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Radiation Oncology (London, England) Sep 2020Lung, breast, and esophageal cancer represent three common malignancies with high incidence and mortality worldwide. The management of these tumors critically relies on... (Review)
Review
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.
Topics: Humans; Pulmonary Fibrosis; Radiation Injuries; Radiation Pneumonitis; Radiotherapy Dosage
PubMed: 32912295
DOI: 10.1186/s13014-020-01654-9 -
Respirology (Carlton, Vic.) May 2020Acute exacerbation (AE) is a severe complication of idiopathic pulmonary fibrosis (AE-IPF). In 2016, an international working group revised its definition and diagnostic...
BACKGROUND AND OBJECTIVE
Acute exacerbation (AE) is a severe complication of idiopathic pulmonary fibrosis (AE-IPF). In 2016, an international working group revised its definition and diagnostic criteria; however, few studies have assessed the frequency and prognosis of AE in patients with other fibrotic interstitial lung diseases (FILD).
METHODS
We used data from 1019 consecutive interstitial lung disease (ILD) patients initially evaluated between January 2008 and July 2015. All subject diagnoses were made by multidisciplinary discussion in December 2018. ILD was categorized as IPF (n = 462) and other FILD which included non-specific interstitial pneumonia (n = 22), chronic hypersensitivity pneumonitis (n = 29), connective tissue disease-associated ILD (n = 205) and unclassifiable ILD (n = 209). Using the 2016 definition of AE-IPF, we identified all subjects with an AE.
RESULTS
During the observational period, 193 patients experienced a first AE (AE-FILD n = 69, AE-IPF n = 124). The time to first AE was significantly longer in FILD than IPF (log-rank test, P < 0.001). After adjusting for potentially influential confounders, FILD remained a significant predictor of longer time to first AE compared with IPF (hazard ratio: 0.453; 95% CI: 0.317-0.647, P = 0.006). In a multivariate Cox proportional analysis, baseline disease severity was closely associated with the incidence of AE-ILD. Even after adjustment for other clinical variables, AE had a negative impact on overall survival. AE-FILD and AE-IPF showed similar poor short-term outcomes.
CONCLUSION
All forms of ILD are at risk of AE and have a similar outcome to AE-IPF.
Topics: Alveolitis, Extrinsic Allergic; Diagnosis, Differential; Female; Humans; Idiopathic Pulmonary Fibrosis; Japan; Lung Diseases, Interstitial; Male; Middle Aged; Prognosis; Pulmonary Fibrosis; Risk Assessment; Severity of Illness Index; Symptom Flare Up; Terminology as Topic
PubMed: 31426125
DOI: 10.1111/resp.13682 -
Proceedings of the National Academy of... Mar 2022The warning cytokine interleukin-33 receptor (IL-33R) mediates local inflammatory responses and plays crucial roles in the pathogenesis of immune diseases such as...
The warning cytokine interleukin-33 receptor (IL-33R) mediates local inflammatory responses and plays crucial roles in the pathogenesis of immune diseases such as pulmonary fibrosis and rheumatoid arthritis. Whether and how IL-33R is regulated remain enigmatic. Here, we identified ubiquitin-specific protease 38 (USP38) as a negative regulator of IL-33R–mediated signaling. USP38 deficiency promotes interleukin-33 (IL-33)–induced downstream proinflammatory responses in vitro and in vivo. mice are more susceptible to inflammatory damage and death and developed more serious pulmonary fibrosis after bleomycin treatment. USP38 is constitutively associated with IL-33R and deconjugates its K27-linked polyubiquitination at K511, resulting in its autophagic degradation. We further show that the E3 ubiquitin ligase tumor necrosis factor receptor–associated factor 6 (TRAF6) catalyzes K27-linked polyubiquitination of IL-33R at K511, and that deficiency of TRAF6 inhibits IL-33–mediated signaling. Our findings suggest that K27-linked polyubiquitination and deubiquitination of IL-33R by TRAF6 and USP38 reciprocally regulate IL-33R level and signaling, which represents a critical mechanism in the regulation of IL-33–triggered lung inflammatory response and pulmonary fibrosis.
Topics: Autophagy; Down-Regulation; Humans; Inflammation; Interleukin-33; Intracellular Signaling Peptides and Proteins; Pulmonary Fibrosis; Signal Transduction; Ubiquitin-Specific Proteases; Ubiquitination
PubMed: 35238669
DOI: 10.1073/pnas.2116279119 -
Science Advances Jul 2023Pulmonary fibrosis (PF) is an age-related interstitial lung disease that results in notable morbidity and mortality. The Food and Drug Administration-approved drugs can...
Pulmonary fibrosis (PF) is an age-related interstitial lung disease that results in notable morbidity and mortality. The Food and Drug Administration-approved drugs can decelerate the progression of PF; however, curing aged patients with severe fibrosis is ineffective because of insufficient accumulation of these drugs and wide necrocytosis of type II alveolar epithelial cells (AEC IIs). Here, we constructed a mesenchymal stem cell (MSC)-based nanoengineered platform via the bioconjugation of MSCs and type I collagenase-modified liposomes loaded with nintedanib (MSCs-Lip@NCAF) for treating severe fibrosis. Specifically, MSCs-Lip@NCAF migrated to fibrotic lungs because of the homing characteristic of MSCs and then Lip@NCAF was sensitively released. Subsequently, Lip@NCAF ablated collagen fibers, delivered nintedanib into fibroblasts, and inhibited fibroblast overactivation. MSCs differentiated into AEC IIs to repair alveolar structure and ultimately promote the regeneration of damaged lungs in aged mice. Our findings indicated that MSCs-Lip@NCAF could be used as a promising therapeutic candidate for PF therapy, especially in aged patients.
Topics: United States; Animals; Mice; Pulmonary Fibrosis; Mesenchymal Stem Cell Transplantation; Lung; Alveolar Epithelial Cells; Mesenchymal Stem Cells
PubMed: 37467328
DOI: 10.1126/sciadv.adg5358 -
Presse Medicale (Paris, France : 1983) Sep 2023Idiopathic pulmonary fibrosis (IPF) is a progressive devastating lung disease with substantial morbidity. It is associated with cough, dyspnea and impaired quality of... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a progressive devastating lung disease with substantial morbidity. It is associated with cough, dyspnea and impaired quality of life. If left untreated, IPF has a median survival of 3 years. IPF affects ∼3 million people worldwide, with increasing incidence in older patients. The current concept of pathogenesis is that pulmonary fibrosis results from repetitive injury to the lung epithelium, with fibroblast accumulation, myofibroblast activation, and deposition of matrix. These injuries, in combination with innate and adaptive immune responses, dysregulated wound repair and fibroblast dysfunction, lead to recurring tissue remodeling and self-perpetuating fibrosis as seen in IPF. The diagnostic approach includes the exclusion of other interstitial lung diseases or underlying conditions and depends on a multidisciplinary team-based discussion combining radiological and clinical features and well as in some cases histology. In the last decade, considerable progress has been made in the understanding of IPF clinical management, with the availability of two drugs, pirfenidone and nintedanib, that decrease pulmonary lung function decline. However, current IPF therapies only slow disease progression and prognosis remains poor. Fortunately, there are multiple clinical trials ongoing with potential new therapies targeting different disease pathways. This review provides an overview of IPF epidemiology, current insights in pathophysiology, diagnostic and therapeutic management approaches. Finally, a detailed description of current and evolving therapeutic approaches is also provided.
Topics: Idiopathic Pulmonary Fibrosis; Humans; Pyridones; Indoles; Disease Progression
PubMed: 37156412
DOI: 10.1016/j.lpm.2023.104166 -
Lancet (London, England) Oct 2021Fibrotic interstitial lung disease (ILD) represents a large group of pulmonary disorders that are often progressive and associated with high morbidity and early... (Review)
Review
Fibrotic interstitial lung disease (ILD) represents a large group of pulmonary disorders that are often progressive and associated with high morbidity and early mortality. Important advancements in the past 10 years have enabled a better understanding, characterisation, and treatment of these diseases. This Series paper summarises the current approach to treatment of fibrotic ILDs, both pharmacological and non-pharmacological, including recent discoveries and practice-changing clinical trials. We further outline controversies and challenges, with discussion of evolving concepts and future research directions.
Topics: Humans; Lung Diseases, Interstitial; Pulmonary Fibrosis
PubMed: 34499866
DOI: 10.1016/S0140-6736(21)01826-2 -
Environmental Pollution (Barking, Essex... Apr 2023Exposure to ambient fine particulate matter (PM) has been linked to a higher pulmonary fibrosis risk. Dysregulation of the epitranscriptome results in abnormal...
Exposure to ambient fine particulate matter (PM) has been linked to a higher pulmonary fibrosis risk. Dysregulation of the epitranscriptome results in abnormal expression of mRNAs during fibrosis development. N4-acetylcytidine (ac4C) is one of the most frequent RNA epigenetic alterations, however, its function in PM-triggered fibrosis is yet unknown. In this study, lung epithelial and murine models were established and exposed to PM to analyze the function of ac4C alteration in pulmonary fibrosis and underlying mechanisms. Meanwhile, the expression levels of only known ac4C "writer" protein, N-acetyltransferase 10 (NAT10), were significantly induced in pulmonary epithelia, relative to the control. Subsequently, NAT10 enhanced the stability of transforming growth factor beta 1 (TGFB1) mRNA as well as protein levels. As an up-stream driver, TGFB1 accelerated EMT and fibrosis process. Inhibition of NAT10 significantly protected against pulmonary EMT and fibrosis driven by PM exposure, whereas TGFB1 overexpression reversed the protective effects of NAT10 inhibition. Thus, NAT10 accelerated PM-triggered pulmonary fibrosis via increasing TGFB1 mRNA stability in an ac4C-dependent manner. Our results reveal a pivotal role of NAT10-regulated mRNA ac4C acetylation in PM-triggered pulmonary fibrosis and uncover the potential epitranscriptional mechanism.
Topics: Animals; Mice; Lung; Particulate Matter; Pulmonary Fibrosis; RNA; RNA, Messenger
PubMed: 36731737
DOI: 10.1016/j.envpol.2023.121149 -
Journal of Ethnopharmacology Dec 2023Numerous studies have provided evidence supporting the significant roles of icariin, in the prevention of multiple chronic diseases like diabetes, liver fibrosis,...
ETHNOPHARMACOLOGICAL RELEVANCE
Numerous studies have provided evidence supporting the significant roles of icariin, in the prevention of multiple chronic diseases like diabetes, liver fibrosis, cardiac fibrosis, renal fibrosis, and pulmonary fibrosis. In particular, Icariside II (ISE II), a prominent flavonoid glycoside derived from Epimedium brevicornum Maxim, the principal metabolite of icariin, has demonstrated noteworthy anti-inflammatory and anti-oxidant properties, along with its ability to protect against lung remodeling. However, the research exploring ISE Ⅱ's application in treating pulmonary fibrosis remains limited.
AIM OF THE STUDY
The aim of this study was to assess the therapeutic efficacy of ISE II in models of pulmonary fibrosis, while also investigating its potential mechanisms of action in cell signaling pathways.
MATERIALS AND METHODS
An in vitro model of pulmonary fibrosis was established by treating NIH-3T3 cells with transforming growth factor-β1 (TGF-β1). Western blot, RT-qPCR, and scratch test were performed to assess the effect of ISE Ⅱ. In addition, a murine model of pulmonary fibrosis was induced by intratracheal instillation of bleomycin, and the therapeutic effect of ISE Ⅱ was tested by orally administering ISE Ⅱ at a dose of 10 mg/kg. Three weeks later, lung function, micro-CT, hydroxyproline content, pathological staining, and cytokines detection of BALF or serum were used to assess the anti-fibrosis effects of ISE Ⅱ. Next, immunofluorescence staining, flow cytometry, and in vivo transcriptomics were used to investigate the underlying mechanisms of action.
RESULTS
Our data revealed a significant inhibitory effect of ISE Ⅱ on the upregulation of α-smooth muscle actin (α-SMA) and collagen production induced by TGF-β1 in fibroblasts. Meanwhile, ISE Ⅱ exerted a therapeutic effect against bleomycin-induced pulmonary fibrosis in mice by improving lung function, decreasing collagen deposition, and reducing the expression of interleukin (IL)-1β, tumor necrosis factor α (TNF-α), TGF-β1 and platelet-derived growth factor (PDGF) in serum and bronchoalveolar lavage fluid (BALF). Additionally, ISE Ⅱ treatment effectively attenuated the infiltration of M2 macrophages, concurrently downregulating the expression level of M2 marker genes, such as CD206, arginase-1(Arg-1), and Chitinase-Like Protein 3 (YM-1). Importantly, we observed a statistically significant reduction in the M2 phenotype of interstitial macrophages (IMs). However, the impact of ISE Ⅱ on the M2 polarization of alveolar macrophages (AMs) did not reach statistical significance. Lastly, transcriptome sequencing results suggested that the anti-pulmonary fibrosis effects of ISE Ⅱ may be mediated by the suppression of the WNT/β-catenin signaling pathway, which modulated M2 polarization in macrophages and contributed to the amelioration of pulmonary fibrosis. By immunohistochemical analysis, it was verified that ISE Ⅱ treatment dramatically inhibited the activation of β-catenin in fibrosis murine.
CONCLUSION
Our findings indicated that ISE Ⅱ exerted anti-fibrotic effects by inhibiting pro-fibrotic macrophage polarization. The underlying mechanism of action might be mediated by modulating the WNT/β-catenin signaling pathway to inhibit the M2 program in IMs.
Topics: Mice; Animals; Transforming Growth Factor beta1; Bleomycin; Pulmonary Fibrosis; Flavonoids; Macrophages; Collagen; Wnt Signaling Pathway; Mice, Inbred C57BL
PubMed: 37331450
DOI: 10.1016/j.jep.2023.116810 -
International Journal of Molecular... May 2023Pulmonary fibrosis (PF) is a life-threatening disorder that severely disrupts normal lung architecture and function, resulting in severe respiratory failure and death....
Pulmonary fibrosis (PF) is a life-threatening disorder that severely disrupts normal lung architecture and function, resulting in severe respiratory failure and death. It has no definite treatment. Empagliflozin (EMPA), a sodium-glucose cotransporter 2 (SGLT2) inhibitor, has protective potential in PF. However, the mechanisms underlying these effects require further elucidation. Therefore, this study aimed to evaluate the ameliorative effect of EMPA against bleomycin (BLM)-induced PF and the potential mechanisms. Twenty-four male Wister rats were randomly divided into four groups: control, BLM treated, EMPA treated, and EMPA+BLM treated. EMPA significantly improved the histopathological injuries illustrated by both hematoxylin and eosin and Masson's trichrome-stained lung tissue sections, as confirmed by electron microscopic examination. It significantly reduced the lung index, hydroxyproline content, and transforming growth factor β1 levels in the BLM rat model. It had an anti-inflammatory effect, as evidenced by a decrease in the inflammatory cytokines' tumor necrosis factor alpha and high mobility group box 1, inflammatory cell infiltration into the bronchoalveolar lavage fluid, and the CD68 immunoreaction. Furthermore, EMPA mitigated oxidative stress, DNA fragmentation, ferroptosis, and endoplasmic reticulum stress, as evidenced by the up-regulation of nuclear factor erythroid 2-related factor expression, heme oxygenase-1 activity, glutathione peroxidase 4 levels, and a decrease in C/EBP homologous protein levels. This protective potential could be explained on the basis of autophagy induction via up-regulating lung expression and the LC3 II immunoreaction observed in this study. Our findings indicated that EMPA protected against BLM-induced PF-associated cellular stress by enhancing autophagy and modulating sestrin2/adenosine monophosphate-activated protein kinase/nuclear factor erythroid 2-related factor 2/heme oxygenase 1 signaling.
Topics: Rats; Male; Animals; Pulmonary Fibrosis; Bleomycin; NF-E2-Related Factor 2; AMP-Activated Protein Kinases; Ferroptosis; Rats, Wistar; Lung
PubMed: 37298433
DOI: 10.3390/ijms24119481 -
Journal of Ethnopharmacology Nov 2023Bufei huoxue (BFHX) is a Traditional Chinese Medicine formulation that consists of Astragalus Exscapus L, Paeonia Lactiflora Pall, and Psoralea Aphylla L. It can...
ETHNOPHARMACOLOGICAL RELEVANCE
Bufei huoxue (BFHX) is a Traditional Chinese Medicine formulation that consists of Astragalus Exscapus L, Paeonia Lactiflora Pall, and Psoralea Aphylla L. It can ameliorate collagen deposition and inhibit EMT. However, it remains unknown whether and how BFHX alleviates IPF.
AIM OF THE STUDY
Our work aimed to explore the therapeutic efficacy of BFHX on IPF and dissect the mechanisms involved.
MATERIALS AND METHODS
A mouse model of IPF was induced by bleomycin. BFHX was administered on the first day of modeling and maintained for 21 days. Pulmonary fibrosis and inflammation were evaluated by micro-CT, lung histopathology, pulmonary function assessment, and cytokines in BALF. In addition, we examined the signaling molecules involved in EMT and ECM by immunofluorescence, western Blot, EdU, and MMP (Δψm) assays.
RESULTS
BFHX alleviated lung parenchyma fibrosis as evidenced by Hematoxylin-eosin (H&E), Masson's trichrome staining, and micro-CT, and it improved lung function. In addition, BFHX treatment not only decreased the levels of interleukin (IL)-6 and tumor necrosis factor-α (TNF-α), but also upregulated E-cadherin (E-Cad) and downregulated α-smooth muscle actin (α-SMA), collagen Ӏ (Col Ӏ), vimentin, and fibronectin (FN). Mechanistically, BFHX repressed TGF-β1-driven Smad2/3 phosphorylation, which, in turn, suppressed EMT and transition of fibroblasts to myofibroblasts in vivo and in vitro.
CONCLUSION
BFHX effectively reduces the occurrence of EMT and inhibits the production of ECM by inhibiting the TGF-β1/Smad2/3 signaling pathway, which provides a potential novel therapeutic strategy for IPF.
Topics: Mice; Animals; Pulmonary Fibrosis; Transforming Growth Factor beta1; Bleomycin; Collagen; Signal Transduction
PubMed: 37277082
DOI: 10.1016/j.jep.2023.116733