BMC Pulm Med. 2024 Jul 27;24(1):362. doi: 10.1186/s12890-024-03167-7.

ABSTRACT

The lung is a highly mechanical organ as it is exposed to approximately 109 strain cycles, (where strain is the length change of tissue structure per unit initial length), with an approximately 4% amplitude change during quiet tidal breathing or 107 strain cycles at a 25% amplitude during heavy exercises, sighs, and deep inspirations. These mechanical indices have been reported to become aberrant in lung diseases such as acute respiratory distress syndrome (ARDS), pulmonary hypertension, bronchopulmonary dysplasia (BPD), idiopathic pulmonary fibrosis (IPF), and asthma. Through recent innovations, various in vitro systems/bioreactors used to mimic the lung's mechanical strain have been developed. Among these, the Flexcell tension system which is composed of bioreactors that utilize a variety of programs in vitro to apply static and cyclic strain on different cell-types established as 2D monolayer cultures or cell-embedded 3D hydrogel models, has enabled the assessment of the response of different cells such as fibroblasts to the lung's mechanical strain in health and disease. Fibroblasts are the main effector cells responsible for the production of extracellular matrix (ECM) proteins to repair and maintain tissue homeostasis and are implicated in the excessive deposition of matrix proteins that leads to lung fibrosis. In this review, we summarise, studies that have used the Flexcell tension bioreactor to assess effects of the mechanical lung on the structure, function, and phenotype of lung fibroblasts in homeostatic conditions and abnormal environments associated with lung injury and disease. We show that these studies have revealed that different strain conditions regulate fibroblast proliferation, ECM protein production, and inflammation in normal repair and the diseased lung.

PMID:39068387 | DOI:10.1186/s12890-024-03167-7

Pharmaceuticals (Basel). 2024 Jul 11;17(7):930. doi: 10.3390/ph17070930.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare and progressive interstitial lung disease characterized by irreversible distortion of lung architecture and subsequent loss of pulmonary function. Pirfenidone is an antifibrotic agent associated with increased progression-free survival and overall survival rates, but it carries multiple side effects. The aim of the study was to examine the efficacy and safety profile of pirfenidone in a real-life context, with a focus on the concomitant use of antithrombotic and/or anticoagulant treatments. The clinical and functional data (forced vital capacity [FVC], forced expiratory volume in 1 s [FEV1], diffusing lung capacity for carbon monoxide [DLCO], and 6 min walking test distance [6MWD]) of all IPF patients treated with pirfenidone and referred to our two centers between 2019 and 2022 were retrospectively analyzed at baseline, 6 and 12 months after the start of treatment. A total of 55 IPF subjects undergoing pirfenidone treatment were included in the analysis (45.5% females, median [IQR] age at disease onset 68.0 [10.0] years, median [IQR] age at baseline 69.0 [10.8] years). Compared to baseline, at 12 months, FVC (86.0% vs. 80.0%; p = 0.023) and DLCO (44.0% vs. 40.0%; p = 0.002) were significantly reduced, while FEV1 (p = 0.304) and 6MWD (p = 0.276) remained stable; no significant change was recorded at 6 months. Most of the reported adverse events were mild or moderate. Gastrointestinal intolerance (9.1%) was the main cause of treatment discontinuation. A total of 5% of patients reported at least one minor bleeding event, although all episodes occurred in those receiving concomitant antithrombotic or anticoagulant. Overall, this real-life experience confirms the efficacy and safety profile of pirfenidone in the case of the concomitant use of antithrombotic and/or anticoagulant drugs.

PMID:39065780 | DOI:10.3390/ph17070930

J Clin Med. 2024 Jul 15;13(14):4127. doi: 10.3390/jcm13144127.

ABSTRACT

N-acetyl-L-cysteine (NAC) was initially introduced as a treatment for mucus reduction and widely used for chronic respiratory conditions associated with mucus overproduction. However, the mechanism of action for NAC extends beyond its mucolytic activity and is complex and multifaceted. Contrary to other mucoactive drugs, NAC has been found to exhibit antioxidant, anti-infective, and anti-inflammatory activity in pre-clinical and clinical reports. These properties have sparked interest in its potential for treating chronic lung diseases, including chronic obstructive pulmonary disease (COPD), bronchiectasis (BE), cystic fibrosis (CF), and idiopathic pulmonary fibrosis (IPF), which are associated with oxidative stress, increased levels of glutathione and inflammation. NAC's anti-inflammatory activity is noteworthy, and it is not solely secondary to its antioxidant capabilities. In ex vivo models of COPD exacerbation, the anti-inflammatory effects have been observed even at very low doses, especially with prolonged treatment. The mechanism involves the inhibition of the activation of NF-kB and neurokinin A production, resulting in a reduction in interleukin-6 production, a cytokine abundantly present in the sputum and breath condensate of patients with COPD and correlates with the number of exacerbations. The unique combination of mucolytic, antioxidant, anti-infective, and anti-inflammatory properties positions NAC as a safe, cost-effective, and efficacious therapy for a plethora of respiratory conditions.

PMID:39064168 | DOI:10.3390/jcm13144127

Life (Basel). 2024 Jul 19;14(7):897. doi: 10.3390/life14070897.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) has the potential to cause fatal pulmonary toxicity after radiotherapy and can increase the morbidity and mortality of non-small-cell lung cancer (NSCLC) patients. In this context, we aimed to develop imaging complexity biomarkers to predict the incidence of severe pulmonary toxicity in patients with NSCLC who have underlying IPF and are treated with radiotherapy. Methods: We retrospectively reviewed the medical records of 19 patients with NSCLC who had underlying IPF and were treated with radiotherapy at the Korea University Guro Hospital between March 2018 and December 2022. To quantify the morphometric complexity of the lung parenchyma, box-counting fractal dimensions and lacunarity analyses were performed on pre-radiotherapy simulation chest computed tomography scans. Results: Of the 19 patients, the incidence of grade 3 or higher radiation pneumonitis was observed in 8 (42.1%). After adjusting for age, sex, smoking status, histology, and diffusing capacity of the lung for carbon monoxide, eight patients with a lower fractal dimension showed a significantly higher hazard ratio of 7.755 (1.168-51.51) for grade 3 or higher pneumonitis than those with a higher fractal dimension. Patients with lower lacunarity exhibited significantly lower hazards in all models, both with and without adjustments. The lower-than-median lacunarity group also showed significantly lower incidence curves for all models built in this study. Conclusions: We devised a technique for quantifying morphometric complexity in NSCLC patients with IPF on radiotherapy and discovered lacunarity as a potential imaging biomarker for grade 3 or higher pneumonitis.

PMID:39063650 | DOI:10.3390/life14070897

Int J Mol Sci. 2024 Jul 18;25(14):7867. doi: 10.3390/ijms25147867.

ABSTRACT

Currently, the global lifespan has increased, resulting in a higher proportion of the population over 65 years. Changes that occur in the lung during aging increase the risk of developing acute and chronic lung diseases, such as acute respiratory distress syndrome, chronic obstructive pulmonary disease, idiopathic pulmonary fibrosis, and lung cancer. During normal tissue homeostasis, cell proliferation and apoptosis create a dynamic balance that constitutes the physiological cell turnover. In basal conditions, the lungs have a low rate of cell turnover compared to other organs. During aging, changes in the rate of cell turnover in the lung are observed. In this work, we review the literature that evaluates the role of molecules involved in cell proliferation and apoptosis in lung aging and in the development of age-related lung diseases. The list of molecules that regulate cell proliferation, apoptosis, or both processes in lung aging includes TNC, FOXM1, DNA-PKcs, MicroRNAs, BCL-W, BCL-XL, TCF21, p16, NOX4, NRF2, MDM4, RPIA, DHEA, and MMP28. However, despite the studies carried out to date, the complete signaling pathways that regulate cell turnover in lung aging are still unknown. More research is needed to understand the changes that lead to the development of age-related lung diseases.

PMID:39063108 | DOI:10.3390/ijms25147867

Int J Mol Sci. 2024 Jul 15;25(14):7754. doi: 10.3390/ijms25147754.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a long-term condition with an unidentified cause, and currently there are no specific treatment options available. Alveolar epithelial type II cells (AT2) constitute a heterogeneous population crucial for secreting and regenerative functions in the alveolus, essential for maintaining lung homeostasis. However, a comprehensive investigation into their cellular diversity, molecular features, and clinical implications is currently lacking. In this study, we conducted a comprehensive examination of single-cell RNA sequencing data from both normal and fibrotic lung tissues. We analyzed alterations in cellular composition between IPF and normal tissue and investigated differentially expressed genes across each cell population. This analysis revealed the presence of two distinct subpopulations of IPF-related alveolar epithelial type II cells (IR_AT2). Subsequently, three unique gene co-expression modules associated with the IR_AT2 subtype were identified through the use of hdWGCNA. Furthermore, we refined and identified IPF-related AT2-related gene (IARG) signatures using various machine learning algorithms. Our analysis demonstrated a significant association between high IARG scores in IPF patients and shorter survival times (p-value < 0.01). Additionally, we observed a negative correlation between the percent predicted diffusing capacity for lung carbon monoxide (% DLCO) and increased IARG scores (cor = -0.44, p-value < 0.05). The cross-validation findings demonstrated a high level of accuracy (AUC > 0.85, p-value < 0.01) in the prognostication of patients with IPF utilizing the identified IARG signatures. Our study has identified distinct molecular and biological features among AT2 subpopulations, specifically highlighting the unique characteristics of IPF-related AT2 cells. Importantly, our findings underscore the prognostic relevance of specific genes associated with IPF-related AT2 cells, offering valuable insights into the advancement of IPF.

PMID:39062997 | DOI:10.3390/ijms25147754

Genes (Basel). 2024 Jul 17;15(7):934. doi: 10.3390/genes15070934.

ABSTRACT

INTRODUCTION: Interstitial lung diseases are a varied group of diseases associated with chronic inflammation and fibrosis. With the emerging and current treatment options, survival rates have vastly improved. Having in mind that the most common type is idiopathic pulmonary fibrosis and that a significant proportion of these patients will develop lung cancer as the disease progresses, prompt diagnosis and personalized treatment of these patients are fundamental.

SCOPE AND METHODS: The scope of this review is to identify and characterize molecular and pathogenetic pathways that can interconnect Interstitial Lung Diseases and lung cancer, especially driver mutations in patients with NSCLC, and to highlight new and emerging treatment options in that view.

RESULTS: Common pathogenetic pathways have been identified in sites of chronic inflammation in patients with interstitial lung diseases and lung cancer. Of note, the expression of driver mutations in EGFR, BRAF, and KRAS G12C in patients with NSCLC with concurrent interstitial lung disease is vastly different compared to those patients with NSCLC without Interstitial Lung Disease.

CONCLUSIONS: NSCLC in patients with Interstitial Lung Disease is a challenging diagnostic and clinical entity, and a personalized medicine approach is fundamental to improving survival and quality of life. Newer anti-fibrotic medications have improved survival in IPF/ILD patients; thus, the incidence of lung cancer is going to vastly increase in the next 5-10 years.

PMID:39062713 | DOI:10.3390/genes15070934

Biomedicines. 2024 Jun 27;12(7):1436. doi: 10.3390/biomedicines12071436.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease for which there is a lack of effective pharmacological treatments. Hirudin, a natural peptide extracted from leeches, has been used for broad pharmacological purposes. In this study, we investigated the therapeutic effects of hirudin on IPF and its related mechanism of action. By constructing a mouse model of pulmonary fibrosis and treating it with hirudin in vivo, we found that hirudin exerted anti-fibrotic, anti-oxidative, and anti-fibroblast senescence effects. Moreover, using an in vitro model of stress-induced premature senescence in primary mouse lung fibroblasts and treating with hirudin, we observed inhibition of fibroblast senescence and upregulation of PGC1-alpha and Sirt3 expression. However, specific silencing of PGC1-alpha or Sirt3 suppressed the anti-fibroblast senescence effect of hirudin. Thus, the PGC1-alpha/Sirt3 pathway mediates the anti-fibroblast senescence effect of hirudin, potentially serving as a molecular mechanism underlying its anti-fibrosis and anti-oxidative stress effects exerted on the lungs.

PMID:39062010 | DOI:10.3390/biomedicines12071436

Biomedicines. 2024 Jun 21;12(7):1384. doi: 10.3390/biomedicines12071384.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) has traditionally been considered the archetype of progressive fibrotic interstitial lung diseases (f-ILDs), but several other f-ILDs can also manifest a progressive phenotype. Integrating genomic signatures into clinical practice for f-ILD patients may help to identify patients predisposed to a progressive phenotype. In addition to the risk of progressive pulmonary fibrosis, there is a growing body of literature examining how pharmacogenomics influences treatment response, particularly regarding the efficacy and safety profiles of antifibrotic and immunomodulatory agents. In this narrative review, we discuss current studies in IPF and other forms of pulmonary fibrosis, including systemic autoimmune disorders associated ILDs, sarcoidosis and hypersensitivity pneumonitis. We also provide insights into the future direction of research in this complex field.

PMID:39061958 | DOI:10.3390/biomedicines12071384

Diseases. 2024 Jul 13;12(7):155. doi: 10.3390/diseases12070155.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) imposes a substantial symptom burden that adversely impacts patients' quality of life. Current anti-fibrotic treatments for IPF provide limited symptomatic relief, necessitating the implementation of complementary disease management strategies to enhance health-related quality of life (HRQOL). Serracor-NK® and Serra Rx260, systemic enzyme supplements, improved symptoms and HRQOL with favorable safety profiles in a proof-of-concept study in PF patients. This prospective, double-blind randomized placebo-controlled trial enrolled 100 IPF patients from six institutions. The supplement group (n = 50) received the oral systemic enzyme supplements Serracor-NK® and Serra Rx260 in addition to standard care for 6 months, while the placebo group (n = 50) received standard care alone. The primary objective was to evaluate the regimen's impact on symptoms, QOL, and well-being using the UCSD shortness of breath (UCSD-SOB) questionnaire, St. George's respiratory questionnaire (SGRQ), and WHO well-being index (WHO-5). Safety evaluation was a secondary objective. A significantly higher proportion of patients in the supplement group demonstrated meaningful improvement in symptoms as compared to the placebo group, as assessed by the UCSD-SOB (p < 0.05) and SGRQ questionnaires (p < 0.05). Additionally, a significantly greater proportion of patients in the supplement group showed improved QOL and well-being (p < 0.05) and reduced health impairment (p < 0.05), as assessed by SGRQ. Mental well-being (WHO-5) and physical activity (SGRQ activity domain) did not differ significantly between the groups. Safety assessments, including liver function tests and vital signs, indicated that the supplement regimen was well tolerated. To conclude, Serracor-NK® and Serra Rx260 alleviate symptoms and enhance HRQOL in IPF patients with a favorable safety profile (Clinical Trials Registry India registration number: CTRI/2020/05/025374).

PMID:39057126 | DOI:10.3390/diseases12070155

Biomed J. 2024 Jul 23:100773. doi: 10.1016/j.bj.2024.100773. Online ahead of print.

ABSTRACT

This issue of the Biomedical Journal highlights major advancements in drug delivery, including aptamer-functionalized liposomes and nanozymes. A new biomarker combination shows promise for improved diagnosis of idiopathic pulmonary fibrosis. Mesenchymal stem cells are suggested to mitigate inflammation in systemic lupus erythematosus, and a potential positive feedback loop driven by a prevalent mRNA modification is suggested to enhance NSCLC progression. Additional articles explore a pathological impact on autophagy leading to muscle dysfunction, the benefits of integrating an orphan drug with standard therapy for glioblastoma patients, and the influence of transcriptional super-enhancers in early-stage esophageal squamous cell carcinoma. Finally, this issue provides insights into the roles of different Blastocystis subtypes, and the use of laser light for treating infantile hemangioma.

PMID:39053731 | DOI:10.1016/j.bj.2024.100773

Heliyon. 2024 Jun 24;10(13):e33314. doi: 10.1016/j.heliyon.2024.e33314. eCollection 2024 Jul 15.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) represents a severe interstitial lung disease characterized by limited therapeutic interventions. Recent study has suggested that sinomenine (SIN), an alkaloid derived from the roots of Sinomenium acutum, demonstrates efficacy in interrupting aerobic glycolysis, a predominant metabolic pathway in myofibroblasts. However, its pharmacological potential in the context of pulmonary fibrosis remains inadequately explored. In the present study, we established a bleomycin (BLM)-induced pulmonary fibrosis mouse model and subjected the mice to a one-week regimen of SIN treatment to assess its efficacy. Additionally, a TGF-β1-induced primary lung fibroblast model was employed to investigate the molecular mechanism underlying the effects of SIN. Our observations revealed robust anti-pulmonary fibrosis properties associated with SIN treatment, as evidenced by reduced extracellular matrix deposition, diminished hydroxyproline contents, improved Ashcroft scores, and enhanced lung function parameters. Furthermore, SIN administration significantly impeded TGF-β1-induced fibroblast-to-myofibroblast differentiation. Mechanistically, SIN exerted its beneficial effects by mitigating aerobic glycolysis, achieved through the inhibition of the expression of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (Pfkfb3). Notably, the protective effects of SIN on fibroblasts were reversed upon ectopic overexpression of Pfkfb3. In conclusion, our data underscore the potential of SIN to attenuate fibroblast-to-myofibroblast differentiation by modulating Pfkfb3-associated aerobic glycolysis and SIN emerges as a promising anti-fibrotic agent for pulmonary fibrosis in clinical practice.

PMID:39050413 | PMC:PMC11268178 | DOI:10.1016/j.heliyon.2024.e33314

Differentiation. 2024 Jul 21:100801. doi: 10.1016/j.diff.2024.100801. Online ahead of print.

ABSTRACT

Fibroblast growth factor 7 (FGF7), also known as keratinocyte growth factor (KGF), is an important member of the FGF family that is mainly expressed by cells of mesenchymal origin while affecting specifically epithelial cells. Thus, FGF7 is widely expressed in diverse tissues, especially in urinary system, gastrointestinal tract (GI-tract), respiratory system, skin, and reproductive system. By interacting specifically with FGFR2-IIIb, FGF7 activates several downstream signal pathways, including Ras, PI3K-Akt, and PLCs. Previous studies of FGF7 mutants also have implicated its roles in various biological processes including development of essential organs and tissue homeostasis in adults. Moreover, more publications have reported that FGF7 and/or FGF7/FGFR2-IIIb-associated signaling pathway are involved in the progression of various heritable or acquired human diseases: heritable conditions like autosomal dominant polycystic kidney disease (ADPKD) and non-syndromic cleft lip and palate (NS CLP), where it promotes cyst formation and affects craniofacial development, respectively; acquired non-malignant diseases such as chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), mucositis, osteoarticular disorders, and metabolic diseases, where it influences inflammation, repair, and metabolic control; and tumorigenesis and malignant diseases, including benign prostatic hyperplasia (BPH), prostate cancer, gastric cancer, and ovarian cancer, where it enhances cell proliferation, invasion, and chemotherapy resistance. Targeting FGF7 pathways holds therapeutic potential for managing these conditions, underscoring the need for further research to explore its clinical applications. Having more insights into the function and underlying molecular mechanisms of FGF7 is warranted to facilitate the development of effective treatments in the future. Here, we discuss FGF7 genomic structure, signal pathway, expression pattern during embryonic development and in adult organs and mutants along with phenotypes, as well as associated diseases.

PMID:39048474 | DOI:10.1016/j.diff.2024.100801

Ann Clin Lab Sci. 2024 May;54(3):363-370.

ABSTRACT

OBJECTIVE: During the progression of chronic idiopathic pulmonary fibrosis (IPF), maladaptive tissue remodeling including excessive extracellular matrix (ECM) deposition occurs, which eventually leads to architectural distortion and loss of organ function in organ fibrosis. ADAM15, which is highly expressed in the developing lungs and kidneys, is a transmembrane-anchored multidomain protein belonging to the family of metalloproteinases. Compared to the extensive studies about functions of matrix metalloproteinases (MMPs), less are discussed about ADAM15, particularly in function and mechanism involving fibrogenesis. Our study aims to fill in this gap.

METHODS: We identified ADAM15 as a novel antifibrotic mediator in lung fibrosis. We found that ADAM15 has cross-talks with transforming growth factor-β1 (TGF-β1), which is the most potent profibrotic mediator. We provided molecular and translational evidence that knockdown of ADAM15 accelerated fibrogenic response induced by TGF-β1 and upregulation of ADAM15 rescued TGF-β1-induced myofibroblast activation in part.

RESULTS: Overexpression of ADAM15 ameliorates fibrotic changes and ADAM15 deficiency exacerbates changes from fibroblast to myofibroblast in NIH/3T3. Results were also presented and identified by the intuitive immunofluorescence staining.

CONCLUSION: In this study, we uncover a new molecular mechanism of tissue fibrogenesis and identify ADAM15 as a potential therapeutic target in the treatment of fibrotic diseases.

PMID:39048163

Inflammation. 2024 Jul 24. doi: 10.1007/s10753-024-02107-1. Online ahead of print.

ABSTRACT

Recent studies increasingly suggest a connection between lipids and idiopathic pulmonary fibrosis (IPF). This study was aimed at exploring potential lipid-related biomarkers for IPF and uncovering the mechanisms underlying pulmonary fibrosis. IPF-related datasets were retrieved from the GEO database, and the ComBat algorithm was used to merge multiple datasets and eliminate batch effects. Weighted gene co-expression network analysis (WGCNA) was utilized to identify modules and genes associated with IPF. Potential hub genes were determined by intersecting these genes with lipid-related genes from the GeneCards database. A machine learning-based integrative approach was developed to construct diagnostic and prognostic signatures, which were validated across several datasets. Additionally, single-cell sequencing data was used to validate the expression differences of core IPF-related genes across various cell types. The effect of ABHD5 on fibroblasts was assessed using the cell counting kit-8, 5-ethynyl-2'-deoxyuridine, and cell scratch assays. The expression levels of fibrotic factors were measured using real-time quantitative polymerase chain reaction and western blot analysis. WGCNA identified a red module potentially related to IPF, and the intersection with lipid-related genes yielded 51 hub genes. These genes were used to build diagnostic and prognostic models that demonstrated robust validation capabilities across multiple datasets. Single-cell sequencing analysis revealed low expression of ABHD5 in the lung tissues of IPF patients, with a higher proportion of fibroblasts exhibiting low ABHD5 expression. Cell experiments showed that under the influence of TGF-β1, knockdown of ABHD5 slightly promoted fibroblast proliferation. Additionally, fibroblasts with low ABHD5 expression exhibited enhanced migratory capabilities and secreted more fibrotic factors. Lipid-related diagnostic and prognostic models for IPF were developed, and ABHD5 may serve as a potential biomarker. Low ABHD5 expression could potentially accelerate the progression of pulmonary fibrosis.

PMID:39046603 | DOI:10.1007/s10753-024-02107-1

Am J Respir Cell Mol Biol. 2024 Jul 23. doi: 10.1165/rcmb.2023-0379OC. Online ahead of print.

ABSTRACT

Changes in the oxidative (redox) environment accompany idiopathic pulmonary fibrosis (IPF). S-glutathionylation of reactive protein cysteines is a post-translational event that transduces oxidant signals into biological responses. We recently demonstrated that increases in S-glutathionylation promote pulmonary fibrosis, which was mitigated by the deglutathionylating enzyme glutaredoxin (GLRX). However, the protein targets of S-glutathionylation that promote fibrogenesis remain unknown. In the present study we addressed whether the extracellular matrix is a target for S-glutathionylation. We discovered increases in collagen 1A1 S-glutathionylation (COL1A1-SSG) in lung tissues from IPF subjects compared to control subjects in association with increases in ER oxidoreductin 1 (ERO1A) and enhanced oxidation of ER-localized peroxiredoxin 4 (PRDX4) reflecting an increased oxidative environment of the endoplasmic reticulum (ER). Human lung fibroblasts exposed to transforming growth factor beta 1 (TGFB1) show increased secretion of COL1A1-SSG. Pharmacologic inhibition of ERO1A diminished oxidation of PRDX4, attenuated COL1A1-SSG and total COL1A1 levels and dampened fibroblast activation. Absence of Glrx enhanced COL1A1-SSG and overall COL1A1 secretion and promoted activation of mechanosensing pathways. Remarkably, COL1A1-SSG resulted in marked resistance to collagenase degradation. Compared to COL1, lung fibroblasts plated on COL1-SSG proliferated more rapidly, and increased expression of genes encoding extracellular matrix crosslinking enzymes and genes linked to mechanosensing pathways. Overall, these findings suggest that glutathione-dependent oxidation of COL1A1 occurs in settings of IPF in association with enhanced ER oxidative stress and may promote fibrotic remodeling due to increased resistance to collagenase-mediated degradation and fibroblast activation.

PMID:39042020 | DOI:10.1165/rcmb.2023-0379OC

ERJ Open Res. 2024 Jul 22;10(4):00335-2023. doi: 10.1183/23120541.00335-2023. eCollection 2024 Jul.

ABSTRACT

BACKGROUND: We used data from the INMARK trial to investigate associations between circulating biomarkers of extracellular matrix (ECM) turnover, inflammation and epithelial dysfunction and disease progression in subjects with idiopathic pulmonary fibrosis (IPF).

METHODS: Subjects with IPF and forced vital capacity (FVC) ≥80% predicted were randomised 1:2 to receive nintedanib 150 mg twice daily or placebo for 12 weeks followed by open-label nintedanib for 40 weeks. Associations between baseline biomarker levels and the proportion of subjects with disease progression (decline in FVC ≥10% predicted or death) over 52 weeks were assessed in subjects randomised to placebo using logistic regression. Associations between baseline demographic/clinical characteristics and biomarker levels and disease progression over 52 weeks were analysed using multivariate models.

RESULTS: Of 230 subjects who received placebo for 12 weeks then open-label nintedanib for 40 weeks, 70 (30.4%) had disease progression over 52 weeks. Baseline levels of CRPM (C-reactive protein (CRP) degraded by matrix metalloproteinase (MMP)-1/8), C3M (collagen 3 degraded by MMP-9), CRP, KL-6 (Krebs von den Lungen-6) and SP-D (surfactant protein D) were not significantly associated with disease progression over 52 weeks in analyses corrected for multiple comparisons. In models including only baseline demographic/clinical characteristics, 61.2-64.2% of subjects were correctly classified as having or not having disease progression over 52 weeks. When both demographic/clinical characteristics and biomarker levels were included in the models, 50.0-64.5% of the test set were correctly classified.

CONCLUSIONS: Among subjects with IPF and preserved FVC, multivariate models based on demographic/clinical characteristics and biomarker levels at baseline did not provide an accurate prediction of which patients would progress.

PMID:39040590 | PMC:PMC11261372 | DOI:10.1183/23120541.00335-2023

medRxiv [Preprint]. 2024 Jul 14:2024.07.13.24310305. doi: 10.1101/2024.07.13.24310305.

ABSTRACT

Most genetic variants identified through genome-wide association studies (GWAS) are suspected to be regulatory in nature, but only a small fraction colocalize with expression quantitative trait loci (eQTLs, variants associated with expression of a gene). Therefore, it is hypothesized but largely untested that integration of disease GWAS with context-specific eQTLs will reveal the underlying genes driving disease associations. We used colocalization and transcriptomic analyses to identify shared genetic variants and likely causal genes associated with critically ill COVID-19 and idiopathic pulmonary fibrosis. We first identified five genome-wide significant variants associated with both diseases. Four of the variants did not demonstrate clear colocalization between GWAS and healthy lung eQTL signals. Instead, two of the four variants colocalized only in cell-type and disease-specific eQTL datasets. These analyses pointed to higher ATP11A expression from the C allele of rs12585036, in monocytes and in lung tissue from primarily smokers, which increased risk of IPF and decreased risk of critically ill COVID-19. We also found lower DPP9 expression (and higher methylation at a specific CpG) from the G allele of rs12610495, acting in fibroblasts and in IPF lungs, and increased risk of IPF and critically ill COVID-19. We further found differential expression of the identified causal genes in diseased lungs when compared to non-diseased lungs, specifically in epithelial and immune cell types. These findings highlight the power of integrating GWAS, context-specific eQTLs, and transcriptomics of diseased tissue to harness human genetic variation to identify causal genes and where they function during multiple diseases.

PMID:39040187 | PMC:PMC11261970 | DOI:10.1101/2024.07.13.24310305

Expert Rev Respir Med. 2024 Jul 22:1-11. doi: 10.1080/17476348.2024.2375420. Online ahead of print.

ABSTRACT

INTRODUCTION: Progressive pulmonary fibrosis (PPF) is a manifestation of a heterogenous group of underlying interstitial lung disease (ILD) diagnoses, defined as non-idiopathic pulmonary fibrosis (IPF) progressive fibrotic ILD meeting at least two of the following criteria in the previous 12 months: worsening respiratory symptoms, absolute decline in forced vital capacity (FVC) more than or equal to 5% and/or absolute decline in diffusing capacity for carbon monoxide (DLCO) more than or equal to 10% and/or radiological progression.

AREAS COVERED: The authors subjectively reviewed a synthesis of literature from PubMed to identify recent advances in the diagnosis and characterisation of PPF, treatment recommendations, and management challenges. This review provides a comprehensive summary of recent advances and highlights future directions for the diagnosis, management, and treatment of PPF.

EXPERT OPINION: Recent advances in defining the criteria for PPF diagnosis and licensing of treatment are likely to support further characterisation of the PPF patient population and improve our understanding of prevalence. The diagnosis of PPF remains challenging with the need for a specialised ILD multidisciplinary team (MDT) approach. The evidence base supports the use of immunomodulatory therapy to treat inflammatory ILDs and antifibrotic therapy where PPF develops. Treatment needs to be tailored to the specific underlying disease and determined on a case-by-case basis.

PMID:39039699 | DOI:10.1080/17476348.2024.2375420

BMJ Case Rep. 2024 Jul 22;17(7):e258140. doi: 10.1136/bcr-2023-258140.

ABSTRACT

This case report presents the diagnostic journey of a man in his mid-70s who experienced shortness of breath, cough, recurrent episodes of fever, weight loss, pruritic erythroderma, uveitis and macrocytic anaemia. The initial diagnosis of cryptogenic organising pneumonia was made based on antibiotic refractory infiltrates seen in the lung CT scan. The patient initially responded favourably to immunosuppression but experienced a recurrence of symptoms when the corticosteroid dose was tapered. Despite ongoing systemic inflammation and refractory symptoms, it took nearly a year to establish the diagnosis of VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory and somatic) syndrome. This case highlights the challenges in diagnosing and managing VEXAS syndrome due to its recent discovery and limited awareness in the medical community, as well as the need to consider this syndrome as a rare differential diagnosis of therapy-refractory pulmonary infiltrates.

PMID:39038873 | DOI:10.1136/bcr-2023-258140