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International Journal of Molecular... Jun 2021Lung fibrosis results from the synergic interplay between regenerative deficits of the alveolar epithelium and dysregulated mechanisms of repair in response to alveolar... (Review)
Review
Lung fibrosis results from the synergic interplay between regenerative deficits of the alveolar epithelium and dysregulated mechanisms of repair in response to alveolar and vascular damage, which is followed by progressive fibroblast and myofibroblast proliferation and excessive deposition of the extracellular matrix. The increased parenchymal stiffness of fibrotic lungs significantly affects respiratory mechanics, making the lung more fragile and prone to non-physiological stress during spontaneous breathing and mechanical ventilation. Given their parenchymal inhomogeneity, fibrotic lungs may display an anisotropic response to mechanical stresses with different regional deformations (micro-strain). This behavior is not described by the standard stress-strain curve but follows the mechano-elastic models of "squishy balls", where the elastic limit can be reached due to the excessive deformation of parenchymal areas with normal elasticity that are surrounded by inelastic fibrous tissue or collapsed induration areas, which tend to protrude outside the fibrous ring. Increasing evidence has shown that non-physiological mechanical forces applied to fibrotic lungs with associated abnormal mechanotransduction could favor the progression of pulmonary fibrosis. With this review, we aim to summarize the state of the art on the relation between mechanical forces acting on the lung and biological response in pulmonary fibrosis, with a focus on the progression of damage in the fibrotic lung during spontaneous breathing and assisted ventilatory support.
Topics: Algorithms; Alveolar Epithelial Cells; Animals; Disease Progression; Disease Susceptibility; Elasticity; Extracellular Matrix; Humans; Idiopathic Pulmonary Fibrosis; Lung; Mechanical Phenomena; Mechanotransduction, Cellular; Models, Biological; Pulmonary Fibrosis
PubMed: 34208586
DOI: 10.3390/ijms22126443 -
The Lancet. Respiratory Medicine Feb 2021
Topics: Humans; Idiopathic Pulmonary Fibrosis; United Kingdom
PubMed: 33275904
DOI: 10.1016/S2213-2600(20)30562-2 -
Oxidative Medicine and Cellular... 2020Pulmonary fibrosis is a progressively aggravating lethal disease that is a serious public health concern. Although the incidence of this disease is increasing, there is... (Review)
Review
Pulmonary fibrosis is a progressively aggravating lethal disease that is a serious public health concern. Although the incidence of this disease is increasing, there is a lack of effective therapies. In recent years, the pathogenesis of pulmonary fibrosis has become a research hotspot. p53 is a tumor suppressor gene with crucial roles in cell cycle, apoptosis, tumorigenesis, and malignant transformation. Previous studies on p53 have predominantly focused on its role in neoplastic disease. Following in-depth investigation, several studies have linked it to pulmonary fibrosis. This review covers the association between p53 and pulmonary fibrosis, with the aim of providing novel ideas to improve the clinical diagnosis, treatment, and prognosis of pulmonary fibrosis.
Topics: Animals; Humans; Prognosis; Pulmonary Fibrosis; Tumor Suppressor Protein p53
PubMed: 33312337
DOI: 10.1155/2020/6635794 -
The American Journal of the Medical... May 2019Pulmonary fibrosis refers to a heterogeneous group of disorders that scar the lung, most often irreversibly. To date, there are limited effective treatments for these... (Review)
Review
Pulmonary fibrosis refers to a heterogeneous group of disorders that scar the lung, most often irreversibly. To date, there are limited effective treatments for these conditions, despite decades of research in this area of investigation. In pulmonary fibrosis, the principle cell responsible for producing the vast majority of scar tissue is the fibroblast, making these cells ideally suited for drug targeting. For decades, the major experimental approach to blocking the activity of lung fibroblasts has been either to inhibit the interaction of fibroblast growth factors with their receptors or interfere with downstream effector molecules regulating extracellular matrix production. However, emerging evidence now indicates that lung fibroblasts also undergo dramatic metabolic reprogramming in the setting of growth factor stimulation. These discoveries, along with preclinical investigations showing marked reductions in lung fibrosis after targeting specific metabolic pathways, has led to a total rethinking of drug development in the pulmonary fibrosis field. Here, we review the major metabolic pathways and highlight some of the key metabolic events that occur in the transition of fibroblasts from quiescent to activated states. Moreover, we discuss the emerging evidence linking changes in fibroblast metabolism to pulmonary fibrosis and propose how targeting specific metabolic pathways could be employed in the treatment of fibrotic lung diseases.
Topics: Fibroblasts; Humans; Lung; Metabolic Networks and Pathways; Pulmonary Fibrosis
PubMed: 30879738
DOI: 10.1016/j.amjms.2019.02.003 -
Journal of Veterinary Diagnostic... Jan 2022A mortality event among recently captured feral donkeys () occurred in south-central Utah in 2016. The deaths were sporadic, and clinical signs were indicative of...
A mortality event among recently captured feral donkeys () occurred in south-central Utah in 2016. The deaths were sporadic, and clinical signs were indicative of respiratory disease, likely associated with an infectious etiology. Ten of 13 donkeys autopsied had moderate-to-severe interstitial fibrosing pneumonia, and one had pyogranulomatous pneumonia. Consensus PCRs directed toward the DNA polymerase and DNA packaging terminase subunit 1 for herpesviruses were performed followed by sequencing of the PCR amplicons and phylogenetic analysis. Asinine herpesvirus 4 (AsHV4) and 5 (AsHV5) were consistently identified in lung tissues of affected donkeys. No other herpesviruses were identified, and herpesviral DNA was not detected in lung tissues of 2 donkeys without evidence of respiratory disease. The detection of asinine gammaherpesviruses may have been associated with the lesions described. AsHV4 and AsHV5 have been reported in previous studies as novel gammaherpesviruses based on sequences obtained from donkeys with interstitial pneumonia and marked syncytial cell formation. Our findings suggest that the association of asinine gammaherpesviruses with respiratory conditions in equids deserves further attention.
Topics: Animals; Equidae; Gammaherpesvirinae; Herpesviridae; Phylogeny; Pulmonary Fibrosis
PubMed: 34689632
DOI: 10.1177/10406387211052998 -
Science Advances Mar 2024Pulmonary fibrosis is an often fatal lung disease. Immune cells such as macrophages were shown to accumulate in the fibrotic lung, but their contribution to the fibrosis...
Pulmonary fibrosis is an often fatal lung disease. Immune cells such as macrophages were shown to accumulate in the fibrotic lung, but their contribution to the fibrosis development is unclear. To recapitulate the involvement of macrophages in the development of pulmonary fibrosis, we developed a fibrotic microtissue model with cocultured human macrophages and fibroblasts. We show that profibrotic macrophages seeded on topographically controlled stromal tissues became mechanically activated. The resulting co-alignment of macrophages, collagen fibers, and fibroblasts promoted widespread fibrogenesis in micro-engineered lung tissues. Anti-fibrosis treatment using pirfenidone disrupts the polarization and mechanical activation of profibrotic macrophages, leading to fibrosis inhibition. Pirfenidone inhibits the mechanical activation of macrophages by suppressing integrin αMβ2 and Rho-associated kinase 2. These results demonstrate a potential pulmonary fibrogenesis mechanism at the tissue level contributed by macrophages. The cocultured microtissue model is a powerful tool to study the immune-stromal cell interactions and the anti-fibrosis drug mechanism.
Topics: Humans; Pulmonary Fibrosis; Lung; Fibrosis; Macrophages; Coculture Techniques
PubMed: 38552026
DOI: 10.1126/sciadv.adj9559 -
The European Respiratory Journal Nov 2022
Topics: Humans; Pulmonary Fibrosis; Plasma Cells; Bleomycin; Fibroblasts
PubMed: 36423920
DOI: 10.1183/13993003.01748-2022 -
Respiratory Medicine Nov 2004Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary disease leading to death within a few years of diagnosis despite medical therapy. On the basis of... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a progressive pulmonary disease leading to death within a few years of diagnosis despite medical therapy. On the basis of methodologies of the Cochrane collaboration, this overview discusses the evidence for IPF therapy. Good-quality studies on oral corticosteroids, the most common medical therapy in use for IPF, are lacking. A few small studies have been carried out on the efficacy of many non-steroid immunosuppressive agents, and the results have been generally disappointing. The most extensively studied medical therapy, gamma interferon, showed a significant effect in a small randomized study, but its efficacy was not confirmed in a larger randomized-controlled trial. The long-awaited good news for patients affected by this deadly disease, and for their physicians, could come in the near future from large randomized-controlled trials with gamma interferon or other immunomodulatory agents.
Topics: Adrenal Cortex Hormones; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Practice Guidelines as Topic; Pulmonary Fibrosis
PubMed: 15526803
DOI: 10.1016/j.rmed.2004.07.019 -
Jornal Brasileiro de Pneumologia :... 2017
Topics: Brazil; Humans; Idiopathic Pulmonary Fibrosis; Pulmonary Fibrosis
PubMed: 29340483
DOI: 10.1590/S1806-37562017000060003 -
Scientific Reports Jun 2017Pulmonary rehabilitation mixture (PRM), a Chinese herbal medicine formula, has been used to treat pulmonary fibrosis for decades. In this study, we systematically...
Pulmonary rehabilitation mixture (PRM), a Chinese herbal medicine formula, has been used to treat pulmonary fibrosis for decades. In this study, we systematically evaluated the pharmacodynamic and pharmacokinetic performance of PRM. The pharmacodynamic results showed that PRM could improve the condition of CoCl-stimulated human type II alveolar epithelial cells, human pulmonary microvascular endothelial cells, human lung fibroblasts and pulmonary fibrosis rats induced by bleomycin, PRM treatment reduced the expression of platelet-derived growth factor, fibroblast growth factor, toll-like receptor 4, high-mobility group box protein 1 and hypoxia-inducible factor 1α. In the pharmacokinetic study, an accurate and sensitive ultra-high performance liquid chromatography tandem mass spectrometry method was developed and validated for the simultaneous determination of calycosin, calycosin-7-O-glucoside, formononetin, ononin and mangiferin of PRM in the rat plasma for the first time. The method was then successfully applied to the comparative pharmacokinetic study of PRM in normal and pulmonary fibrosis rats. The five constituents could be absorbed in the blood after the oral administration of PRM and exhibited different pharmacokinetic behaviors in normal and pulmonary fibrosis rats. In summary, PRM exhibited a satisfactory pharmacodynamic and pharmacokinetic performance, which highlights PRM as a potential multi-target oral drug for the treatment of pulmonary fibrosis.
Topics: Administration, Oral; Animals; Bleomycin; Cell Proliferation; Chromatography, High Pressure Liquid; Disease Models, Animal; Drugs, Chinese Herbal; Endothelial Cells; Fibroblasts; Humans; Male; Mass Spectrometry; Pulmonary Fibrosis; Rats
PubMed: 28615638
DOI: 10.1038/s41598-017-02774-1