Respir Investig. 2024 Jul 11;62(5):785-793. doi: 10.1016/j.resinv.2024.06.006. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the archetypal interstitial lung disease. It is a chronic progressive condition that is challenging to manage as the clinical course of the disease is often difficult to predict. The prevalence of IPF is rising globally and in Japan, where it is estimated to affect 27 individuals per 100,000 of the population. Greater patient numbers and the poor prognosis associated with IPF diagnosis mean that there is a growing need for disease management approaches that can slow or even reverse disease progression and improve survival. Considerable progress has been made in recent years, with the approval of two antifibrotic therapies for IPF (pirfenidone and nintedanib), the availability of Japanese treatment guidelines, and the creation of global and Japanese disease registries. Despite this, significant unmet needs remain with respect to the diagnosis, treatment, and management of this complex disease. Each of these challenges will be discussed in this review, including making a timely and differential diagnosis of IPF, uptake and adherence to antifibrotic therapy, patient access to pulmonary rehabilitation, lung transplantation and palliative care, and optimal strategies for monitoring and staging disease progression, with a particular focus on the status in Japan. In addition, the review will reflect upon how ongoing research, clinical trials of novel therapies, and technologic advancements (including artificial intelligence, biomarkers, and genomic classification) may help address these challenges in the future.

PMID:38996779 | DOI:10.1016/j.resinv.2024.06.006

Vitam Horm. 2024;125:311-365. doi: 10.1016/bs.vh.2024.01.003. Epub 2024 Mar 30.

ABSTRACT

Advanced glycation end products (AGEs) are compounds formed via non-enzymatic reactions between reducing sugars and amino acids or proteins. AGEs can accumulate in various tissues and organs and have been implicated in the development and progression of various diseases, including lung diseases. The receptor of advanced glycation end products (RAGE) is a receptor that can bind to advanced AGEs and induce several cellular processes such as inflammation and oxidative stress. Several studies have shown that both AGEs and RAGE play a role in the pathogenesis of lung diseases, such as chronic obstructive pulmonary disease, asthma, idiopathic pulmonary fibrosis, cystic fibrosis, and acute lung injury. Moreover, the soluble form of the receptor for advanced glycation end products (sRAGE) has demonstrated its ability to function as a decoy receptor, possessing beneficial characteristics such as anti-inflammatory, antioxidant, and anti-fibrotic properties. These qualities make it an encouraging focus for therapeutic intervention in managing pulmonary disorders. This review highlights the current understanding of the roles of AGEs and (s)RAGE in pulmonary diseases and their potential as biomarkers and therapeutic targets for preventing and treating these pathologies.

PMID:38997169 | DOI:10.1016/bs.vh.2024.01.003

Cell. 2024 Jul 11;187(14):3506-3530. doi: 10.1016/j.cell.2024.05.015.

ABSTRACT

Fibrotic interstitial lung diseases (fILDs) have poor survival rates and lack effective therapies. Despite evidence for immune mechanisms in lung fibrosis, immunotherapies have been unsuccessful for major types of fILD. Here, we review immunological mechanisms in lung fibrosis that have the potential to impact clinical practice. We first examine innate immunity, which is broadly involved across fILD subtypes. We illustrate how innate immunity in fILD involves a complex interplay of multiple cell subpopulations and molecular pathways. We then review the growing evidence for adaptive immunity in lung fibrosis to provoke a re-examination of its role in clinical fILD. We close with future directions to address key knowledge gaps in fILD pathobiology: (1) longitudinal studies emphasizing early-stage clinical disease, (2) immune mechanisms of acute exacerbations, and (3) next-generation immunophenotyping integrating spatial, genetic, and single-cell approaches. Advances in these areas are essential for the future of precision medicine and immunotherapy in fILD.

PMID:38996486 | DOI:10.1016/j.cell.2024.05.015

Medicine (Baltimore). 2024 Jul 12;103(28):e38269. doi: 10.1097/MD.0000000000038269.

ABSTRACT

The objective of this study is to investigate the efficacy and safety of flexible transbronchial cryobiopsy (TBCB) in the diagnosis of diffuse parenchymal lung disease (DPLD) in a routine bronchoscopy examination room under analgesia and sedation, using neither endotracheal intubation or rigid bronchoscope nor fluoroscopy or general anesthesia. The data from 50 DPLD patients with unknown etiology who were treated in the Affiliated Hospital of Guilin Medical College from May 2018 to September 2020 were collected, and 43 were eventually included. The specimens obtained from these 43 patients were subjected to pathological examination, pathogenic microorganism culture, etc, and were analyzed in the clinical-radiological-pathological diagnosis mode to confirm the efficacy of TBCB in diagnosing the cause of DPLD. Subsequently, the intraoperative and postoperative complications of TBCB and their severity were closely observed and recorded to comprehensively evaluate the safety of TBCB. For the 43 patients included, a total of 85 TBCB biopsies were performed (1.98 [1, 4] times/case), and 82 valid tissue specimens were obtained (1.91 [1, 4] pieces/case), accounting for 96.5% (82/85) of the total sample. The average specimen size was 12.41 (1, 30) mm2. Eventually, 38 cases were diagnosed, including 11 cases of idiopathic pulmonary fibrosis, 5 cases of connective tissue-related interstitial lung disease, 5 cases of nonspecific interstitial pneumonia, 4 cases of tuberculosis, 4 cases of occupational lung injury, 3 cases of interstitial pneumonia with autoimmune characteristics, 1 case of lung cancer, 2 cases of interstitial lung disease (unclassified interstitial lung disease), 1 case of hypersensitivity pneumonitis, 1 case of pulmonary alveolar proteinosis, and 1 case of fungal infection. The remaining 5 cases were unclarified. For infectious diseases, the overall etiological diagnosis rate was 88.4% (38/43). With respect to complications, pneumothorax occurred in 4 cases (9.3%, 4/43, including 1 mild case and 3 moderate cases), of which 3 cases (75%) were closed by thoracic drainage and 1 case (25%) was absorbed without treatment. In addition, 22 cases experienced no bleeding (51.2%) and 21 cases suffered bleeding to varying degrees based on different severity assessment methods. TBCB is a minimally invasive, rapid, economical, effective, and safe diagnostic technique.

PMID:38996169 | DOI:10.1097/MD.0000000000038269

Medicine (Baltimore). 2024 Jul 12;103(28):e38920. doi: 10.1097/MD.0000000000038920.

ABSTRACT

Nintedanib, a multi-intracellular tyrosine kinase inhibitor, reduces progression of idiopathic pulmonary fibrosis (IPF) and has been approved to use in other progressive fibrosing interstitial lung diseases (ILD) recently. However, the factors that affect the discontinuation of treatment due to adverse events is uncertain. The dorsal muscle group area at the T12 vertebral level (T12DMA) assessed on computed tomography (CT) images has been reported to be associated with mortality in chronic obstructive pulmonary disease (COPD) and other diseases. The relationship between T12DMA and the discontinuation of nintedanib remains unclear.

METHODS: 39 patients with IPF or other progressive fibrosing ILDs who started nintedanib at a regular dose (300 mg/day) were enrolled. We compared the characteristics between patients who stopped nintedanib at a regular dose before 6 months and/or continue to take nintedanib at a low dose (150 mg/day) and patients who were still taking nintedanib at a regular dose over 6 months. This study retrospectively investigated clinical parameters including T12DMA index (T12DMA/height2) to evaluate whether these parameters might serve as risk factor for the tolerability of nintedanib in patients with IPF and other progressive fibrosing ILDs.

RESULTS: Discontinuation or dose reductions of nintedanib due to adverse events were observed in 14 (35.8%) patients. A multiple logistic regression model showed T12DMA index to be the only significant risk factor for predicting for the early termination of nintedanib (odd rate, 0.549; 95% confidence interval, 0.327-0.922; P = .023).

CONCLUSIONS: This study revealed that T12DMA index was a risk factor for the early termination of nintedanib. The initial dose of nintedanib adjusted to the differences in skeletal muscle mass and careful management of adverse events may contribute to the longer nintedanib treatment, which would lead to a better clinical outcome.

PMID:38996147 | DOI:10.1097/MD.0000000000038920

Cells. 2024 Jul 6;13(13):1152. doi: 10.3390/cells13131152.

ABSTRACT

Lung parenchymal hypoxia has emerged as a cardinal feature of idiopathic pulmonary fibrosis (IPF). Hypoxia promotes cancer cell invasion and metastasis through signaling that is dependent upon the lysophosphatidic acid (LPA) receptor, LPA1 (LPAR1). Abundant data indicate that LPA1-dependent signaling also enhances lung fibrogenesis in IPF. We recently reported that fibroblasts isolated from the lungs of individuals with IPF have an increased capacity to form subcellular matrix-degradative structures known as invadosomes, an event that correlates with the degree of lung fibrosis. We therefore hypothesized that hypoxia promotes invadosome formation in lung fibroblasts through LPA1-dependent signaling. Here, it is demonstrated that invadosome formation by fibroblasts from the lungs of individuals with advanced IPF is inhibited by both the tyrosine receptor kinase inhibitor nintedanib and inhibition of LPA1. In addition, exposure of normal human lung fibroblasts to either hypoxia or LPA increased their ability to form invadosomes. Mechanistically, the hypoxia-induced invadosome formation by lung fibroblasts was found to involve LPA1 and PDGFR-Akt signaling. We concluded that hypoxia increases the formation of invadosomes in lung fibroblasts through the LPA1 and PDGFR-Akt signaling axis, which represents a potential target for suppressing lung fibrosis.

PMID:38995003 | DOI:10.3390/cells13131152

Cells. 2024 Jun 29;13(13):1129. doi: 10.3390/cells13131129.

ABSTRACT

Aging is the main risk factor for chronic lung diseases (CLDs) including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging like cellular senescence are increased in these patients in different lung cell types including fibroblasts. However, little is known about the different triggers that induce a senescence phenotype in different disease backgrounds and its role in CLD pathogenesis. Therefore, we characterized senescence in primary human lung fibroblasts (phLF) from control, IPF, or COPD patients at baseline and after exposure to disease-relevant insults (H2O2, bleomycin, TGF-β1) and studied their capacity to support progenitor cell potential in a lung organoid model. Bulk-RNA sequencing revealed that phLF from IPF and COPD activate different transcriptional programs but share a similar senescence phenotype at baseline. Moreover, H2O2 and bleomycin but not TGF-β1 induced senescence in phLF from different disease origins. Exposure to different triggers resulted in distinct senescence programs in phLF characterized by different SASP profiles. Finally, co-culture with bleomycin- and H2O2-treated phLF reduced the progenitor cell potential of alveolar epithelial progenitor cells. In conclusion, phLF from COPD and IPF share a conserved senescence response that varies depending on the insult and impairs alveolar epithelial progenitor capacity ex vivo.

PMID:38994981 | DOI:10.3390/cells13131129

Front Transplant. 2023 Aug 23;2:1146779. doi: 10.3389/frtra.2023.1146779. eCollection 2023.

ABSTRACT

OBJECTIVE: We investigated the impact of body mass index (BMI) on post-operative outcomes and survival of patients with interstitial pulmonary fibrosis (IPF) undergoing lung transplantation.

METHODS: We retrospectively reviewed 222 patients with IPF that underwent lung transplant (LT) at our institution from 2005 to 2019. Recipients were divided in 4 groups: group-1 consisted of underweight patients (BMI ≤18.5 kg/m2), group-2 of normal weight patients (BMI 18.5-25 kg/m2), group-3 of over-weight patients (BMI 25-29.9 kg/m2) and group-4 of obese patients (BMI ≥30 kg/m2).

RESULTS: Group-1 consisted of 13 (6%) patients, group-2 of 67 (30%) patients, group-3 of 79 (36%) patients, group-4 consisted of 63 (28%) patients. Median BMI for group-1 was 17 [interquartile range (IQR): 17, 18], for group-2 was 23 (22, 24), for group-3 was 29 (28, 29.5) and group-4 was 32 (31, 33). Patients in group-1 were significantly younger (p < 0.01). Single LT comprised the majority of operation type in group-2 to group-4 and it was significantly higher than group 1 (p < 0.01). Median follow-up time was 39 months (13-76). A total of 79 (35.5%) patients died by the end of study. Overall, five deaths occurred in group-1, 17 in group-2, 33 in group-3, and 24 in group-4. Kaplan-Meier analysis showed that mortality was not statistically significant between the groups (p = 0.24). Cox-regression analysis was used to assess other possible risk factors that could influence the effect of BMI on mortality, including transplant type (single, double), lung allocation score, and age, diabetes and creatinine levels at surgery. None of these factors were shown to affect patient mortality (p > 0.05). Overall reasons for death included graft failure (24%), infection (23%), respiratory failure (14%), and malignancy (13%).

CONCLUSIONS: Body mass index does not impact long-term survival of patients with IPF undergoing lung transplantation.

PMID:38993923 | PMC:PMC11235251 | DOI:10.3389/frtra.2023.1146779

Int J Biol Sci. 2024 Jun 11;20(9):3353-3371. doi: 10.7150/ijbs.92620. eCollection 2024.

ABSTRACT

Radiation-induced pulmonary fibrosis (RIPF) represents a serious complication observed in individuals undergoing thoracic radiation therapy. Currently, effective interventions for RIPF are unavailable. Prior research has demonstrated that nintedanib, a Food and Drug Administration (FDA)-approved anti-fibrotic agent for idiopathic pulmonary fibrosis, exerts therapeutic effects on chronic fibrosing interstitial lung disease. This research aimed to investigate the anti-fibrotic influences of nintedanib on RIPF and reveal the fundamental mechanisms. To assess its therapeutic impact, a mouse model of RIPF was established. The process involved nintedanib administration at various time points, both prior to and following thoracic radiation. In the RIPF mouse model, an assessment was conducted on survival rates, body weight, computed tomography features, histological parameters, and changes in gene expression. In vitro experiments were performed to discover the mechanism underlying the therapeutic impact of nintedanib on RIPF. Treatment with nintedanib, administered either two days prior or four weeks after thoracic radiation, significantly alleviated lung pathological changes, suppressed collagen deposition, and improved the overall health status of the mice. Additionally, nintedanib demonstrated significant mitigation of radiation-induced inflammatory responses in epithelial cells by inhibiting the PI3K/AKT and MAPK signaling pathways. Furthermore, nintedanib substantially inhibited fibroblast-to-myofibroblast transition by suppressing the TGF-β/Smad and PI3K/AKT/mTOR signaling pathways. These findings suggest that nintedanib exerts preventive and therapeutic effects on RIPF by modulating multiple targets instead of a single anti-fibrotic pathway and encourage the further clinical trials to determine the efficacy of nintedanib in patients with RIPF.

PMID:38993568 | PMC:PMC11234214 | DOI:10.7150/ijbs.92620

Respir Med. 2024 Jul 9:107738. doi: 10.1016/j.rmed.2024.107738. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease of unknown etiology. The aim of this study was to evaluate the environmental and occupational risk factors of IPF.

METHODS: This hospital-based, case-control study included 206 patients with IPF selected from the Seoul National University Bundang Hospital Interstitial Lung Disease registry and 167 controls without lung disease. Data on occupation, lifestyle, transportation, and types of environmental and occupational dust exposure were obtained using a questionnaire. IPF diagnosis was confirmed based on the recent guidelines, and the possibility of hypersensitivity pneumonitis was excluded. Multiple logistic regression was performed to determine the risk factors for IPF.

RESULTS: After adjusting for age and sex, ever-smokers (odds ratio [OR], 2.35; 95% confidence interval [CI]: 1.51-3.68) and individuals who smoked more than 30 pack-years (OR, 2.79; 95%CI: 1.70-4.68) showed an increased risk for IPF. Any occupational dust exposure (adjusted OR, 2.08; 95%CI: 1.19-3.72), especially exposure to chemicals (adjusted OR, 3.52; 99%CI: 1.56-9.05), was associated with IPF after adjusting for age, sex, and smoking.

CONCLUSIONS: Smoking and occupational dust exposure are associated with an increased risk for IPF. Both factors have dose and duration-dependent relationships with the risk for IPF.

PMID:38992818 | DOI:10.1016/j.rmed.2024.107738

Int J Dermatol. 2024 Jul 11. doi: 10.1111/ijd.17380. Online ahead of print.

NO ABSTRACT

PMID:38991989 | DOI:10.1111/ijd.17380

Radiol Cardiothorac Imaging. 2024 Aug;6(4):e230068. doi: 10.1148/ryct.230068.

ABSTRACT

Purpose To compare the diagnostic performance of the American Thoracic Society, Japanese Respiratory Society, and Asociación Latinoamericana del Tórax (ATS/JRS/ALAT) versus the American College of Chest Physicians (ACCP) imaging classifications for hypersensitivity pneumonitis (HP). Materials and Methods Patients in the institutional review board-approved Interstitial Lung Disease (ILD) registry referred for multidisciplinary discussion (MDD) at the authors' institution (January 1, 2006-April 1, 2021) were included in this retrospective study when ILD was diagnosed at MDD. MDD diagnoses included HP, connective tissue disease-ILD, and idiopathic pulmonary fibrosis. Retrospective review of thin-section CT images was performed in consensus by two cardiothoracic radiologists blinded to the diagnosis. Diagnostic patterns were determined for thin-section CT images using both classifications. Discordance rates were determined. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were assessed using MDD diagnosis as the reference standard. Results A total of 297 patients were included in the study: 200 (67%) with HP, 49 (16%) with connective tissue disease-ILD, and 48 (16%) with idiopathic pulmonary fibrosis at MDD. The discordance rate between the two classifications was 21%. Assuming low HP prevalence (10%), ATS/JRS/ALAT classification outperformed ACCP classification, with greater accuracy (92.3% vs 87.6%) and greater positive predictive value (60.7% vs 42.9%). Assuming high prevalence (50%), accuracy and negative predictive value were superior using ACCP classification (81.7% vs 79.7% and 77.7% vs 72.6%, respectively), and positive predictive value was superior using ATS/JRS/ALAT classification (93.3% vs 87.1%). Conclusion Accuracy of the ATS/JRS/ALAT and ACCP HP classifications was greater in settings with low and high HP prevalence, respectively. Diagnostic performance of both classifications was discordant in a minority of cases. Keywords: CT, Thorax, Hypersensitivity Pneumonitis, Interstitial Lung Disease Supplemental material is available for this article. © RSNA, 2024.

PMID:38990131 | DOI:10.1148/ryct.230068

Adv Med Sci. 2024 Jul 8:S1896-1126(24)00038-5. doi: 10.1016/j.advms.2024.07.004. Online ahead of print.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis (IPF), a chronic and progressively worsening condition characterized by interstitial lung inflammation and fibrosis of unknown etiology, has a grim prognosis. The treatment options for IPF are limited and new therapeutic strategies are urgently needed. Dietary restriction can improve various inflammatory diseases, but its therapeutic effect on bleomycin (BLM)-induced pulmonary fibrosis mouse model remains unclear. This study aims to investigate whether intermittent fasting (IF) can alleviate BLM-induced pulmonary inflammation and fibrosis.

METHODS: Pulmonary fibrosis mouse models were induced by BLM. The IF group underwent 24-hour fasting cycles for one week prior and three weeks following BLM administration. Meanwhile, the ad libitum feeding group had unrestricted access to food throughout the experiment. The evaluation focused on lung pathology via histological staining, qPCR analysis of collagen markers, and immune cell profiling through flow cytometry.

RESULTS: IF group significantly reduced inflammation and fibrosis in lung tissues of BLM-induced mice compared to ad libitum feeding group. qPCR results showed IF remarkably decreased the mRNA expression of Col 1a and Col 3a in the lungs of BLM-induced mouse models. IF also reduced the numbers of regulatory T cells (Tregs), T helper 17 (Th17) cells, monocytes, and monocyte-derived alveolar macrophages (MoAMs) in the lung tissues.

CONCLUSIONS: IF may improve BLM-induced pulmonary fibrosis by decreasing numbers of immune cells including Treg cells, Th17 cells, monocytes, and MoAMs in the lungs. This study offers experimental validation for dietary intervention as a viable treatment modality in IPF management.

PMID:38986767 | DOI:10.1016/j.advms.2024.07.004

Phytother Res. 2024 Jul 10. doi: 10.1002/ptr.8285. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with an unknown underlying cause. There is no complete cure for IPF; however, two anti-fibrotic agents (Nintedanib and pirfenidone) are approved by the USFDA to extend the patient's life span. Therefore, alternative therapies supporting the survival of fibrotic patients have been studied in recent literature. The abundance of phenolic compounds, particularly flavonoids, has gathered attention due to their potential health benefits. Various flavonoids, like naringin, quercetin, baicalin, baicalein, puerarin, silymarin, and kaempferol, exhibit anti-inflammatory and anti-oxidant properties, which help decrease lung fibrosis. Various databases, including PubMed, EBSCO, ProQuest, and Scopus, as well as particular websites, such as the World Health Organisation and the National Institutes of Health, were used to conduct a literature search. Several mechanisms of action of flavonoids are reported with the help of in vivo and cell line studies emphasizing their ability to modulate oxidative stress, inflammation, and fibrotic processes in the lungs. They are reported for the restoration of biomarkers like hydroxyproline, cytokines, superoxide dismutase, malondialdehyde and others associated with IPF and for modulating various pathways responsible for the progression of pulmonary fibrosis. Yet, flavonoids have some drawbacks, such as poor solubility, challenging drug loading, stability issues, and scarce bioavailability. Therefore, novel formulations of flavonoids are explored, including liposomes, solid lipid microparticles, polymeric nanoparticles, nanogels, and nanocrystals, to enhance the therapeutic efficacy of flavonoids in pulmonary fibrosis. This review focuses on the role of flavonoids in mitigating idiopathic pulmonary fibrosis, their mode of action and novel formulations.

PMID:38986681 | DOI:10.1002/ptr.8285

Mol Biol Cell. 2024 Jul 10:mbcE23110428. doi: 10.1091/mbc.E23-11-0428. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), one of the most common forms of interstitial lung disease, is a poorly understood, chronic, and often fatal fibroproliferative condition with only two FDA-approved medications. Understanding the pathobiology of the fibroblast in IPF is critical to evaluating and discovering novel therapeutics. Using a decellularized lung matrix derived from IPF patients, we generate three-dimensional (3D) hydrogels as in vitro models of lung physiology and characterize the phenotype of fibroblasts seeded into the hydrogels. When cultured in IPF ECM hydrogels, IPF fibroblasts display differential contractility compared to their normal counterparts, lose the classical myofibroblast marker α-smooth muscle actin, and increase expression of proinflammatory cytokines compared to fibroblasts seeded two-dimensionally (2D) on tissue culture dishes. We validate this proinflammatory state in fibroblast-conditioned media studies with monocytes and monocyte-derived macrophages. These findings add to a growing understanding of the lung microenvironment effect on fibroblast phenotypes, shed light on the potential role of fibroblasts as immune signaling hubs during lung fibrosis, and suggest intervention in fibroblast-immune cell crosstalk as a possible novel therapeutic avenue.

PMID:38985514 | DOI:10.1091/mbc.E23-11-0428

Stem Cells. 2024 Jul 10:sxae044. doi: 10.1093/stmcls/sxae044. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis is a chronic progressive interstitial lung disease characterized by alveolar epithelial cell (AEC) injury and fibroblast activation. Inadequate autophagy in AECs may result from the activation of several signaling pathways following AEC injury, with glycoproteins serving as key receptor proteins. The core fucosylation (CF) modification in glycoproteins is crucial. Mesenchymal stem cells derived from bone marrow (BMSCs) have the ability to regenerate damaged tissue and treat pulmonary fibrosis (PF). This study aimed to elucidate the relationship and mechanism of interaction between BMSCs, CF modification, and autophagy in PF.

METHODS: C57BL/6 male mice, alveolar epithelial cell-specific FUT8 conditional knockout (CKO) mice, and MLE12 cells were administered bleomycin (BLM), FUT8 siRNA, and mouse BMSCs, respectively. Experimental techniques including tissue staining, western blotting, immunofluorescence, autophagic flux detection, and flow cytometry were utilized in this study.

RESULTS: First, we found that autophagy was inhibited while FUT8 expression was elevated in PF mice and BLM-induced AEC injury models. Subsequently, CKO mice and MLE12 cells transfected with FUT8 siRNA were employed to demonstrate that inhibition of CF modification induces autophagy in AECs and mitigates PF. Finally, mouse BMSCs were utilized to demonstrate that they alleviate the detrimental autophagy of AECs by inhibiting CF modification and decreasing PF.

CONCLUSIONS: Suppression of CF modification enhanced the suppression of AEC autophagy and reduced PF in mice. Additionally, through the prevention of CF modification, BMSCs can assist AECs deficient in autophagy and partially alleviate PF.

PMID:38982795 | DOI:10.1093/stmcls/sxae044

Sci Rep. 2024 Jul 9;14(1):15778. doi: 10.1038/s41598-024-66947-5.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most predominant type of idiopathic interstitial pneumonia and has an increasing incidence, poor prognosis, and unclear pathogenesis. In order to investigate the molecular mechanisms underlying IPF further, we performed single-cell RNA sequencing analysis on three healthy controls and five IPF lung tissue samples. The results revealed a significant shift in epithelial cells (ECs) phenotypes in IPF, which may be attributed to the differentiation of alveolar type 2 cells to basal cells. In addition, several previously unrecognized basal cell subtypes were preliminarily identified, including extracellular matrix basal cells, which were increased in the IPF group. We identified a special population of fibroblasts that highly expressed extracellular matrix-related genes, POSTN, CTHRC1, COL3A1, COL5A2, and COL12A1. We propose that the close interaction between ECs and fibroblasts through ligand-receptor pairs may have a critical function in IPF development. Collectively, these outcomes provide innovative perspectives on the complexity and diversity of basal cells and fibroblasts in IPF and contribute to the understanding of possible mechanisms in pathological lung fibrosis.

PMID:38982264 | DOI:10.1038/s41598-024-66947-5

J Clin Invest. 2024 Jul 9:e174598. doi: 10.1172/JCI174598. Online ahead of print.

ABSTRACT

Reciprocal interactions between alveolar fibroblasts and epithelial cells are crucial for lung homeostasis, injury repair, and fibrogenesis, but underlying mechanisms remain unclear. To investigate, we administered the fibroblast-selective TGFβ1 signaling inhibitor, epigallocatechin gallate (EGCG), to Interstitial Lung Disease (ILD) patients undergoing diagnostic lung biopsy and conducted single-cell RNA sequencing on spare tissue. Biopsies from untreated patients showed higher fibroblast TGFβ1 signaling compared to non-disease donor or end-stage ILD tissues. In vivo, EGCG downregulated TGFβ1 signaling and several pro-inflammatory and stress pathways in biopsy samples. Notably, EGCG reduced fibroblast secreted frizzle-like receptor protein 2 (sFRP2), an unrecognized TGFβ1 fibroblast target gene induced near type II alveolar epithelial cells (AEC2s) in situ. Using AEC2-fibroblast coculture organoids and precision cut lung slices (PCLS) from non-diseased donors, we found TGFβ1 signaling promotes a spread AEC2 KRT17+ basaloid state, whereupon sFRP2 then activates a mature Krt5+ basal cell program. Wnt-receptor Frizzled 5 (Fzd5) expression and downstream calcineurin signaling were required for sFRP2-induced nuclear NFATc3 accumulation and KRT5 expression. These findings highlight stage-specific TGFβ1 signaling in ILD, the therapeutic potential of EGCG in reducing IPF-related transcriptional changes, and identify TGFβ1-non-canonical Wnt pathway crosstalk via sFRP2 as a novel mechanism for dysfunctional epithelial signaling in Idiopathic Pulmonary Fibrosis/ILD.

PMID:38980870 | DOI:10.1172/JCI174598

Angew Chem Int Ed Engl. 2024 Jul 9:e202408473. doi: 10.1002/anie.202408473. Online ahead of print.

ABSTRACT

We report an endoperoxide compound (E5) which can deliver three therapeutic components by a thermal cycloreversion, namely, singlet oxygen, triplet oxygen and 3-methyl-N-phenyl-2-pyridone, thus targeting multiple mechanisms for treating non-small cell lung cancer and idiopathic pulmonary fibrosis. In aqueous environment, E5 undergoes clean reaction to afford three therapeutic components with a half-life of 8.3 hours without the generation of other by-products, which not only achieves good cytotoxicity toward lung cancer cells and decreases the levels of HIF-1α protein, but also inhibits the TGF-β1 induced fibrosis in vitro. In vivo experiments also demonstrated the efficacy of E5 in inhibiting tumor growth and relieving idiopathic pulmonary fibrosis, while exhibiting good biocompatibility. Many lines of evidence reveal the therapeutic efficacy of singlet oxygen and 3-methyl-N-phenyl-2-pyridone, and triplet oxygen could downregulate HIF-1α and relieve tumor hypoxia which is a critical issue in conventional PDT. Unlike other combination therapies, in which multiple therapeutic agents are given in independent formulations, our work demonstrates single molecule endoperoxide prodrugs could be developed as new platforms for treatment of cancers and related diseases.

PMID:38979839 | DOI:10.1002/anie.202408473

Lung. 2024 Jul 8. doi: 10.1007/s00408-024-00723-0. Online ahead of print.

ABSTRACT

INTRODUCTION: Cough is common in interstitial lung disease (ILD) and is associated with disease progression, yet its mechanisms are understudied. We investigated cough hypersensitivity features and impact in ILD.

METHODS: Participants with ILD and cough (n = 195) completed a multiple choice and free text questionnaire on cough sensations/triggers and impacts.

RESULTS: The majority of participants were male (54%), aged > 65 (64%), with idiopathic pulmonary fibrosis (IPF, 75%). Common cough triggers were body position (74%), physical activity (72%), and talking (62%). Common laryngeal sensations were globus (43%), and itch/tickle (42%). Cough impacted everyday life in 55%, and all activities in 31%, causing exhaustion (59%), social embarrassment (70%), urinary incontinence (46% females), and syncope/pre-syncope (12%). The total number of cough-provoking sensations/triggers correlated with impacts; ρ = 0.73, p < 0.001.

CONCLUSION: Cough hypersensitivity symptoms are prevalent in ILD and detrimentally affect quality of life. Further studies investigating mechanisms of cough hypersensitivity and targeted pharmacotherapy are warranted.

PMID:38977494 | DOI:10.1007/s00408-024-00723-0