Turk J Med Sci. 2021 Dec;51(6):3082-3088. Epub 2021 Dec 13.

ABSTRACT

BACKGROUND: Phase III trials have demonstrated a significant efficacy and an acceptable safety for pirfenidone in patients having mild to moderate idiopathic pulmonary fibrosis (IPF). Real-life data on the use of pirfenidone 200 mg tablets are limited. This study aimed to investigate the efficacy and safety of pirfenidone 200 mg tablets for the treatment of IPF in a real-life setting.

METHODS: A retrospective, multicenter study conducted in four university hospitals in Turkey between January 2017 and January 2019. Clinical records of patients diagnosed with mild to moderate IPF and receiving pirfenidone (200 mg tablets, total 2400 mg/day) were reviewed retrospectively and consecutively. Pulmonary function measurements including forced vital capacity (FVC%) and diffusing capacity of the lungs for carbon monoxide (DLCO%) were analyzed at baseline and after 6-month of pirfenidone treatment. Descriptive statistics were expressed as mean, standard error or median (minimum-maximum), number and percentage, where appropriate.

RESULTS: The study included 82 patients, of whom 87.8% were males (mean age, 66 years). After 6-month of treatment, 7 patients discontinued the treatment. Of the remaining 75 patients, 71 (94.6%) remained stable, 4 (5.4%) had progressive disease as evident by a decline in the FVC% of at least 10% while on treatment, and 45 (61.3%) had improved cough. At least one adverse event (AE) associated with the treatment was observed in 28 (37.3%) patients.

DISCUSSION: Pirfenidone 200 mg was effective and well tolerated and associated with relatively mild and manageable AEs in IPF patients.

PMID:36161644

Front Pharmacol. 2022 Sep 8;13:998245. doi: 10.3389/fphar.2022.998245. eCollection 2022.

ABSTRACT

Transforming growth factor β receptor (TGF-β1R) and receptor tyrosine kinases (RTKs), such as VEGFRs, PDGFRs and FGFRs are considered important therapeutic targets in blocking myofibroblast migration and activation of idiopathic pulmonary fibrosis (IPF). To screen and design innovative prodrug to simultaneously target these four classes of receptors, we proposed an approach based on network pharmacology combining virtual screening and machine learning activity prediction, followed by efficient in vitro and in vivo models to evaluate drug activity. We first constructed Collagen1A2-A549 cells with type I collagen as the main biomarker and evaluated the activity of compounds to inhibit collagen expression at the cellular level. The data from the first round of Collagen1A2-A549 cell screening were substituted into the machine learning model, and the model was optimized accordingly. As a result, the false positive rate of the model was reduced from 85.0% to 66.7%, and two prospective compounds, Z103080500 and Z104578368, were finally selected. Collagen levels were reduced effectively by both Z103080500 (67.88% reduction) and Z104578368 (69.54% reduction). Moreover, these two compounds showed low cellular cytotoxicity. Subsequently, the effect of Z103080500 and Z104578368 was evaluated in a bleomycin-induced C57BL/6 mouse IPF model. These results showed that 50 mg/kg Z103080500 and Z104578368 could effectively reduce the number of inflammatory cells and the expression level of α-SMA. Meanwhile, Z103080500 and Z104578368 reduced the expression of major markers and inflammatory factors of IPF, such as collagen, IFN-γ, IL-17 and HYP, indicating that these screened Z103080500 and Z104578368 effectively delayed lung tissue inflammation and had a potential therapeutic effect on IPF. Our findings demonstrate that a screening and evaluation model for prodrug against IPF has been successfully established. It is of great significance to further modify these compounds to enhance their potency and activity.

PMID:36160399 | PMC:PMC9493029 | DOI:10.3389/fphar.2022.998245

Case Rep Oncol. 2022 Aug 30;15(2):776-782. doi: 10.1159/000526077. eCollection 2022 May-Aug.

ABSTRACT

Since the launch of imatinib in 2001, tyrosine kinase inhibitors are being used in chemotherapy for a wide range of malignant tumors. Drugs that inactivate multiple molecular mechanisms are called multikinase inhibitors (MKIs). Nintedanib is a type of MKI that inhibits downstream cascades in three systems: vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor inhibitions. It was initially developed as an anticancer drug for non-small-cell lung carcinoma; however, it was also found to inhibit the proliferation of fibroblasts associated with chronic inflammation in the lungs. Therefore, it is being more widely used to treat idiopathic pulmonary fibrosis, a benign disease, than as an antineoplastic agent. Several studies have reported adverse events associated with the concurrent use of MKIs with surgery or radiotherapy. Specifically, there has been a report cautioning against delayed wound healing associated with the use of nintedanib in patients undergoing surgery. However, there is no specific mention of its concurrent use during irradiation. We describe a case of a 72-year-old man with severely delayed recovery from radiation mucositis when nintedanib was being administered for benign disease.

PMID:36157698 | PMC:PMC9459593 | DOI:10.1159/000526077

Rev Med Chil. 2022 Feb;150(2):154-162. doi: 10.4067/S0034-98872022000200154.

ABSTRACT

BACKGROUND: Idiopathic Pulmonary Fibrosis (IPF) is a subtype of interstitial lung disease (ILD) that significantly affects people's quality of life, whose prevalence and mortality has increased.

AIM: To determine the prevalence and lethality of ILD in the Los Ríos Region between the years 2018 and 2019.

MATERIAL AND METHODS: Review of a database of all patients attended at an outpatient clinic of the regional hospital. Those patients with the diagnosis of ILD and seen between 2018 and 2019 were selected. Mortality and its causes were verified with death certificates.

RESULTS: In the study period, 339 cases with ILD, aged 71 ± 10 years (64% women) were identified. The calculated ILD prevalence was 84 cases per 100,000 inhabitants, with a higher predominancy in Futrono and Paillaco communes. IPF and Connective Tissue Diseases were the predominant subtypes. Overall lethality was 18%, with more deaths among patients with IPF (n = 31).

CONCLUSIONS: In the Los Ríos Region, ILDs have a relevant prevalence and lethality.

PMID:36156640 | DOI:10.4067/S0034-98872022000200154

Kyobu Geka. 2022 Sep;75(10):825-830.

ABSTRACT

The initial treatment for the patient with primary or secondary spontaneous pneumothorax occupying less than 15% of the hemithorax is observation. And then the treatment with primary spontaneous pneumothorax greater than 15% of the volume of hemithorax is a simple thoracoscopic aspiration. However, the treatment with secondary spontaneous pneumothorax greater than 15% of the volume of hemithorax is tube thoracotomy. Conservative treatment for continuous air leakage with secondary spontaneous pneumothorax is instillation of a sclerosing agent( small amount of picibanil 3 KE). Surgical treatment for continuous air leakage with secondary spontaneous pneumothorax due to severe idiopathic pulmonary fibrosis (IPF) is intractable. We have experienced three cases in which surgical treatment is difficult in secondary spontaneous pneumothorax with underlying lung diseases. The first cases are a pneumothorax with a giant bulla or severe lung emphysema. Second cases are a pneumothorax with a fragile lung. Third cases are a pneumothorax with a hardened lung. We need devised surgical approaches to these cases.

PMID:36155577

Mol Cell Biol. 2022 Sep 26:e0017122. doi: 10.1128/mcb.00171-22. Online ahead of print.

ABSTRACT

Cellular senescence is a stable form of cell cycle arrest associated with proinflammatory responses. Senescent cells can be cleared by the immune system as a part of normal tissue homeostasis. However, senescent cells can also accumulate in aged and diseased tissues, contributing to inflammation and disease progression. The mechanisms mediating the impaired immune-mediated clearance of senescent cells are poorly understood. Here, we report that senescent cells upregulate the immune checkpoint molecule PD-L1, the ligand for PD-1 on immune cells, which drives immune cell inactivation. The induction of PD-L1 in senescence is dependent on the proinflammatory program. Furthermore, the secreted factors released by senescent cells are sufficient to upregulate PD-L1 in nonsenescent control cells, mediated by the JAK-STAT pathway. In addition, we show that prolongevity intervention rapamycin downregulates PD-L1 in senescent cells. Last, we found that PD-L1 is upregulated in several tissues in naturally aged mice and in the lungs of idiopathic pulmonary fibrosis patients. Together, our results report that senescence and aging are associated with upregulation of a major immune checkpoint molecule, PD-L1. Targeting PD-L1 may offer new therapeutic opportunities in treating senescence and age-associated diseases.

PMID:36154662 | DOI:10.1128/mcb.00171-22

J Med Chem. 2022 Sep 26. doi: 10.1021/acs.jmedchem.2c00660. Online ahead of print.

ABSTRACT

Galectin-3 is a carbohydrate-binding protein central to regulating mechanisms of diseases such as fibrosis, cancer, metabolic, inflammatory, and heart disease. We recently found a high affinity (nM) thiodigalactoside GB0139 which currently is in clinical development (PhIIb) as an inhaled treatment of idiopathic pulmonary fibrosis. To enable treatment of systemically galectin-3 driven disease, we here present the first series of selective galectin-3 inhibitors combining high affinity (nM) with oral bioavailability. This was achieved by optimizing galectin-3 specificity and physical chemical parameters for a series of disubstituted monogalactosides. Further characterization showed that this class of compounds reduced profibrotic gene expression in liver myofibroblasts and displayed antifibrotic activity in CCl4-induced liver fibrosis and bleomycin-induced lung fibrosis mouse models. On the basis of the overall pharmacokinetic, pharmacodynamic, and safety profile, GB1211 was selected as the clinical candidate and is currently in phase IIa clinical trials as a potential therapy for liver cirrhosis and cancer.

PMID:36154172 | DOI:10.1021/acs.jmedchem.2c00660

J R Coll Physicians Edinb. 2022 Jun;52(2):100-104. doi: 10.1177/14782715221103402. Epub 2022 Jun 17.

ABSTRACT

BACKGROUND: COVID-19 pneumonia is complicated with residual lung fibrosis, as evidenced by imaging and postmortem pathological findings. In addition to steroids, we compared the efficacy of nintedanib and pirfenidone in the management of COVID-19 lung fibrosis measured by CT severity score (CTSS).

METHODS: All cases of COVID-19 pneumonia diagnosed as COVID-19 positive by RT-PCR having SpO2 ⩽ 96% and CTSS ⩾ 10 even after 15 days were included in the study. The patients were divided into three groups. All three groups received steroids at a dose of 1 mg/kg body weight of prednisolone or equivalent. The first group received steroids alone, the second group received pirfenidone with steroids and the third group received nintedanib with steroids. All patients were followed up at 6 and 12 weeks. The primary endpoint of our study was to find out any improvement in CTSS.

RESULTS: Out of 90 patients, 56 patients completed the study. Among three groups, 19 (33.9%) patients received steroids (control) only, 16 (28.6%) patients received steroids with pirfenidone and 21 (37.5%) patients received steroids with nintedanib. The study population had a mean (±SD) age of 52.5 ± 10.1 years, mean (±SD) C-reactive protein of 97.1 ± 102.2 mg/L (normal <6 mg/L), mean (±SD) serum ferritin 459.4 ± 305.5 ng/mL (normal <250 ng/mL), mean (±SD) serum d-dimer level 2.1 ± 2.6 μg/mL (normal <0.5 μg/mL) and mean (±SD) CTSS of 16.9 ± 4.3. There was significant improvement in CTSS in group receiving nintedanib compared to pirfenidone at 12 weeks (3.67 ± 1.21 vs 9.07 ± 1.12) with a p-value <0.01.

CONCLUSION: Along with steroids in the treatment of COVID-19 lung fibrosis, there was a significant improvement in lung CTSS with nintedanib compared to pirfenidone.

PMID:36146989 | DOI:10.1177/14782715221103402

Int J Mol Sci. 2022 Sep 10;23(18):10493. doi: 10.3390/ijms231810493.

ABSTRACT

Pulmonary fibrosis is a chronic progressive form of interstitial lung disease, characterized by the histopathological pattern of usual interstitial pneumonia. Apart from aberrant alterations of protein-coding genes, dysregulation of non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs (circRNAs), is crucial to the initiation and progression of pulmonary fibrosis. CircRNAs are single-stranded RNAs that form covalently closed loops without 5' caps and 3' tails. Different from canonical splicing of mRNA, they are produced from the back-splicing of precursor mRNAs and have unique biological functions, as well as potential biomedical implications. They function as important gene regulators through multiple actions, including sponging microRNAs and proteins, regulating transcription, and splicing, as well as protein-coding and translation in a cap-independent manner. This review comprehensively summarizes the alteration and functional role of circRNAs in pulmonary fibrosis, with a focus on the involvement of the circRNA in the context of cell-specific pathophysiology. In addition, we discuss the diagnostic and therapeutic potential of targeting circRNA and their regulatory pathway mediators, which may facilitate the translation of recent advances from bench to bedside in the future.

PMID:36142402 | PMC:PMC9504269 | DOI:10.3390/ijms231810493

Autoimmun Rev. 2022 Sep 20:103202. doi: 10.1016/j.autrev.2022.103202. Online ahead of print.

ABSTRACT

Interstitial lung disease is an overarching term for a wide range of disorders characterized by inflammation and/or fibrosis in the lungs. Most prevalent forms, among others, include idiopathic pulmonary fibrosis (IPF) and connective tissue disease associated interstitial lung disease (CTD-ILD). Currently, only disease modifying treatment options are available for IPF and progressive fibrotic CTD-ILD, leading to reduction or stabilization in the rate of lung function decline at best. Management of these patients would greatly advance if we identify new strategies to improve (1) early detection of ILD, (2) predicting ILD progression, [3] predicting response to therapy and [4] understanding pathophysiology. Over the last years, positron emission tomography (PET) and single photon emission computed tomography (SPECT) have emerged as promising molecular imaging techniques to improve ILD management. Both are non-invasive diagnostic tools to assess molecular characteristics of an individual patient with the potential to apply personalized treatment. In this review, we encompass the currently available pre-clinical and clinical studies on molecular imaging with PET and SPECT in IPF and CTD-ILD. We provide recommendations for potential future clinical applications of these tracers and directions for future research.

PMID:36150433 | DOI:10.1016/j.autrev.2022.103202

Am J Respir Cell Mol Biol. 2022 Sep 23. doi: 10.1165/rcmb.2022-0002OC. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an age-related disease. Failure of the proteostasis network with age, including insufficient autophagy, contributes to the pathology of IPF. Mechanisms underlying autophagy disruption in IPF are unclear and may involve regulation of ubiquitin-specific protease (USP) by post-translational modifications. To expand our previous observation of low USP13 expression in IPF, this study evaluated the role of USP13 in age-related lung fibrosis. Here, we demonstrated that Usp13-deficient aged mice exhibited impaired autophagic activity and increased vulnerability to bleomycin-induced fibrosis. Mechanistically, USP13 interacted with and deubiquitinated Beclin 1, and Beclin 1 overexpression abolished the effects of USP13 disruption. Additionally, Beclin 1 inhibition resulted in insufficient autophagy and more severe lung fibrosis after BLM injury, consistent with the phenotype of aged Usp13-deficient mice. Collectively, we show a protective role of USP13 in age-related pulmonary fibrosis. Ageing-mediated USP13 loss impairs autophagic activity and facilitates lung fibrosis through Beclin 1 deubiquitination. Our findings support the notion that age-dependent dysregulation of autophagic regulators enhances vulnerability to lung fibrosis.

PMID:36150040 | DOI:10.1165/rcmb.2022-0002OC

Front Pharmacol. 2022 Sep 6;13:981604. doi: 10.3389/fphar.2022.981604. eCollection 2022.

ABSTRACT

Background: Increasing evidence has demonstrated that there was a strong correlation between COVID-19 and idiopathic pulmonary fibrosis (IPF). However, the studies are limited, and the real biological mechanisms behind the IPF progression were still uncleared. Methods: GSE70866 and GSE 157103 datasets were downloaded. The weight gene co-expression network analysis (WGCNA) algorithms were conducted to identify the most correlated gene module with COVID-19. Then the genes were extracted to construct a risk signature in IPF patients by performing Univariate and Lasso Cox Regression analysis. Univariate and Multivariate Cox Regression analyses were used to identify the independent value for predicting the prognosis of IPF patients. What's more, the Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and gene set enrichment analysis (GSEA) were conducted to unveil the potential biological pathways. CIBERSORT algorithms were performed to calculate the correlation between the risk score and immune cells infiltrating levels. Results: Two hundred thirty three differentially expressed genes were calculated as the hub genes in COVID-19. Fourteen of these genes were identified as the prognostic differentially expressed genes in IPF. Three (MET, UCHL1, and IGF1) of the fourteen genes were chosen to construct the risk signature. The risk signature can greatly predict the prognosis of high-risk and low-risk groups based on the calculated risk score. The functional pathway enrichment analysis and immune infiltrating analysis showed that the risk signature may regulate the immune-related pathways and immune cells. Conclusion: We identified prognostic differentially expressed hub genes related to COVID-19 in IPF. A risk signature was constructed based on those genes and showed great value for predicting the prognosis in IPF patients. What's more, three genes in the risk signature may be clinically valuable as potential targets for treating IPF patients and IPF patients with COVID-19.

PMID:36147332 | PMC:PMC9489050 | DOI:10.3389/fphar.2022.981604

Pharmaceutics. 2022 Sep 19;14(9):1974. doi: 10.3390/pharmaceutics14091974.

ABSTRACT

With rapid and non-invasive characteristics, the respiratory route of administration has drawn significant attention compared with the limitations of conventional routes. Respiratory delivery can bypass the physiological barrier to achieve local and systemic disease treatment. A scientometric analysis and review were used to analyze how respiratory delivery can contribute to local and systemic therapy. The literature data obtained from the Web of Science Core Collection database showed an increasing worldwide tendency toward respiratory delivery from 1998 to 2020. Keywords analysis suggested that nasal and pulmonary drug delivery are the leading research topics in respiratory delivery. Based on the results of scientometric analysis, the research hotspots mainly included therapy for central nervous systems (CNS) disorders (Parkinson's disease, Alzheimer's disease, depression, glioblastoma, and epilepsy), tracheal and bronchial or lung diseases (chronic obstructive pulmonary disease, asthma, acute lung injury or respiratory distress syndrome, lung cancer, and idiopathic pulmonary fibrosis), and systemic diseases (diabetes and COVID-19). The study of advanced preparations contained nano drug delivery systems of the respiratory route, drug delivery barriers investigation (blood-brain barrier, BBB), and chitosan-based biomaterials for respiratory delivery. These results provided researchers with future research directions related to respiratory delivery.

PMID:36145722 | DOI:10.3390/pharmaceutics14091974

Pharmaceutics. 2022 Aug 27;14(9):1803. doi: 10.3390/pharmaceutics14091803.

ABSTRACT

Rational: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease and is associated with high mortality due to a lack of effective treatment. Excessive deposition of the extracellular matrix by activated myofibroblasts in the alveolar space leads to scar formation that hinders gas exchange. Therefore, selectively removing activated myofibroblasts with the aim to repair and remodel fibrotic lungs is a promising approach. Stromal-derived growth factor (SDF-1) is known to stimulate cellular signals which attract stem cells to the site of injury for tissue repair and remodeling. Here, we investigate the effect of overexpression of SDF-1β on lung structure using the bleomycin-injured rat lung model. Methods: Intratracheal administration of bleomycin was performed in adult male rats (F344). Seven days later, in vivo electroporation-mediated gene transfer of either SDF-1β or the empty vector was performed. Animals were sacrificed seven days after gene transfer and histology, design-based stereology, flow cytometry, and collagen measurement were performed on the tissue collected. For in vitro experiments, lung fibroblasts obtained from IPF patients were used. Results: Seven days after SDF-1β gene transfer to bleomycin-injured rat lungs, reduced total collagen, reduced collagen fibrils, improved histology and induced apoptosis of myofibroblasts were observed. Furthermore, it was revealed that TNF-α mediates SDF-1β-induced apoptosis of myofibroblasts; moreover, SDF-1β overexpression increased alveolar epithelial cell numbers and proliferation in vivo and also induced their migration in vitro. Conclusions: Our study demonstrates a new antifibrotic mechanism of SDF-1β overexpression and suggests SDF-1β as a potential new approach for the treatment of lung fibrosis.

PMID:36145551 | DOI:10.3390/pharmaceutics14091803

Medicina (Kaunas). 2022 Sep 16;58(9):1288. doi: 10.3390/medicina58091288.

ABSTRACT

Background and Objectives: Diffuse interstitial lung diseases (DILD) are a heterogeneous group of over 200 entities, some with dramatical evolution and poor prognostic. Because of their overlapping clinical, physiopathological and imagistic nature, successful management requires early detection and proper progression evaluation. This paper tests a complex networks (CN) algorithm for imagistic aided diagnosis fitness for the possibility of achieving relevant and novel DILD management data. Materials and Methods: 65 DILD and 31 normal high resolution computer tomography (HRCT) scans were selected and analyzed with the CN model. Results: The algorithm is showcased in two case reports and then statistical analysis on the entire lot shows that a CN algorithm quantifies progression evaluation with a very fine accuracy, surpassing functional parameters' variations. The CN algorithm can also be successfully used for early detection, mainly on the ground glass opacity Hounsfield Units band of the scan. Conclusions: A CN based computer aided diagnosis could provide the much-required data needed to successfully manage DILDs.

PMID:36143965 | DOI:10.3390/medicina58091288

J Clin Med. 2022 Sep 11;11(18):5336. doi: 10.3390/jcm11185336.

ABSTRACT

BACKGROUND: Although patients with idiopathic pulmonary fibrosis (IPF) often receive treatment with antifibrotic drugs (AFDs) and pulmonary rehabilitation (PR) concurrently, there are no reports on the effect of PR on patients with IPF receiving AFDs. Therefore, we investigated the effect of PR on patients with IPF receiving AFDs.

METHODS: Eighty-seven eligible patients with IPF (61 male; 72.0 ± 8.1 years; GAP severity stage I/II/III: 26/32/12) were recruited for the study. Patients who completed a 3-month outpatient PR program and those who did not participate were classified into four groups according to use of AFDs: PR group (n = 29), PR+AFD group (n = 11), treatment-free observational group (control group; n = 26), and AFD group (n = 21). There was no significant difference in age, sex, or severity among the groups. Patients were evaluated for physical functions such as 6-min walk distance (6MWD) and muscle strength, dyspnea, and health-related quality of life (HRQOL) at baseline and at 3 months.

RESULTS: In the PR group, dyspnea and 6MWD showed significant improvement after the 3-month PR program (p &lt; 0.05 and p &lt; 0.01, respectively). HRQOL was significantly worse at 3 months (p &lt; 0.05) in the AFD group, but not in the other groups. The change in 6MWD from baseline to the 3-month time point was significantly higher in the PR+AFD group than in the AFD groups (p &lt; 0.01).

CONCLUSIONS: It was suggested that AFD treatment reduced exercise tolerance and HRQOL at 3 months; however, the concurrent use of PR may prevent or mitigate these effects.

PMID:36142983 | DOI:10.3390/jcm11185336

Biomedicines. 2022 Sep 16;10(9):2298. doi: 10.3390/biomedicines10092298.

ABSTRACT

Mesenchyme Stem Cells (MSCs) are the most used types of stem cells in regenerative medicine. Regenerative medicine is a rapidly emerging medicine section that creates new methods to regrow, restore, and replace diseased and damaged tissues, organs, and cells. Scholars have shown a positive correlation between MSCs-based therapies and successful treatment of diseases like cardiac ischemia, cartilage problems, bone diseases, diabetes, and even neurological disorders. Although MSCs have several varying features that make them unique, their immuno-regulatory effects in tissue repair emerge from their secretion of paracrine growth factors, exosomes, and cytokines. These cells secrete a secretome, which has regenerative and reparative properties that lead to injury amelioration, immune modulation, or fibrosis reduction. Recent studies have shown that the administration MCSs derived conditioned medium (MSCs-CM) in acute doses in humans is safe and well-tolerated. Studies from animal models and human clinical trials have also shown that they are efficacious tools in regenerative medicine. In this review, we will explore the therapeutic potential of MSCs-CM in pulmonary fibrosis, with further insight into the treatment of Idiopathic Pulmonary Fibrosis (IPF).

PMID:36140399 | DOI:10.3390/biomedicines10092298

Biomedicines. 2022 Aug 31;10(9):2129. doi: 10.3390/biomedicines10092129.

ABSTRACT

Interstitial lung disease (ILD) is the leading cause of mortality in systemic sclerosis (SSc). Progressive pulmonary fibrosis (PPF) is defined as progression in 2 domains including clinical, radiological or lung-function parameters. Our aim was to assess predictors of functional decline in SSc-ILD patients and compare disease behavior to that in idiopathic pulmonary fibrosis (IPF) patients. Patients with normal forced vital capacity (FVC &gt; 80% predicted; SSc-ILD: n = 31; IPF: n = 53) were followed for at least 1 year. Predictors of functional decline including clinical symptoms, comorbidities, lung-function values, high-resolution CT pattern, and treatment data were analyzed. SSc-ILD patents were significantly younger (59.8 ± 13.1) and more often women (93 %) than IPF patients. The median yearly FVC decline was similar in both groups (SSc-ILD = -67.5 and IPF = -65.3 mL/year). A total of 11 SSc-ILD patients met the PPF criteria for functional deterioration, presenting an FVC decline of -153.9 mL/year. Cough and pulmonary hypertension were significant prognostic factors for SSc-ILD functional progression. SSc-ILD patients with normal initial spirometry presenting with cough and PH are at higher risk for showing progressive functional decline.

PMID:36140231 | DOI:10.3390/biomedicines10092129

Antioxidants (Basel). 2022 Sep 10;11(9):1789. doi: 10.3390/antiox11091789.

ABSTRACT

Glutathione (GSH), a major antioxidant in mammalian cells, regulates several vital cellular processes, such as nutrient metabolism, protein synthesis, and immune responses. In addition to its role in antioxidant defense, GSH controls biological processes through its conjugation to reactive protein cysteines in a post-translational modification known as protein S-glutathionylation (PSSG). PSSG has recently been implicated in the pathogenesis of multiple diseases including idiopathic pulmonary fibrosis (IPF). Hallmarks of IPF include repeated injury to the alveolar epithelium with aberrant tissue repair, epithelial cell apoptosis and fibroblast resistance to apoptosis, and the accumulation of extracellular matrix and distortion of normal lung architecture. Several studies have linked oxidative stress and PSSG to the development and progression of IPF. Additionally, it has been suggested that the loss of epithelial cell homeostasis and increased apoptosis, accompanied by the release of various metabolites, creates a vicious cycle that aggravates disease progression. In this short review, we highlight some recent studies that link PSSG to epithelial cell apoptosis and highlight the potential implication of metabolites secreted by apoptotic cells.

PMID:36139863 | DOI:10.3390/antiox11091789

Cells. 2022 Sep 13;11(18):2848. doi: 10.3390/cells11182848.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by aberrant activation of the alveolar epithelium, the expansion of the fibroblast population, and the accumulation of extracellular matrix. Global gene expression of human lung fibroblasts stimulated with TGFβ-1, a strong fibrotic mediator revealed the overexpression of ZNF365, a zinc finger protein implicated in cell cycle control and telomere stabilization. We evaluated the expression and localization of ZNF365 in IPF lungs and in the fibrotic response induced by bleomycin in WT and deficient mice of the orthologous gene Zfp365. In IPF, ZNF365 was overexpressed and localized in fibroblasts/myofibroblasts and alveolar epithelium. Bleomycin-induced lung fibrosis showed an upregulation of Zfp365 localized in lung epithelium and stromal cell populations. Zfp365 KO mice developed a significantly higher fibrotic response compared with WT mice by morphology and hydroxyproline content. Silencing ZNF365 in human lung fibroblasts and alveolar epithelial cells induced a significant reduction of growth rate and increased senescence markers, including Senescence Associated β Galactosidase activity, p53, p21, and the histone variant γH2AX. Our findings demonstrate that ZNF365 is upregulated in IPF and experimental lung fibrosis and suggest a protective role since its absence increases experimental lung fibrosis mechanistically associated with the induction of cell senescence.

PMID:36139424 | DOI:10.3390/cells11182848