming growth factorβ1 in kidney fibrosis is undebatable. This study assessed whether the overexpression of transforming growth factorβ1 is associated with insulin resistance and the rapid progression of transforming growth factorβ1-mediated nephropathy under diabetic conditions. Diabetes mellitus was induced with streptozotocin in wild-type mice and transgenic mice with the kidney-specific overexpression of human transforming growth factorβ1. Mice treated with saline were the controls. Glucose tolerance and kidney fibrosis were evaluated. The blood glucose levels, the values of the homeostasis model assessment for insulin resistance, and the area of kidney fibrosis were significantly increased, and the renal function was significantly impaired in the diabetic transforming growth factorβ1 transgenic mice compared to the non-diabetic transgenic mice, diabetic wild-type mice, and non-diabetic mice. Transforming growth factorβ1 impaired the regulatory effect of insulin on glucose in the hepatocyte and skeletal muscle cell lines. This study shows that transforming growth factorβ1 overexpression is associated with insulin resistance and rapidly progressive kidney fibrosis under diabetic conditions in mice. Full article
(This article belongs to the Special Issue Cell Death in Acute Organ Injury and Fibrosis)
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18 pages, 49460 KiB  
Article
Mechano Growth Factor Accelerates ACL Repair and Improves Cell Mobility of Mechanically Injured Human ACL Fibroblasts by Targeting Rac1-PAK1/2 and RhoA-ROCK1 Pathways
by Yongqiang Sha, Beibei Zhang, Liping Chen, Huhai Hong and Qingjia Chi
Int. J. Mol. Sci. 2022, 23(8), 4331; https://doi.org/10.3390/ijms23084331 - 14 Apr 2022
Cited by 7 | Viewed by 2526
Abstract
Exceeded mechanical stress leads to a sublethal injury to anterior cruciate ligament (ACL) fibroblasts, and it will hinder cell mobility and ACL regeneration, and even induce osteoarthritis. The mechano growth factor (MGF) could be responsible for mechanical stress and weakening its negative effects [...] Read more.
Exceeded mechanical stress leads to a sublethal injury to anterior cruciate ligament (ACL) fibroblasts, and it will hinder cell mobility and ACL regeneration, and even induce osteoarthritis. The mechano growth factor (MGF) could be responsible for mechanical stress and weakening its negative effects on cell physiological behaviors. In this study, effects of MGF on cell mobility and relevant molecules expression in injured ACL fibroblasts were detected. After an injurious mechanical stretch, the analysis carried out, at 0 and 24 h, respectively, showed that the cell area, roundness, migration, and adhesion of ACL fibroblasts were reduced. MGF (10, 100 ng/mL) treatment could improve cell area, roundness and promote cell migration and adhesion capacity compared with the injured group without MGF. Further study indicated that cell mobility-relevant molecules (PAK1/2, Cdc42, Rac1, RhoA, and ROCK1) expression in ACL fibroblasts was down-regulated at 0 or 24 h after injurious stretch (except Rac1 and RhoA at 0 h). Similarly, MGF improved cell mobility-relevant molecule expression, especially the ROCK1 expression level in ACL fibroblasts at 0 or 24 h after injurious stretch. Protein expression of ROCK1 in injured ACL fibroblasts was also reduced and could be recovered by MGF treatment. In a rabbit partial ACL transection (ACLT) model, ACL exhibited poor regenerative capacity in collagen and extracellular matrix (ECM) synthesis after partial ACLT for 2 or 4 weeks, and MGF remarkably accelerated ACL regeneration and restored its mechanical loading capacity after partial ACLT for four weeks. Our findings suggest that MGF weakens the effects of pathological stress on cell mobility of ACL fibroblasts and accelerates ACL repair, and might be applied as a future treatment approach to ACL rupture in the clinic. Full article
(This article belongs to the Special Issue Cell Death in Acute Organ Injury and Fibrosis)
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Review

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21 pages, 1539 KiB  
Review
Pathological Roles of Pulmonary Cells in Acute Lung Injury: Lessons from Clinical Practice
by Noriyuki Enomoto
Int. J. Mol. Sci. 2022, 23(23), 15027; https://doi.org/10.3390/ijms232315027 - 30 Nov 2022
Cited by 5 | Viewed by 2958
Abstract
Interstitial lung diseases (ILD) are relatively rare and sometimes become life threatening. In particular, rapidly progressive ILD, which frequently presents as acute lung injury (ALI) on lung histopathology, shows poor prognosis if proper and immediate treatments are not initiated. These devastating conditions include [...] Read more.
Interstitial lung diseases (ILD) are relatively rare and sometimes become life threatening. In particular, rapidly progressive ILD, which frequently presents as acute lung injury (ALI) on lung histopathology, shows poor prognosis if proper and immediate treatments are not initiated. These devastating conditions include acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), clinically amyopathic dermatomyositis (CADM), epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI)-induced lung injury, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) infection named coronavirus disease 2019 (COVID-19). In this review, clinical information, physical findings, laboratory examinations, and findings on lung high-resolution computed tomography and lung histopathology are presented, focusing on majorly damaged cells in each disease. Furthermore, treatments that should be immediately initiated in clinical practice for each disease are illustrated to save patients with these diseases. Full article
(This article belongs to the Special Issue Cell Death in Acute Organ Injury and Fibrosis)
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