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Biomedicine & Pharmacotherapy =... Jul 2020Src family kinases (SFKs) is a non-receptor protein tyrosine kinases family. They are crucial in signal transduction and regulation of various cell biological processes,... (Review)
Review
Src family kinases (SFKs) is a non-receptor protein tyrosine kinases family. They are crucial in signal transduction and regulation of various cell biological processes, such as proliferation, differentiation and apoptosis. The role and mechanism of SFKs in tumorigenesis have been widely studied. However, more and more studies have also shown that SFKs are involved in the pathogenesis of pulmonary fibrosis (PF). Myofibroblasts activation, epithelial-mesenchymal transition and inflammation response are three pivotal pathomechanisms in the development of pulmonary fibrotic disease. In this article, we summarize the roles of SFKs in these biological processes. SFKs play a crucial role in the pathogenesis of PF, making it a promising molecular target for the treatment of these diseases. We will pay special attention to the role of SFKs in idiopathic pulmonary fibrosis (IPF), and also emphasize the important findings in other pulmonary fibrotic diseases because their pathological mechanisms are similar. We will then describe the translation results obtained with SFKs inhibitors in basic and clinical studies.
Topics: Animals; Epithelial-Mesenchymal Transition; Humans; Idiopathic Pulmonary Fibrosis; Inflammation; Molecular Targeted Therapy; Myofibroblasts; Pulmonary Fibrosis; Signal Transduction; src-Family Kinases
PubMed: 32388241
DOI: 10.1016/j.biopha.2020.110183 -
Seminars in Radiation Oncology Apr 2021Radiation-induced lung injury encompasses radiation-induced pneumonitis, inflammation of the lung which may manifest as a dose-limiting acute or subacute toxicity, and... (Review)
Review
Radiation-induced lung injury encompasses radiation-induced pneumonitis, inflammation of the lung which may manifest as a dose-limiting acute or subacute toxicity, and radiation-induced lung fibrosis, a late effect of lung exposure to radiation. This review aims to highlight developments in molecular radiation biology of radiation-induced lung injury and their implications in clinical practice.
Topics: Humans; Lung; Lung Injury; Pulmonary Fibrosis; Radiation Pneumonitis; Radiobiology
PubMed: 33610273
DOI: 10.1016/j.semradonc.2020.11.006 -
Respiratory Research Nov 2020Pulmonary hypertension (PH) developing secondarily in pulmonary fibrosis (PF) patients (PF-PH) is a frequent co-morbidity. The high prevalence of PH in PF patients is... (Review)
Review
Pulmonary hypertension (PH) developing secondarily in pulmonary fibrosis (PF) patients (PF-PH) is a frequent co-morbidity. The high prevalence of PH in PF patients is very concerning since the presence of PH is a strong predictor of mortality in PF patients. Until recently, PH was thought to arise solely from fibrotic destruction of the lung parenchyma, leading to hypoxic vasoconstriction and loss of vascular bed density. Thus, potential cellular and molecular dysregulation of vascular remodeling as a driver of PF-PH has been under-investigated. The recent demonstrations that there is no correlation between the severity of the fibrosis and development of PH, along with the finding that significant vascular histological and molecular differences exist between patients with and without PH have shifted the etiological paradigm of PF-PH. This review aims to provide a comprehensive translational overview of PH in PF patients from clinical diagnosis and outcome to the latest understanding of the histology and molecular pathophysiology of PF-PH.
Topics: Animals; Echocardiography; Humans; Hypertension, Pulmonary; Inflammation Mediators; Lung; Pulmonary Fibrosis; Respiratory Function Tests; Vascular Remodeling
PubMed: 33208169
DOI: 10.1186/s12931-020-01570-2 -
Human Genomics Jun 2022The increased resolution of single-cell RNA-sequencing technologies has led to major breakthroughs and improved our understanding of the normal and pathologic conditions... (Review)
Review
The increased resolution of single-cell RNA-sequencing technologies has led to major breakthroughs and improved our understanding of the normal and pathologic conditions of multiple tissues and organs. In the study of parenchymal lung disease, single-cell RNA-sequencing has better delineated known cell populations and identified novel cells and changes in cellular phenotypes and gene expression patterns associated with disease. In this review, we aim to highlight the advances and insights that have been made possible by applying these technologies to two seemingly very different lung diseases: fibrotic interstitial lung diseases, a group of relentlessly progressive lung diseases leading to pulmonary fibrosis, and COVID-19 pneumonia, an acute viral disease with life-threatening complications, including pulmonary fibrosis. We discuss changes in cell populations and gene expression, highlighting potential common features, such as alveolar cell epithelial injury and aberrant repair and monocyte-derived macrophage populations, as well as relevance and implications to mechanisms of disease and future directions.
Topics: COVID-19; Humans; Lung; Pulmonary Fibrosis; RNA; Single-Cell Analysis
PubMed: 35698166
DOI: 10.1186/s40246-022-00393-0 -
Toxicology and Applied Pharmacology Dec 2020Pulmonary fibrosis is characterized by destruction and remodeling of the lung due to an accumulation of collagen and other extracellular matrix components in the tissue.... (Review)
Review
Pulmonary fibrosis is characterized by destruction and remodeling of the lung due to an accumulation of collagen and other extracellular matrix components in the tissue. This results in progressive irreversible decreases in lung capacity, impaired gas exchange and eventually, hypoxemia. A number of inhaled and systemic toxicants including bleomycin, silica, asbestos, nanoparticles, mustard vesicants, nitrofurantoin, amiodarone, and ionizing radiation have been identified. In this article, we review the role of innate and adaptive immune cells and mediators they release in the pathogenesis of fibrotic pathologies induced by pulmonary toxicants. A better understanding of the pathogenic mechanisms underlying fibrogenesis may lead to the development of new therapeutic approaches for patients with these debilitating and largely irreversible chronic diseases.
Topics: Adaptive Immunity; Animals; Chronic Disease; Hazardous Substances; Humans; Immunity, Innate; Lung; Pulmonary Fibrosis
PubMed: 33031836
DOI: 10.1016/j.taap.2020.115272 -
Matrix Metalloproteinases and Their Inhibitors in Pulmonary Fibrosis: EMMPRIN/CD147 Comes into Play.International Journal of Molecular... Jun 2022Pulmonary fibrosis (PF) is characterized by aberrant extracellular matrix (ECM) deposition, activation of fibroblasts to myofibroblasts and parenchymal disorganization,... (Review)
Review
Pulmonary fibrosis (PF) is characterized by aberrant extracellular matrix (ECM) deposition, activation of fibroblasts to myofibroblasts and parenchymal disorganization, which have an impact on the biomechanical traits of the lung. In this context, the balance between matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs) is lost. Interestingly, several MMPs are overexpressed during PF and exhibit a clear profibrotic role (MMP-2, -3, -8, -11, -12 and -28), but a few are antifibrotic (MMP-19), have both profibrotic and antifibrotic capacity (MMP7), or execute an unclear (MMP-1, -9, -10, -13, -14) or unknown function. TIMPs are also overexpressed in PF; hence, the modulation and function of MMPs and TIMP are more complex than expected. EMMPRIN/CD147 (also known as basigin) is a transmembrane glycoprotein from the immunoglobulin superfamily (IgSF) that was first described to induce MMP activity in fibroblasts. It also interacts with other molecules to execute non-related MMP aactions well-described in cancer progression, migration, and invasion. Emerging evidence strongly suggests that CD147 plays a key role in PF not only by MMP induction but also by stimulating fibroblast myofibroblast transition. In this review, we study the structure and function of MMPs, TIMPs and CD147 in PF and their complex crosstalk between them.
Topics: Basigin; Extracellular Matrix; Humans; Matrix Metalloproteinases; Pulmonary Fibrosis; Tissue Inhibitor of Metalloproteinases
PubMed: 35805895
DOI: 10.3390/ijms23136894 -
Immunity, Inflammation and Disease Nov 2023Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating lung disease characterized by irreversible scarring of the lungs. The cause of IPF is unknown, but... (Review)
Review
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) is a progressive and debilitating lung disease characterized by irreversible scarring of the lungs. The cause of IPF is unknown, but it is thought to involve a combination of genetic and environmental factors. There is no cure for IPF, and treatment is focused on slowing disease progression and relieving symptoms.
AIMS
We aimed in this review to investigate and provide the latest insights into IPF management modalities, including the potential of Saracatinibas a substitute for current IPF drugs. We also investigated the therapeutic potential of Sotatercept in addressing pulmonary hypertension associated with IPF.
MATERIALS AND METHODS
We conducted a comprehensive literature review of relevant studies on IPF management. We searched electronic databases, including PubMed, Scopus, Embase, and Web of science.
RESULTS
The two Food and Drug Administration-approved drugs for IPF, Pirfenidone, and Nintedanib, have been pivotal in slowing disease progression, yet experimental evidence suggests that Saracatinib surpasses their efficacy. Preclinical trials investigating the potential of Saracatinib, a tyrosine kinase inhibitor, have shown to be more effective than current IPF drugs in slowing disease progression in preclinical studies. Also, Sotatercept,a fusion protein, has been shown to reduce pulmonary vascular resistance and improve exercise tolerance in patients with PH associated with IPF in clinical trials.
CONCLUSIONS
The advancements discussed in this review hold the promise of improving the quality of life for IPF patients and enhancing our understanding of this condition. There remains a need for further research to confirm the efficacy and safety of new IPF treatments and to develop more effective strategies for managing exacerbations.
Topics: United States; Humans; Hypertension, Pulmonary; Quality of Life; Idiopathic Pulmonary Fibrosis; Disease Progression
PubMed: 38018591
DOI: 10.1002/iid3.1079 -
Seminars in Cell & Developmental Biology May 2020Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease characterized by progressive scarring of the lung tissue, leading to respiratory failure. There is no... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a fatal chronic lung disease characterized by progressive scarring of the lung tissue, leading to respiratory failure. There is no cure for IPF, and current anti-fibrotic treatments modestly arrest its further progression. IPF prevalence and incidence increase with age, which is a recognized risk factor. Intense clinical and basic research over the last fifteen years has shown that hallmarks of accelerated aging are present in the lungs of patients with IPF. Different cell types in IPF lungs exhibit premature hallmarks of aging, including telomere attrition and cellular senescence. In this Review, we discuss recent insights into the mechanisms behind these age-related alterations and their contribution to the development of lung fibrosis. We focus on the genetic and molecular basis of telomere attrition in alveolar type II epithelial cells, which promote cellular senescence and lung fibrosis. Mechanistically, senescent cells secrete pro-fibrotic factors that activate scar-forming myofibroblasts. Ultimately, senescent alveolar epithelial cells lose their regenerative capacity, impeding fibrosis resolution. In addition, mitochondrial dysfunction is strongly associated with the appearance of senescent epithelial cells and senescent myofibroblasts in IPF, which persist in the fibrotic tissue by adapting their metabolic pathways and becoming resistant to apoptosis. We discuss emerging novel therapeutic strategies to treat IPF by targeting cellular senescence with the so-called senotherapeutics.
Topics: Animals; Antifibrinolytic Agents; Cellular Senescence; Humans; Idiopathic Pulmonary Fibrosis
PubMed: 31879264
DOI: 10.1016/j.semcdb.2019.12.008 -
Pharmacology & Therapeutics Jul 2023Pulmonary fibrotic diseases are characterized by proliferation of lung fibroblasts and myofibroblasts and excessive deposition of extracellular matrix proteins.... (Review)
Review
Pulmonary fibrotic diseases are characterized by proliferation of lung fibroblasts and myofibroblasts and excessive deposition of extracellular matrix proteins. Depending on the specific form of lung fibrosis, there can be progressive scarring of the lung, leading in some cases to respiratory failure and/or death. Recent and ongoing research has demonstrated that resolution of inflammation is an active process regulated by families of small bioactive lipid mediators termed "specialized pro-resolving mediators." While there are many reports of beneficial effects of SPMs in animal and cell culture models of acute and chronic inflammatory and immune diseases, there have been fewer reports investigating SPMs and fibrosis, especially pulmonary fibrosis. Here, we will review evidence that resolution pathways are impaired in interstitial lung disease, and that SPMs and other similar bioactive lipid mediators can inhibit fibroblast proliferation, myofibroblast differentiation, and accumulation of excess extracellular matrix in cell culture and animal models of pulmonary fibrosis, and we will consider future therapeutic implications of SPMs in fibrosis.
Topics: Animals; Pulmonary Fibrosis; Lung; Fibrosis; Cell Differentiation; Inflammation; Lipids; Inflammation Mediators
PubMed: 37244406
DOI: 10.1016/j.pharmthera.2023.108460 -
Molecules (Basel, Switzerland) Jan 2023Pulmonary fibrosis (PF) is one of the sequelae of Corona Virus Disease 2019 (COVID-19), and currently, lung transplantation is the only viable treatment option. Hence,...
Pulmonary fibrosis (PF) is one of the sequelae of Corona Virus Disease 2019 (COVID-19), and currently, lung transplantation is the only viable treatment option. Hence, other effective treatments are urgently required. We investigated the therapeutic effects of an approved botanical drug, cepharanthine (CEP), in a cell culture model of transforming growth factor-β1 (TGF-β1) and bleomycin (BLM)-induced pulmonary fibrosis rat models both in vitro and in vivo. In this study, CEP and pirfenidone (PFD) suppressed BLM-induced lung tissue inflammation, proliferation of blue collagen fibers, and damage to lung structures in vivo. Furthermore, we also found increased collagen deposition marked by α-smooth muscle actin (α-SMA) and Collagen Type I Alpha 1 (COL1A1), which was significantly alleviated by the addition of PFD and CEP. Moreover, we elucidated the underlying mechanism of CEP against PF in vitro. Various assays confirmed that CEP reduced the viability and migration and promoted apoptosis of myofibroblasts. The expression levels of myofibroblast markers, including COL1A1, vimentin, α-SMA, and Matrix Metallopeptidase 2 (MMP2), were also suppressed by CEP. Simultaneously, CEP significantly suppressed the elevated Phospho-NF-κB p65 (p-p65)/NF-κB p65 (p65) ratio, NOD-like receptor thermal protein domain associated protein 3 (NLRP3) levels, and elevated inhibitor of NF-κB Alpha (IκBα) degradation and reversed the progression of PF. Hence, our study demonstrated that CEP prevented myofibroblast activation and treated BLM-induced pulmonary fibrosis in a dose-dependent manner by regulating nuclear factor kappa-B (NF-κB)/ NLRP3 signaling, thereby suggesting that CEP has potential clinical application in pulmonary fibrosis in the future.
Topics: Animals; Rats; Bleomycin; Collagen; COVID-19; Fibroblasts; Inflammation; Lung; Myofibroblasts; NF-kappa B; NLR Family, Pyrin Domain-Containing 3 Protein; Pulmonary Fibrosis; Transforming Growth Factor beta1
PubMed: 36677811
DOI: 10.3390/molecules28020753