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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 -
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 -
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 -
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 -
Biochimica Et Biophysica Acta.... Dec 2021Ferroptosis is a newly discovered type of regulated cell death, characterized by the iron-dependent accumulation of lipid reactive oxygen species, which has been...
Ferroptosis is a newly discovered type of regulated cell death, characterized by the iron-dependent accumulation of lipid reactive oxygen species, which has been implicated in numerous human diseases. However, its role in pulmonary fibrosis, a fatal lung disease with unknown etiology, is largely unknown. Here, we investigated the role of ferroptosis in pulmonary fibrosis. We found a large amount of iron deposition in the lung tissue of patients with pulmonary fibrosis. We observed ferroptosis in alveolar type II (ATII) cells, fibrotic lung tissues of BLM-induced pulmonary fibrosis mice. BLM-induced increase in iron level was accompanied by pathological changes, collagen deposition, and ferroptosis in ATII cells, indicating iron deposition-induced ferroptosis, which promoted the development of pulmonary fibrosis. Moreover, deferoxamine (DFO) completely prevented the pro-fibrosis effects of BLM by reducing iron deposition and ferroptosis in ATII cells. Genes associated with intracellular iron metabolism and homeostasis, such as transferrin receptor 1, divalent metal transporter 1, and ferroportin-1, and showed abnormal expression levels in animal tissues and lung epithelial MLE-12 cells, which responded to BLM stimulation. Overall, we demonstrated that BLM-induced iron deposition in MLE-12 cells is prone to both mitochondrial dysfunction and ferroptosis and that DFO reverses this phenotype. In the future, understanding the role of ferroptosis may shed new light on the etiology of pulmonary fibrosis. Ferroptosis inhibitors or genetic engineering of ferroptosis-related genes might offer potential targets to treat pulmonary fibrosis.
Topics: Animals; Bleomycin; Cation Transport Proteins; Deferoxamine; Disease Models, Animal; Ferroptosis; Gene Expression Regulation; Humans; Iron; Lung; Mice; Pulmonary Alveoli; Pulmonary Fibrosis; Reactive Oxygen Species; Receptors, Transferrin
PubMed: 34175430
DOI: 10.1016/j.bbadis.2021.166204 -
Molecular & Cellular Proteomics : MCP Apr 2023The heterogeneity of idiopathic pulmonary fibrosis (IPF) limits its diagnosis and treatment. The association between the pathophysiological features and the serum...
The heterogeneity of idiopathic pulmonary fibrosis (IPF) limits its diagnosis and treatment. The association between the pathophysiological features and the serum protein signatures of IPF currently remains unclear. The present study analyzed the specific proteins and patterns associated with the clinical parameters of IPF based on a serum proteomic dataset by data-independent acquisition using MS. Differentiated proteins in sera distinguished patients with IPF into three subgroups in signal pathways and overall survival. Aging-associated signatures by weighted gene correlation network analysis coincidently provided clear and direct evidence that aging is a critical risk factor for IPF rather than a single biomarker. Expression of LDHA and CCT6A, which was associated with glucose metabolic reprogramming, was correlated with high serum lactic acid content in patients with IPF. Cross-model analysis and machine learning showed that a combinatorial biomarker accurately distinguished patients with IPF from healthy individuals with an area under the curve of 0.848 (95% CI = 0.684-0.941) and validated from another cohort and ELISA assay. This serum proteomic profile provides rigorous evidence that enables an understanding of the heterogeneity of IPF and protein alterations that could help in its diagnosis and treatment decisions.
Topics: Humans; Proteomics; Idiopathic Pulmonary Fibrosis; Blood Proteins; Biomarkers; Chaperonin Containing TCP-1
PubMed: 36870568
DOI: 10.1016/j.mcpro.2023.100524 -
Clinics in Chest Medicine Jun 2021Idiopathic pulmonary fibrosis (IPF) is a devastating disease for patients and their loved ones. Since initial efforts to characterize this disease in the 1960s,... (Review)
Review
Idiopathic pulmonary fibrosis (IPF) is a devastating disease for patients and their loved ones. Since initial efforts to characterize this disease in the 1960s, understanding of IPF has evolved considerably. Such evolution has continually challenged prior diagnostic and treatment paradigms, ushering in an era of higher confidence diagnoses with less invasive procedures and more effective treatments. This review details how research and clinical experience over the past half century have led to a rethinking of IPF. Here, the evolution in understanding of IPF pathogenesis, diagnostic evaluation and treatment approach is discussed.
Topics: Humans; Idiopathic Pulmonary Fibrosis
PubMed: 34024402
DOI: 10.1016/j.ccm.2021.03.005