scholarly journals Radiation-induced lung toxicity – cellular and molecular mechanisms of pathogenesis, management, and literature review

2020 ◽  
Vol 15 (1) ◽  
Author(s):  
Lukas Käsmann ◽  
Alexander Dietrich ◽  
Claudia A. Staab-Weijnitz ◽  
Farkhad Manapov ◽  
Jürgen Behr ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Patient Outcomes ◽  
Lung Fibrosis ◽  
Major Part ◽  
Molecular Mechanisms ◽  
Limiting Factors ◽  
Incidence And Mortality ◽  
High Incidence ◽  
Radiation Induced

Abstract Lung, breast, and esophageal cancer represent three common malignancies with high incidence and mortality worldwide. The management of these tumors critically relies on radiotherapy as a major part of multi-modality care, and treatment-related toxicities, such as radiation-induced pneumonitis and/or lung fibrosis, are important dose limiting factors with direct impact on patient outcomes and quality of life. In this review, we summarize the current understanding of radiation-induced pneumonitis and pulmonary fibrosis, present predictive factors as well as recent diagnostic and therapeutic advances. Novel candidates for molecularly targeted approaches to prevent and/or treat radiation-induced pneumonitis and pulmonary fibrosis are discussed.

scholarly journals Anti-fibrosis effect for Hirsutella sinensis mycelium based on inhibition of mTOR p70S6K phosphorylation

2017 ◽  
Vol 23 (7) ◽  
pp. 615-624 ◽  
Author(s):  
Huimin Yue ◽  
Yarong Zhao ◽  
Haining Wang ◽  
Feiya Ma ◽  
Fei Liu ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Molecular Mechanisms ◽  
Histopathological Examination ◽  
Smooth Muscle Actin ◽  
A549 Cells ◽  
Mtor Pathway ◽  
Cordyceps Sinensis ◽  
Tgf Β1

Hirsutella sinensis, cultured in vitro, is an attractive substitute for Cordyceps sinensis as health supplement. The aim of this study was to demonstrate whether H. sinensis mycelium (HSM) attenuates murine pulmonary fibrosis induced by bleomycin and to explore the underlying molecular mechanisms. Using lung fibrosis modle induced by intratracheal instillation of bleomycin (BLM; 4 mg/kg), we observed that the administration of HSM reduced HYP, TGF-β1 and the production of several pro-fibrosis cytokines (α-smooth muscle actin, fibronectin and vimentin) in fibrotic mice lung sections. Histopathological examination of lung tissues also demonstrated that HSM improved BLM-induced pathological damage. Concurrently, HSM supplementation markedly reduced the chemotaxis of alveolar macrophages and potently suppressed the expression of inflammatory cytokines. Also, HSM influenced Th1/Th2 and Th17/Treg imbalance and blocked the phosphorylation of mTOR pathway in vivo. Alveolar epithelial A549 cells acquired a mesenchymal phenotype and an increased expression of myofibroblast markers of differentiation (vimentin and fibronectin) after treatment with TGF-β1. HSM suppressed these markers and blocked the phosphorylation of mTOR pathway in vitro. The results provide evidence supporting the use of HSM in the intervention of pulmonary fibrosis and suggest that HSM is a potential therapeutic agent for lung fibrosis.

Proffered Paper: Radiation-induced lung fibrosis: from molecular mechanisms to novel treatment concepts

2016 ◽  
Vol 61 ◽  
pp. S5
Author(s):  
F. Wirsdörfer ◽  
S. De Leve ◽  
F. Cappuccini ◽  
A.V. Meyer ◽  
L.F. Thompson ◽  
...  
Keyword(s):  
Lung Fibrosis ◽  
Molecular Mechanisms ◽  
Novel Treatment ◽  
Radiation Induced ◽  
Treatment Concepts

scholarly journals Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis

2005 ◽  
Vol 201 (6) ◽  
pp. 925-935 ◽  
Author(s):  
Amir Abdollahi ◽  
Minglun Li ◽  
Gong Ping ◽  
Christian Plathow ◽  
Sophie Domhan ◽  
...  
Keyword(s):  
Growth Factor ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Kinase Inhibitors ◽  
Platelet Derived Growth Factor ◽  
Growth Factor Signaling ◽  
Pdgf Receptor ◽  
Pdgf Signaling ◽  
Radiation Induced

Pulmonary fibrosis is the consequence of a variety of diseases with no satisfying treatment option. Therapy-induced fibrosis also limits the efficacy of chemotherapy and radiotherapy in numerous cancers. Here, we studied the potential of platelet-derived growth factor (PDGF) receptor tyrosine kinase inhibitors (RTKIs) to attenuate radiation-induced pulmonary fibrosis. Thoraces of C57BL/6 mice were irradiated (20 Gy), and mice were treated with three distinct PDGF RTKIs (SU9518, SU11657, or Imatinib). Irradiation was found to induce severe lung fibrosis resulting in dramatically reduced mouse survival. Treatment with PDGF RTKIs markedly attenuated the development of pulmonary fibrosis in excellent correlation with clinical, histological, and computed tomography results. Importantly, RTKIs also prolonged the life span of irradiated mice. We found that radiation up-regulated expression of PDGF (A–D) isoforms leading to phosphorylation of PDGF receptor, which was strongly inhibited by RTKIs. Our findings suggest a pivotal role of PDGF signaling in the pathogenesis of pulmonary fibrosis and indicate that inhibition of fibrogenesis, rather than inflammation, is critical to antifibrotic treatment. This study points the way to a potential new approach for treating idiopathic or therapy-related forms of lung fibrosis.

scholarly journals Promising Biomarkers of Radiation-Induced Lung Injury: A Review

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1181
Author(s):  
Xinglong Liu ◽  
Chunlin Shao ◽  
Jiamei Fu
Keyword(s):  
Lung Injury ◽  
Molecular Mechanisms ◽  
Tumor Treatment ◽  
Risk Models ◽  
Thoracic Cancer ◽  
Clinical Background ◽  
Radiation Induced ◽  
Precise Prediction ◽  
Preclinical Animal Models

Radiation-induced lung injury (RILI) is one of the main dose-limiting side effects in patients with thoracic cancer during radiotherapy. No reliable predictors or accurate risk models are currently available in clinical practice. Severe radiation pneumonitis (RP) or pulmonary fibrosis (PF) will reduce the quality of life, even when the anti-tumor treatment is effective for patients. Thus, precise prediction and early diagnosis of lung toxicity are critical to overcome this longstanding problem. This review summarizes the primary mechanisms and preclinical animal models of RILI reported in recent decades, and analyzes the most promising biomarkers for the early detection of lung complications. In general, ideal integrated models considering individual genetic susceptibility, clinical background parameters, and biological variations are encouraged to be built up, and more prospective investigations are still required to disclose the molecular mechanisms of RILI as well as to discover valuable intervention strategies.

scholarly journals Scarred Lung. An Update on Radiation-Induced Pulmonary Fibrosis

2021 ◽  
Vol 7 ◽  
Author(s):  
Natalia Jarzebska ◽  
Ekaterina S. Karetnikova ◽  
Alexander G. Markov ◽  
Michael Kasper ◽  
Roman N. Rodionov ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Pulmonary Fibrosis ◽  
Lung Fibrosis ◽  
Treatment Options ◽  
Inflammatory Cells ◽  
Oxygen Species ◽  
Current State ◽  
Complex Process ◽  
Long Time ◽  
Radiation Induced

Radiation-induced pulmonary fibrosis is a common severe long-time complication of radiation therapy for tumors of the thorax. Current therapeutic options used in the clinic include only supportive managements strategies, such as anti-inflammatory treatment using steroids, their efficacy, however, is far from being satisfactory. Recent studies have demonstrated that the development of lung fibrosis is a dynamic and complex process, involving the release of reactive oxygen species, activation of Toll-like receptors, recruitment of inflammatory cells, excessive production of nitric oxide and production of collagen by activated myofibroblasts. In this review we summarized the current state of knowledge on the pathophysiological processes leading to the development of lung fibrosis and we also discussed the possible treatment options.

scholarly journals The Role of Mesenchymal Stem Cells in Radiation-Induced Lung Fibrosis

2019 ◽  
Vol 20 (16) ◽  
pp. 3876 ◽  
Author(s):  
Zanoni ◽  
Cortesi ◽  
Zamagni ◽  
Tesei
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Lung Fibrosis ◽  
Tissue Repair ◽  
Molecular Mechanisms ◽  
Acute Stage ◽  
Lung Epithelial Cells ◽  
Treatment Modalities ◽  
Tissue Repair And Regeneration ◽  
Radiation Induced

Radiation therapy is one of the most important treatment modalities for thoracic tumors. Despite significant advances in radiation techniques, radiation-induced lung injury (RILI) still occurs in up to 30% of patients undergoing thoracic radiotherapy, and therefore remains the main dose-limiting obstacle. RILI is a potentially lethal clinical complication of radiotherapy that has 2 main stages: an acute stage defined as radiation pneumonitis, and a late stage defined as radiation-induced lung fibrosis. Patients who develop lung fibrosis have a reduced quality of life with progressive and irreversible organ malfunction. Currently, the most effective intervention for the treatment of lung fibrosis is lung transplantation, but the lack of available lungs and transplantation-related complications severely limits the success of this procedure. Over the last few decades, advances have been reported in the use of mesenchymal stem cells (MSCs) for lung tissue repair and regeneration. MSCs not only replace damaged lung epithelial cells but also promote tissue repair through the secretion of anti-inflammatory and anti-fibrotic factors. Here, we present an overview of MSC-based therapy for radiation-induced lung fibrosis, focusing in particular on the molecular mechanisms involved and describing the most recent preclinical and clinical studies carried out in the field.

scholarly journals Lipid Mediators Regulate Pulmonary Fibrosis: Potential Mechanisms and Signaling Pathways

2020 ◽  
Vol 21 (12) ◽  
pp. 4257 ◽  
Author(s):  
Vidyani Suryadevara ◽  
Ramaswamy Ramchandran ◽  
David W. Kamp ◽  
Viswanathan Natarajan
Keyword(s):  
Pulmonary Fibrosis ◽  
Signaling Pathways ◽  
Lung Fibrosis ◽  
Molecular Mechanisms ◽  
Cell Types ◽  
Lipid Mediators ◽  
Alveolar Epithelial Cells ◽  
Sphingolipid Metabolism ◽  
Unknown Etiology ◽  
Preclinical Animal Models

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. The molecular mechanisms involved in the pathophysiology of IPF are incompletely defined. Several lung cell types including alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells have been implicated in the development and progression of fibrosis. Regardless of the cell types involved, changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast, deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis. Lipid mediators derived from phospholipids, sphingolipids, and polyunsaturated fatty acids play an important role in the pathogenesis of pulmonary fibrosis and have been described to exhibit pro- and anti-fibrotic effects in IPF and in preclinical animal models of lung fibrosis. This review describes the current understanding of the role and signaling pathways of prostanoids, lysophospholipids, and sphingolipids and their metabolizing enzymes in the development of lung fibrosis. Further, several of the lipid mediators and enzymes involved in their metabolism are therapeutic targets for drug development to treat IPF.

scholarly journals Cellular Senescence: Pathogenic Mechanisms in Lung Fibrosis

2021 ◽  
Author(s):  
Tanyalak Parimon ◽  
Miriam Hohmann ◽  
Changfu Yao
Keyword(s):  
Pulmonary Fibrosis ◽  
Cellular Senescence ◽  
Lung Fibrosis ◽  
Molecular Mechanisms ◽  
Current Knowledge ◽  
Alveolar Type ◽  
Basal Cells ◽  
Regulatory Pathways ◽  
Pathogenic Mechanisms

:Pulmonary fibrosis is a chronic and fatal lung disease that significantly impacts the aging population globally. To date, anti-fibrotic, immunosuppressive, and other adjunct therapy demonstrate a limited efficacy. Advancing our understanding of pathogenic mechanisms of lung fibrosis provides a future path for the cure. Cellular senescence has gained substantial interest in the past decades due to the increased incidence of fibroproliferative lung diseases in the older age group. Furthermore, the pathologic state of cellular senescence that includes maladaptive tissue repair, decreased regeneration, and chronic inflammation resembles key features of progressive lung fibrosis. This review describes regulatory pathways of cellular senescence and discusses the current knowledge on the senescence of critical cellular players of lung fibrosis, including epithelial cells (alveolar type 2 cells, basal cells, etc.), fibroblasts, and immune cells, their phenotypic changes, and the cellular and molecular mechanisms by which these cells contribute to the pathogenesis of pulmonary fibrosis. A few challenges in the field include establishing appropriate in vivo experimental models and identifying senescence targeted signaling molecules and specific therapy to target senescent cells, known collectively as "senolytic" or “senotherapeutic” agents.

How to improve the overall quality of cardiac morphometric data

2015 ◽  
Vol 309 (1) ◽  
pp. H9-H14 ◽  
Author(s):  
A. Martin Gerdes
Keyword(s):  
Cardiac Remodeling ◽  
Molecular Mechanisms ◽  
Cardiac Tissue ◽  
Ventricular Remodeling ◽  
Morphological Changes ◽  
National Institutes Of Health ◽  
Morphological Data ◽  
Quantitative Morphology ◽  
High Incidence

By the mid-1990s, experts realized that drugs leading to improved ventricular remodeling were doing something remarkable in cardiac patients. The “age of cardiac remodeling” had begun. This created an experimental need for high-quality assessment of changes in cardiac tissue composition, including myocyte shape, myocardial fibrosis/collagen, and vascular remodeling. Many working in the field today have little or no training related to recognition of fixation artifacts or common errors associated with quantitative morphology. Unfortunately, such skills had become somewhat of a lost art during the ages of cardiac physiology in the mid-20th century and molecular biology, gaining prominence by the mid-1970s. Consequently, cardiac remodeling studies today are often seriously flawed to the point where data are not reproducible and subsequent researchers may be chasing the molecular basis of a nonexistent or erroneous phenotype. The current unacceptably high incidence of irreproducible data is a serious waste of time and resources as recently noted in comments by the National Institutes of Health director. The goal of this “how to” article is to share some lessons I have learned during nearly 40 years of assessing morphological changes in the heart. It is possible for any laboratory to routinely publish highly reproducible morphological data that stand the test of time and contribute to our fundamental knowledge of cardiac remodeling and the molecular mechanisms that drive it.

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