Acta Pharmacol Sin. 2025 Feb 25. doi: 10.1038/s41401-025-01488-9. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lethal disease. Profibrotic fibroblast polarization during wound healing is one of the main causes of IPF, and the molecular mechanisms involved have yet to be fully determined. LIM domain-only protein 7 (LMO7), which acts as an E3 ubiquitin ligase, is highly expressed in the lung, brain and heart and plays important roles in embryonic development, cancer progression, inflammatory bowel disease and Dreifuss muscular dystrophy (EDMD). In this study, we investigated the role of LMO7 in pulmonary fibrosis. Bleomycin (BLM)-induced lung fibrosis was established in mice. For AAV-mediated gene therapy, AAV-Lmo7 shRNA (AAV-Lmo7 shRNA) was intratracheally administered 6 days before BLM injection. Through transcriptome analysis, we found that the expression of LMO7 was significantly upregulated in the fibroblasts of IPF patients and BLM-induced mice. Knockdown of LMO7 impaired the profibrotic phenotype of fibroblasts in BLM-treated mice and in primary lung fibroblasts stimulated with TGF-β in vitro. We observed that LMO7 binds to SMAD7, mediating its degradation by polyubiquitination of lysine 70 and increasing the stability of TGF-β receptor 1 (TGFβR1). Finally, intratracheal administration of adeno-associated virus (AAV)-mediated Lmo7 shRNA significantly ameliorated the progression of BLM-induced lung fibrosis. Our results suggest that LMO7 is a promising target for blocking profibrotic fibroblast polarization for the treatment of fibrotic lung disease. A model for the role of LMO7 in TGF-β/SMAD signaling during pulmonary fibrosis. During pulmonary fibrosis, ubiquitin E3 ligase LMO7 is up-regulated, and binds with. SMAD7. LMO7 mediates the ubiquitination of SMAD7 on Lysine 70, leading to its degradation, and further enhances the stability of transforming growth factor-beta receptor 1 (TGFβR1).

PMID:40000880 | DOI:10.1038/s41401-025-01488-9

Rheumatology (Oxford). 2025 Feb 25:keaf108. doi: 10.1093/rheumatology/keaf108. Online ahead of print.

ABSTRACT

OBJECTIVES: Antineutrophil cytoplasmic antibodies (ANCAs) are occasionally positive in patients with interstitial lung disease (ILD). The positivity rates of ANCAs in various types of ILD and the role of ANCAs in ILD are still unclear. The purpose of this study was to estimate the prevalence of ANCAs in Chinese people diagnosed with ILD (including idiopathic pulmonary fibrosis) and identify differences in clinical features, radiographic features, and survival between patients with ANCA-positive and ANCA-negative ILD.

METHODS: We retrospectively reviewed the data of 706 ILD patients with available ANCA results from March 2010 to October 2023 at the First Affiliated Hospital of Ningbo University. Patient demographics, symptoms, laboratory parameters, chest CT, and pulmonary function testing results were collected and analysed at each patient's initial diagnosis. The prevalence and associations of ANCAs with clinical characteristics and survival were evaluated.

RESULTS: ANCAs were positive in 158 of the 706 (22.4%) ILD patients. Compared with ANCA-negative ILD patients, ANCA-positive ILD patients tended to be older, had higher CRP and ESR levels, and had a significantly greater proportion of rheumatoid factor positivity. In total, 58.2% (92/158) of patients were ANCA-positive on average (41.6 ± 31.4) months after ILD diagnosis. Patients with ANCA-positive ILD had higher all-cause mortality than did those with ANCA-negative ILD (33.5% vs 25.0%, p = 0.033). The usual interstitial pneumonia (UIP) pattern (56.3%) was the most common chest HRCT pattern. The proportions of patients with honeycombing (p < 0.001) and oddly shaped cysts (p < 0.001) were significantly greater in the ANCA-positive ILD group than in the ANCA-negative ILD group. Acute exacerbation (AE) of ILD (HR 2.40, 95% CI 1.37-4.22, p = 0.002) was independently associated with shorter survival, and receiving glucocorticoids combined with immunosuppressants (HR 0.30, 95% CI 0.16-0.57, p < 0.001) was independently associated with longer survival in ANCA-positive ILD patients.

CONCLUSIONS: The prevalence of ANCAs in patients with ILD is not rare, and ANCA testing in ILD patients is necessary. Oddly shaped cysts with or without a UIP pattern may be a characteristic chest imaging manifestation of ANCA-positive ILDs. The frequency of AEs in ANCA-positive ILD patients is high, and more attention should be given to ANCA-positive ILD patients who have AEs.

PMID:39999033 | DOI:10.1093/rheumatology/keaf108

Lung. 2025 Feb 25;203(1):35. doi: 10.1007/s00408-025-00789-4.

ABSTRACT

PURPOSE: The natural history of IPF remains unpredictable despite antifibrotic treatment. In addition, some patients discontinue treatment due to the occurrence of adverse events. To date, no data exist on either the effect of long-term treatment or predictors of treatment response. In the present study, we aim to evaluate the functional trajectory of IPF patients treated with antifibrotics for at least three years and to establish predictors of treatment response.

METHODS: This multicenter study enrolled long-term survivors IPF patients provided they had stopped treatment for no longer than one month during at least three-year study period. Based on the absolute decline of FVC%predicted (pred.) observed during the 3-year treatment and normalized per year, patients were defined as progressors (≥ 5%) or non-progressors (< 5%).

RESULTS: We identify 172 IPF patients who completed three years of antifibrotic treatment with no interruption. The 27% of these IPF patients progressed despite complete adherence to treatment. Progressors were more likely to be non-smokers compared to non-progressors, with higher occurrence of diarrhea and with a more preserved lung function at diagnosis. FVC %pred. and liters at diagnosis, a greater FVC decline in the 1-st year of follow up, being non-smokers, and complaining of diarrhea over treatment are independent predictors of progression.

CONCLUSION: Almost one third of IPF patients adherent to three years of antifibrotics experience progression. A functional decline at first year of treatment despite preserved lung function at diagnosis, non-smoking status, and occurrence of diarrhea over treatment are independent predictors of disease progression.

PMID:39998625 | DOI:10.1007/s00408-025-00789-4

J Fungi (Basel). 2025 Jan 29;11(2):102. doi: 10.3390/jof11020102.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and interstitial disease with an unclear cause, believed to involve genetic, environmental, and molecular factors. Recent research suggested that Pneumocystis jirovecii (PJ) could contribute to disease exacerbations and severity. This article explores how PJ colonization might influence the pathogenesis of IPF. We performed a proteomic analysis to study the profile of control and IPF patients, with/without PJ. We recruited nine participants from the Virgen del Rocio University Hospital (Seville, Spain). iTRAQ and bioinformatics analyses were performed to identify differentially expressed proteins (DEPs), including a functional analysis of DEPs and of the protein-protein interaction networks built using the STRING database. We identified a total of 92 DEPs highlighting the protein vimentin when comparing groups. Functional differences were observed, with the glycolysis pathway highlighted in PJ-colonized IPF patients; as well as the pentose phosphate pathway and miR-133A in non-colonized IPF patients. We found 11 protein complexes, notably the JAK-STAT signaling complex in non-colonized IPF patients. To our knowledge, this is the first study that analyzed PJ colonization's effect on IPF patients. However, further research is needed, especially on the complex interactions with the AKT/GSK-3β/snail pathway that could explain some of our results.

PMID:39997396 | DOI:10.3390/jof11020102

Cells. 2025 Feb 10;14(4):251. doi: 10.3390/cells14040251.

ABSTRACT

Epigenetics regulates gene expression and thus cellular processes that underlie the pathogenesis of chronic lung diseases such as chronic obstructive pulmonary disease (COPD), asthma, and idiopathic pulmonary fibrosis (IPF). Environmental factors (e.g., air pollution, smoking, infections, poverty), but also conditions such as gastroesophageal reflux, induce epigenetic changes long before lung disease is diagnosed. Therefore, epigenetic signatures have the potential to serve as biomarkers that can be used to identify younger patients who are at risk for premature loss of lung function or diseases such as IPF. Epigenetic analyses also contribute to a better understanding of chronic lung disease. This can be used directly to improve therapies, as well as for the development of innovative drugs. Here, we highlight the role of epigenetics in the development and progression of chronic lung disease, with a focus on DNA methylation.

PMID:39996724 | DOI:10.3390/cells14040251

J Labelled Comp Radiopharm. 2025 Jan-Feb;68(1-2):e4133. doi: 10.1002/jlcr.4133.

ABSTRACT

(R)-2-(4-(5-Chloropyrimidin-2-yl)piperidin-1-yl)-4-((1-(hydroxymethyl)cyclobutyl)amino)-6,7-dihydrothieno[3,2-d]pyrimidine 5-oxide (BI 1015550, 1) is a potent and selective inhibitor of phosphodiesterase type 4 (PDE4) being developed for the treatment of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). We report the synthesis of this drug candidate labelled with carbon 14 and deuterium. The carbon 14 synthesis was completed in three radioactive steps in 27% overall yield, with a specific activity of 52 mCi/mmol (1.92 GBq/mmol), radiochemical purity, and enantiomeric excess higher than 99%. The deuterium labelled compound was prepared in seven steps in 67% overall yield and with isotopic enrichment, chemical purity, and enantiomeric excess higher than 99%.

PMID:39995220 | DOI:10.1002/jlcr.4133

Nat Biotechnol. 2025 Feb 24. doi: 10.1038/s41587-025-02569-0. Online ahead of print.

ABSTRACT

Human lungs contain unique cell populations in distal respiratory airways or terminal and respiratory bronchioles (RA/TRBs) that accumulate in persons with lung injury and idiopathic pulmonary fibrosis (IPF), a lethal lung disease. As these populations are absent in rodents, deeper understanding requires a human in vitro model. Here we convert human pluripotent stem cells (hPS cells) into expandable spheres, called induced respiratory airway progenitors (iRAPs), consisting of ~98% RA/TRB-associated cell types. One hPS cell can give rise to 1010 iRAP cells. We differentiate iRAPs through a stage consistent with transitional type 2 alveolar epithelial (AT2) cells into a population corresponding to mature AT1 cells with 95% purity. iRAPs with deletion of Heřmanský-Pudlák Syndrome 1 (HPS1), which causes pulmonary fibrosis in humans, replicate the aberrant differentiation and recruitment of profibrotic fibroblasts observed in IPF, indicating that intrinsic dysfunction of RA/TRB-associated alveolar progenitors contributes to HPS1-related IPF. iRAPs may provide a system suitable for IPF drug discovery and validation.

PMID:39994483 | DOI:10.1038/s41587-025-02569-0

Sci Rep. 2025 Feb 24;15(1):6670. doi: 10.1038/s41598-025-91060-6.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterised by progressive worsening of lung function. In some cases, IPF is accompanied by air-trapping and emphysema. This study aimed to evaluate air trapping quantified with RV/TLC in patients with IPF. This retrospective study included 122 patients diagnosed with IPF in South Korea between January 2011 and December 2020. Air trapping was defined as RV/TLC ≥ 0.40. Increased RV/TLC was found in 34.4% of all patients. The RV/TLC negatively correlated with lung function (forced expiratory volume in 1 s and functional vital capacity [FVC]) and showed consistent results after 1 year of follow-up. After propensity score matching, FVC and diffusion capacity between the groups showed no statistical difference. No difference in lung function decline was found between the increased and not increased RV/TLC groups. Regarding univariable analysis, the patients in the increased RV/TLC group had a lower risk of all-cause mortality (hazard ratio 1.753, P = 0.034). Using multivariable analysis, age, pirfenidone treatment, and FVC were significant factors for survival but not increased RV/TLC. Increased RV/TLC was related to emphysema and demonstrated a negative relationship with lung function. Although increased RV/TLC might relate to poor clinical outcome, it was not independent prognostic factor for IPF.

PMID:39994366 | DOI:10.1038/s41598-025-91060-6

Front Immunol. 2025 Feb 7;16:1458341. doi: 10.3389/fimmu.2025.1458341. eCollection 2025.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a degenerative respiratory condition characterized by significant mortality rates and a scarcity of available treatment alternatives. Cuproptosis, a novel form of copper-induced cell death, has garnered attention for its potential implications. The study aimed to explore the diagnostic value of cuproptosis-related hub genes in patients with IPF. Additionally, multiple bioinformatics analyses were employed to identify immune-related biomarkers associated with the diagnosis of IPF, offering valuable insights for future treatment strategies.

METHODS: Four microarray datasets were selected from the Gene Expression Omnibus (GEO) collection for screening. Differentially expressed genes (DEGs) associated with IPF were analyzed. Additionally, weighted gene coexpression network analysis (WGCNA) was employed to identify the DEGs most associated with IPF. Ultimately, we analyzed five cuproptosis-related hub genes and assessed their diagnostic value for IPF in both the training and validation sets. Additionally, four immune-related hub genes were screened using a protein-protein interaction (PPI) network and evaluated through the receiver operating characteristic (ROC) curve. Lastly, single-cell RNA-seq was employed to further investigate differential gene distribution.

RESULTS: We identified a total of 92 DEGs. Bioinformatics analysis highlighted five cuproptosis-related genes as candidate biomarkers, including three upregulated genes (CFH, STEAP1, and HDC) and two downregulated genes (NUDT16 and FMO5). The diagnostic accuracy of these five genes in the cohort was confirmed to be reliable. Additionally, we identified four immune-related hub genes that demonstrated strong diagnostic performance for IPF, with CXCL12 showing an AUROC of 0.90. We also examined the relationship between these four genes and immune cells. CXCL12 was significantly negatively associated with neutrophils, while CXCR2 was associated exclusively with neutrophils, consistent with our single-cell sequencing results. CTSG showed a primarily positive association with follicular helper T, and SPP1 was most strongly associated with macrophages. Finally, our single-cell sequencing data revealed that in patients with IPF, CXCL12 was highly expressed in the endothelial cell subset (ECs), while SPP1 exhibited high expression in multiple cellular populations. The expression of the CTSG showed statistically significant differences in monocyte macrophages.

CONCLUSION: The research methodically depicted the intricate interplay among five cuproptosis-related genes, four immune-related hub genes, and IPF, offering new ideas for diagnosing and treating patients with IPF.

PMID:39991151 | PMC:PMC11842377 | DOI:10.3389/fimmu.2025.1458341

Theranostics. 2025 Jan 13;15(6):2092-2103. doi: 10.7150/thno.106367. eCollection 2025.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by an excessive collagen deposition ultimately leading to tissue stiffening and functional decline. Beyond IPF, other progressive pulmonary fibrosis are often associated with connective tissue diseases and may develop in ∼18-32% of patients. Therapeutic options are limited to nintedanib and pirfenidone which are only able to reduce fibrosis progression without curing it. The current lack of biomarker to accurately assess and predict disease progression and therapy efficacy for IPF remains a major clinical concern. Methods: In our study, collagen deposition was monitored in bleomycin-induced lung fibrosis in mice by in vivo molecular imaging using a collagen-targeted radiopharmaceutical, [68Ga]Ga-NODAGA-collagelin. Fibrosis progression was also monitored using computed tomography, the gold standard technique to detect lung fibrosis in patients. Results: We demonstrated that the bleomycin-induced increase in collagen lung content can be accurately quantified by [68Ga]Ga-NODAGA-collagelin PET imaging in correlation with disease stage and severity. The lung uptake of [68Ga]Ga-NODAGA-collagelin was mainly found in fibrotic areas of lungs in bleomycin-receiving mice. Most interestingly, [68Ga]Ga-NODAGA-collagelin PET imaging allowed the in vivo non-invasive monitoring of nintedanib efficacy as well as the anti-fibrotic effect of the JAK inhibitor, tofacitinib. Conclusion: Thus, collagen-targeted PET imaging appears as a promising non-invasive tool for staging, monitoring and prediction of disease progression and therapy efficacy towards personalized medicine in IPF.

PMID:39990206 | PMC:PMC11840721 | DOI:10.7150/thno.106367

Toxicol Rep. 2025 Jan 31;14:101941. doi: 10.1016/j.toxrep.2025.101941. eCollection 2025 Jun.

ABSTRACT

Silicosis is an occupational fibrotic lung disease caused by exposure to respirable crystalline silica dust particles produced during industrial activities. Other crystalline silica-induced pulmonary disorders include a predisposition to mycobacterial infections, obstructive airway diseases, idiopathic pulmonary fibrosis, and lung cancer. This review paper discusses the burden of silicosis and associated co-morbidities in developed as well as developing countries globally using the published data of various government agencies, related organizations, and epidemiological findings. Moreover, it sheds light on diverse mechanisms of silicosis, outlining molecular events and peculiar alterations in lung parenchyma leading to this occupational lung disease. Evaluation of pathophysiological mechanisms could aid in the identification of novel target molecules and treatments; to date, there is no curative treatment for silicosis. In recent periods, a lot of attention has been focused on the development and fabrication of suitable nanocarriers for improved and sustained drug delivery in the pulmonary system. Nanoparticle-based therapeutic modality has been evaluated in in-vitro and ex-vivo silicosis models for prolongation of drug activity and improved therapeutic outcomes. The preclinical findings open the doors to clinical trials for operational and regenerative nanoformulations, which eventually create a positive change in medical practice. The following review summarizes various therapeutic approaches available and in the pipe line for silicosis and also stresses the preventive practices for effectively combating this occupational hazard.

PMID:39989982 | PMC:PMC11847043 | DOI:10.1016/j.toxrep.2025.101941

Expert Opin Ther Targets. 2025 Feb 22. doi: 10.1080/14728222.2025.2471579. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with a dismal prognosis. While the standard-of-care (SOC) drugs approved for IPF represent a significant advancement in antifibrotic therapies, they primarily slow disease progression and have limited overall efficacy and many side effects. Consequently, IPF remains a condition with high unmet medical and pharmacological needs.

AREAS COVERED: A wide variety of molecules and mechanisms have been implicated in the pathogenesis of IPF, many of which have been targeted in clinical trials. In this review, we discuss the latest therapeutic targets that affect extracellular matrix (ECM) homeostasis and the activation of lung fibroblasts, with a specific focus on ECM invasion.

EXPERT OPINION: A promising new approach involves targeting ECM invasion by fibroblasts, a process that parallels cancer cell behavior. Several cancer drugs are now being tested in IPF for their ability to inhibit ECM invasion, offering significant potential for future treatments. The delivery of these therapies by inhalation is a promising development, as it may enhance local effectiveness and minimize systemic side effects, thereby improving patient safety and treatment efficacy.

PMID:39985559 | DOI:10.1080/14728222.2025.2471579

Compr Physiol. 2025 Feb;15(1):e70004. doi: 10.1002/cph4.70004.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease characterized by progressive scarring of the lung parenchyma. While two drugs have been approved by the US Food and Drug Administration (FDA) for IPF, median survival remains limited at 3 years, and the discovery of novel therapeutic targets is urgently needed. Recent studies indicate that immune cells play a critical role in regulating fibrosis. In this Mini Review, we discuss the recent literature focused on cells of the myeloid lineage that serve as key agents of pathologic interorgan communication in fibrosis. These cells are recruited from the bone marrow and have been found to be key drivers of the fibrotic process in the lung.

PMID:39980172 | DOI:10.1002/cph4.70004

Mol Med. 2025 Feb 20;31(1):70. doi: 10.1186/s10020-025-01128-2.

ABSTRACT

BACKGROUND: Lack of understanding of interstitial lung disease (ILD) associated with systemic sclerosis (SSc) and rheumatoid arthritis (RA) hinders the early and accurate identification of these devastating diseases. Current clinical tools limitations highlight the need to complement them with accessible and non-invasive methods. Accordingly, we focused on identifying useful matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) as new biomarkers with clinical value in the diagnosis and prognosis of RA-ILD+ and SSc-ILD+.

METHODS: Peripheral blood was collected from patients with RA-ILD+ (n = 49) and SSc-ILD+ (n = 38); as well as with RA-ILD- (n = 25), SSc-ILD- (n = 20) and idiopathic pulmonary fibrosis (IPF) (n = 39). MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-10, MMP-12, TIMP-1, and TIMP-2 serum levels were measured using xMAP Technology.

RESULTS: Concerning early connective tissue disease (CTD)-ILD+ diagnosis, increased MMP-7, MMP-9, MMP-10, and MMP-12 levels were found in RA-ILD+ and SSc-ILD+ patients in relation to RA-ILD- and SSc-ILD- patients, respectively. RA-ILD+ patients showed higher MMP-2 levels and lower TIMP-1 levels than RA-ILD- patients. Interestingly, a reliable utility for identifying ILD in CTD was confirmed for the MMP-2, MMP-7, MMP-9, MMP-10, MMP-12, and TIMP-1 combination in RA and MMP-7, MMP-9, MMP-10, and MMP-12 combinatorial signature in SSc. Regarding accurate CTD-ILD+ diagnosis, RA-ILD+ and SSc-ILD+ patients showed lower MMP-7 and MMP-10 levels than IPF patients. Lower MMP-9 and TIMP-1 levels and higher MMP-3 levels were found in RA-ILD+ compared to IPF. Remarkably, effectively better differentiation between CTD-ILD+ and IPF was confirmed for a 5-biomarker signature consisting of MMP-3, MMP-7, MMP-9, MMP-10, and TIMP-1 in RA as well as for the MMP-7 and MMP-10 combination in SSc. Finally, in RA-ILD+ patients, higher MMP-10 levels were associated with worse pulmonary function, increased MMP-2 levels were related to the treatment with conventional synthetic disease-modifying anti-rheumatic drugs, and decreased TIMP-1 levels were linked with positivity rheumatoid factor status.

CONCLUSIONS: MMPs and TIMPs form combinatorial biomarker signatures with clinical value for non-invasive, early, and accurate diagnosis of RA-ILD+ and SSc-ILD+, constituting promising screening tools in clinical practice.

PMID:39979794 | DOI:10.1186/s10020-025-01128-2

Eur Respir J. 2025 Feb 20:2401114. doi: 10.1183/13993003.01114-2024. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterized by significant, but poorly understood immune and antibody responses. This study examines the spatial transcriptomes and microenvironmental niches of antibody-producing plasma cells and tertiary lymphoid structures (TLS) in IPF lungs, and the molecular pathways influencing antibody accumulation and pulmonary fibrosis.

METHODS: Explant lung tissues from IPF patients and control normal lungs were used for spatial transcriptome assays and validating RNA-scope and immunofluorescence assays. Fibroblasts derived from IPF and control lungs were examined for their capability to attract plasma cells. Neutralizing antibodies were administered to investigate molecules affecting pulmonary plasma cell accumulation and fibrosis in bleomycin-treated mice.

RESULTS: Human IPF lungs exhibited a remarkably widespread distribution of plasma cells and local antibodies in the fibrotic regions, disseminating from plasma cell-generating TLS. Novel mural cells wrapped the vessels in TLS regions, expressing CCR7 ligands that attracted T cells into TLS to promote plasma cell generation. Distinct IPF-associated fibroblasts further secreted CXCL12, providing an extramedullary niche to foster the dissemination and accumulation of plasma cells in the fibrotic regions. Neutralization of CCR7 ligands or CXCL12 reduced plasma cell and local antibody accumulation in the lungs of bleomycin-treated mice, leading to reduced TGFβ concentrations and alleviated pulmonary fibrosis.

CONCLUSIONS: Plasma cells and local antibodies are widely distributed in the fibrotic regions of IPF lungs. Distinct subsets of IPF-associated mural cells and fibroblasts promote pathological plasma cell and antibody accumulation. These findings have potential implications for strategies aimed at targeting immune and antibody responses to combat IPF.

PMID:39978854 | DOI:10.1183/13993003.01114-2024

Crit Rev Immunol. 2025;45(2):77-89. doi: 10.1615/CritRevImmunol.2025056518.

ABSTRACT

BACKGROUND: Sarcoidosis is a complex inflammatory disease of unknown etiology affecting mostly the lungs and poses a significant diagnostic challenge, particularly in regions where tuberculosis (TB) is endemic. The diagnostic complexity intensifies due to shared clinical and radiological features between sarcoidosis and TB, as well as similarities with idiopathic pulmonary fibrosis (IPF) in cases that progress to pulmonary fibrosis. Accurately distinguishing between these diseases is critical for timely and effective patient management.

OBJECTIVE: This study breaks new ground by evaluating the diagnostic power of the bronchoalveolar lavage (BAL) CD4/ CD8 ratio, along with key activation and memory markers to differentiate sarcoidosis from TB, IPF, and other-interstitial lung diseases (ILDs).

METHODS: A cohort of 68 patients with ILDs, including sarcoidosis (n = 37), TB (n = 19), IPF (n = 6), and Other-ILDs (n = 6) were assessed. The CD4/CD8 ratio and a panel of activation and memory markers were analyzed through flow cytometry.

RESULTS: Sarcoidosis exhibited a significantly higher CD4/CD8 ratio compared to those with TB, IPF, and Other-ILDs. An optimal cutoff value of 3.7 for the CD4/CD8 ratio in sarcoidosis with an area under the ROC curve (AUC) of 0.7%, had a specificity of 96.8%, and a sensitivity of 43.2%. In addition, a significant difference was detected in CD38, CD45RA, CD45RO, and CD62L expression.

CONCLUSION: Combining the CD4/CD8 ratio (> 3.7) with the expression of CD38, CD62L, and memory markers is a promising new tool for the differential diagnosis of sarcoidosis.

PMID:39976519 | DOI:10.1615/CritRevImmunol.2025056518

ACS Pharmacol Transl Sci. 2024 Nov 12;8(2):380-393. doi: 10.1021/acsptsci.4c00456. eCollection 2025 Feb 14.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a rare interstitial lung disease typified by a progressive fibrosing phenotype. IPF has been associated with aberrant HDAC activity, particularly HDAC6. Combining synthetic and modeling studies, a new family of spirotetrahydroisoquinoline-capped histone deacetylase inhibitors 5a-o was developed. These analogues were prepared via the three-component Castagnoli-Cushman reaction (CCR) as the key step. Structure-activity relationship (SAR) studies identified 5n (fibrostat) as a preferential HDAC6 inhibitor with a suitable degree of selectivity compared to HDAC1, HDAC3, HDAC5, HDAC8, HDAC10, and HDAC11. 5n was able to negatively modulate the expression of fibrotic markers, fibronectin and collagen 1, in fibroblasts derived from bronchoalveolar lavages of IPF patients. In another ex vivo IPF human model, 5n (fibrostat) reduced the expression of fibronectin and negatively affected the expression of collagen 1 and vimentin, the latter being associated with invasiveness. Finally, fibrostat did not show toxicity in rat-perfused heart and zebrafish larvae.

PMID:39974640 | PMC:PMC11833724 | DOI:10.1021/acsptsci.4c00456

medRxiv [Preprint]. 2025 Feb 2:2025.01.30.25321017. doi: 10.1101/2025.01.30.25321017.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rare, incurable lung disease with a median survival of 3-5 years after diagnosis. Treatment options are limited. Genetic association studies can identify new genes involved in disease that might represent potential new drug targets, and it has been shown that drug targets with support from genetic studies are more likely to be successful in clinical development. Previous genome-wide association studies (GWAS) of IPF susceptibility have identified more than 20 signals implicating genes involved in multiple mechanisms, including telomere dysfunction, cell-cell adhesion, host defence immunity, various signalling pathways and, more recently, mitotic spindle assembly complex.

AIM: To leverage new datasets and genotype imputation to discover further genes involved in development of IPF that could yield new pathobiological avenues for exploration and to guide future drug target discovery.

METHODS: We conducted a GWAS of IPF susceptibility including seven IPF case-control studies comprising 5,159 IPF cases and 27,459 controls of European ancestry, where IPF diagnosis was made by a respiratory clinician according to international guidelines. Genotypes were obtained from Whole Genome Sequencing (WGS) or from array-based imputation to the TOPMed WGS reference panel. New signals were replicated in independent biobanks with IPF defined using Electronic Healthcare Records. Bayesian fine-mapping was performed to identify the most likely causal variant(s) and bioinformatic investigation undertaken to map associated variants to putative causal genes.

RESULTS: We identified three novel genetic signals of association with IPF susceptibility. Genes prioritised by functional evidence at these signals included MUC1 , which encodes a large transmembrane glycoprotein and known biomarker of lung fibrosis, and NTN4 encoding Netrin-4 whose known roles include angiogenesis. The third signal may map to SLC6A6, a taurine and beta-alanine transporter gene, previously implicated in retinal, cardiac and kidney dysfunction.

CONCLUSION: Our study has identified new associations not previously identified by previous large biobank-based studies thereby highlighting the value of utilising clinically-curated IPF case-control studies, and new genotype imputation. We present new evidence for disease-driving roles of MUC1 and of endothelial cell and vascular changes in IPF.

PMID:39974050 | PMC:PMC11838657 | DOI:10.1101/2025.01.30.25321017

Int J Surg Pathol. 2025 Feb 20:10668969251316910. doi: 10.1177/10668969251316910. Online ahead of print.

ABSTRACT

Malakoplakia is a rare granulomatous disease characterized histologically by Michaelis-Gutmann bodies and sheets of macrophages with granular eosinophilic cytoplasm. While it most commonly affects the genitourinary tract, it can manifest in various locations, including cutaneous sites. This report details a rare example of scrotal malakoplakia in an 82-year-old man with a history of idiopathic pulmonary fibrosis, developing 7 months post-lung transplant, during ongoing chronic immunosuppressive therapy. Histopathological examination confirmed the diagnosis. This report highlights the importance of considering malakoplakia in the differential diagnosis of scrotal lesions, particularly in immunocompromised patients where the clinical presentation may be atypical.

PMID:39973204 | DOI:10.1177/10668969251316910

Mol Med. 2025 Feb 19;31(1):63. doi: 10.1186/s10020-025-01119-3.

ABSTRACT

BACKGROUND: As an endoplasmic reticulum (ER) protein, Reticulum 3 (RTN3) has been reported to play a crucial role in neurodegenerative diseases, lipid metabolism, and chronic kidney disease. The involvement of RTN3 in idiopathic pulmonary fibrosis (IPF), a progressive and fatal interstitial lung disease, remains unexplored.

METHODS: In this study, we explored the role of RTN3 in pulmonary fibrosis using public datasets, IPF patient samples, and animal models. We investigated its pathogenic mechanisms in lung fibroblasts and alveolar macrophages.

RESULTS: We found decreased levels of RTN3 in IPF patients, bleomycin-induced mice, and TGFβ-treated cell lines. RTN3-null mice exhibited more severe pulmonary fibrosis phenotypes in old age or after bleomycin treatment. Collagen synthesis was significantly increased in RTN3-null mice lung tissues and lung fibroblasts. Mechanistic studies revealed that RTN3 deficiency reduced the ER-anchored CRTH2 in lung fibroblasts, which serves as an antifibrotic molecule via antagonizing collagen biosynthesis. Simultaneously, RTN3 deficiency reduced the autophagy degradation of CRTH2 which acts as an activator of profibrotic macrophage differentiation. Both effects of RTN3 and CRTH2 in lung fibroblasts and alveolar macrophages aggravated age-or bleomycin-induced pulmonary fibrosis. Additionally, we also identified a mutation of RTN3 in patients with ILD.

CONCLUSIONS: Our research demonstrated that RTN3 plays a significant role in the lung, and reduction of RTN3 levels may be a risk factor for IPF and related diseases.

PMID:39972424 | DOI:10.1186/s10020-025-01119-3