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

Nat Commun. 2025 Feb 19;16(1):1761. doi: 10.1038/s41467-025-57024-0.

ABSTRACT

Lung macrophages play a pivotal role in pulmonary fibrosis, with monocyte-derived alveolar macrophages driving disease progression. However, the mechanisms regulating their pro-fibrotic behavior and survival remain unclear, and effective therapeutic strategies are lacking. Here we show that triggering receptors expressed on myeloid cells 2 are predominantly expressed on monocyte-derived alveolar macrophages in fibrotic mouse lungs and are significantly elevated in lung macrophages from patients with idiopathic pulmonary fibrosis. Deletion or knockdown of this receptor disrupts intracellular survival signaling, promotes macrophage apoptosis, and attenuates their pro-fibrotic phenotype. We further demonstrate that a lipid mediator and a high-avidity ligand of this receptor, encountered by macrophages in the alveolar milieu, enhance macrophage survival and activity. Ablation of TREM2 or blocking this receptor with soluble receptors or specific antibodies effectively alleviates lung fibrosis in male mice. These findings identify this receptor as a critical regulator of macrophage-mediated fibrosis and a promising therapeutic target for intervention.

PMID:39971937 | DOI:10.1038/s41467-025-57024-0

BMJ Open Respir Res. 2025 Feb 19;12(1):e002773. doi: 10.1136/bmjresp-2024-002773.

ABSTRACT

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease (ILD) and the most common idiopathic interstitial pneumonia. The UK IPF Registry was established in 2013 to collect data pertaining to clinical features, therapeutic approaches and outcomes. From February 2023, the Registry expanded to include any ILD with evidence of fibrosis.

DESIGN: The UK IPF Registry is a national, multicentre observational registry, including both prospective and retrospective data of patients with IPF in secondary or tertiary care. Cases eligible for inclusion were those with a diagnosis of IPF, presenting at participating centres from January 2013.

RESULTS: Between January 2013 and February 2023, 5052 IPF cases were registered from 64 participating centres. There was a male preponderance (77.8%) with mean±SD age of 74±8.1 years, 66% were ex-smokers and 76% had at least one comorbidity. Over a third (36.7%) experienced symptoms for more than 24 months prior to their first clinic visit. The majority of cases were discussed at a multidisciplinary team (MDT) meeting and the most common radiological patterns at presentation were probable (54.6%) and definite (42.7%) usual interstitial pneumonia. There was a reduction in surgical lung biopsies from 14% in 2013 to 5.5% in 2022. Antifibrotic therapy prescription rose from 36.0% in 2013 to 55.9% in 2023. The use of nintedanib (approved by National Institute of Clinical Excellence in January 2016) rose from 6.7% in 2013 to 31.5% in 2022 and pirfenidone (approved in April 2013) was initially used in around a third of cases before dropping to between 16.8% and 24.9% after nintedanib was approved.

CONCLUSION: These data reflect clinical practice across the UK and it is intended the data will have a role in informing the future of IPF care and providing a model for benchmarking, ultimately increasing knowledge and improving clinical care for this devastating disease.

PMID:39971593 | DOI:10.1136/bmjresp-2024-002773

Cell Signal. 2025 Feb 17:111667. doi: 10.1016/j.cellsig.2025.111667. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a fatal pulmonary condition, is marked by fibrosis and is devoid of efficacious treatments. The aim of our research was to explore the influence of miR-410-3p on the advancement of IPF. For creating a model of lung fibrosis, tracheal injections of 5 mg/kg bleomycin (BLM) were administered to mice, and added 10 ng/mL of TGF-β1 into MRC-5 cell medium. The evaluation of gene and protein expression was conducted using RT-qPCR and western blotting techniques. The assessment of fibrosis in MRC-5 cells and mouse pulmonary tissue involved the use of CCK-8, ELISA, flow cytometry, and HE staining methods. The results of our study revealed a rise in miR-410-3p levels in both TGF-β1-stimulated MRC-5 cells and BLM-exposed mouse pulmonary tissue. Inhibiting miR-410-3p improved cellular survival, lessened oxidative stress (MDA, ROS), decreased levels of inflammatory cytokines (TNF-α, IL-1β, IL-6), curtailed fibrosis-associated proteins (α-SMA, Collagen I, Collagen III, FN1), and amplified the expression of SOD and E-cadherin. The treatment effectively reduced cell fibrosis and improved lung tissue health, thus hindering the advancement of IPF. Mechanically, knocking down miR-410-3p activates AMPK/SIRT1 molecular axis to inhibit NF-κB signaling by up-regulating METRNL expression, thereby inhibiting oxidative stress and inflammation levels, and ultimately improving IPF. In summary, our research indicates that focusing on miR-410-3p might be an effective approach in IPF treatment.

PMID:39971221 | DOI:10.1016/j.cellsig.2025.111667

Am J Physiol Lung Cell Mol Physiol. 2025 Feb 19. doi: 10.1152/ajplung.00171.2024. Online ahead of print.

ABSTRACT

In this research, we delve into the association between epigenetic aging and idiopathic pulmonary fibrosis (IPF), a debilitating lung disease that progresses over time. Utilizing the Illumina MethylationEPIC array, we assessed DNA methylation levels in donated human lung tissue from IPF patients, categorizing the disease into mild, moderate, and severe stages based on clinical assessments. We employed seven epigenetic clocks to determine age acceleration, which is the discrepancy between biological (epigenetic) and chronological age. Our findings revealed a notable acceleration of biological aging in IPF tissues compared to healthy controls, with four clocks-Horvath's, Hannum's, PhenoAge, and DunedinPACE-showing significant correlations. DunedinPACE, in particular, indicated a more rapid aging process in the more severe regions within the lungs of IPF cases. These results suggest that the biological aging process in IPF is expedited and closely tied to the severity of the disease. The study underscores the potential of DNA methylation as a biomarker for IPF, providing valuable insights into the underlying methylation patterns and the dynamics of epigenetic aging in affected lung tissue. This research supports the broader application of epigenetic clocks in clinical prognosis and highlights the critical role of biological age in the context of medical research and healthcare.

PMID:39970931 | DOI:10.1152/ajplung.00171.2024

Cell Mol Life Sci. 2025 Feb 19;82(1):79. doi: 10.1007/s00018-025-05613-z.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial pneumonia, with increasing incidence and prevalence. One of the cellular characteristics is the differentiation of fibroblasts to myofibroblasts. However, the metabolic-related signaling pathway regulated by circular RNAs (circRNAs) during this process remains unclear. Here, we demonstrated that circ0066187 promoted fibroblast-to-myofibroblast differentiation by metabolic-related signaling pathway. Mechanism analysis research identified that circ0066187 directly targeted signal transducer and activator of transcription 3 (STAT3)-mediated metabolism signal pathway to enhance fibroblast-to-myofibroblast differentiation by sponging miR-29b-2-5p, resulting in pulmonary fibrosis. Integrative multi-omics analysis of metabolomics and proteomics revealed three pathways co-enriched in proteomics and metabolomics, namely, Protein digestion and absorption, PI3K-Akt signaling pathway, and FoxO signaling pathway. In these three signaling pathways, seven differentially expressed metabolites such as L-glutamine, L-proline, adenosine monophosphate (AMP), L-arginine, L-phenylalanine, L-lysine and L-tryptophan, and six differentially expressed proteins containing dipeptidyl peptidase-4 (DPP4), cyclin D1 (CCND1), cyclin-dependent kinase 2 (CDK2), fibroblast growth factor 2 (FGF2), collagen type VI alpha 1 (COL6A1) and superoxide dismutase 2 (SOD2) were co-enriched. Gain-and loss-of-function studies and rescue experiments were performed to verify that circ0066187 promoted STAT3 expression by inhibiting miR-29b-2-5p expression to control the above metabolites and proteins. As a result, these metabolites and proteins provided the material basis and energy requirements for the progression of pulmonary fibrosis. In conclusion, circ0066187 can function as a profibrotic metabolism-related factor, and interference with circ0066187 can prevent pulmonary fibrosis. The finding supported that circ0066187 can be a metabolism-related therapeutic target for IPF treatment.

PMID:39969586 | DOI:10.1007/s00018-025-05613-z

Biomater Sci. 2025 Feb 19. doi: 10.1039/d4bm00906a. Online ahead of print.

ABSTRACT

Fibrosis, a pathological hallmark of various chronic diseases, involves the excessive accumulation of extracellular matrix (ECM) components leading to tissue scarring and functional impairment. Understanding how cells interact with the ECM in fibrotic diseases such as idiopathic pulmonary fibrosis (IPF), is crucial for developing effective therapeutic strategies. This study explores the effects of decellularized extracellular matrix (dECM) coatings derived from non-IPF and IPF donor lung tissue samples on the behavior of primary human lung fibroblasts (HLFs). Utilizing a substrate coating method that preserves the diversity of in situ ECM, we studied both the concentration-dependent effects and the intrinsic biochemical cues of ECM on cell morphology, protein expression, mechanobiology biomarkers, and gene expression. Morphological analysis revealed that HLFs displayed altered spreading, shape, and nuclear characteristics in response to dECM coatings relative to control plastic, indicating a response to the physical and biochemical cues. Protein expression studies showed an upregulation of α-smooth muscle actin (α-SMA) in cells interacting with both non-IPF and IPF dECM coatings, that was more prominent at IPF dECM-coated surface. In addition, YAP localization, a marker of mechanotransduction, was also dysregulated on dECM coatings, reflecting changes in mechanical signaling pathways. Gene expression profiles were differentially regulated by the different dECM coatings. The developed dECM coating strategy in this work facilitates the integration of tissue-specific biochemical cues onto standard cell culture platforms, which is ideal for high-throughput screening. Importantly, it minimizes the requirement for human tissue samples, especially when compared to more sample-intensive 3D models like dECM-based hydrogels.

PMID:39968884 | DOI:10.1039/d4bm00906a

Front Oncol. 2025 Feb 4;15:1487334. doi: 10.3389/fonc.2025.1487334. eCollection 2025.

ABSTRACT

BACKGROUND: Alpha-fetoprotein (AFP)-producing hepatoid adenocarcinoma of lung (HAL) is a rare type of lung cancer, with its characteristics being not yet fully clarified. We recently encountered a case of HAL combined with idiopathic pulmonary fibrosis (IPF), which has never been reported.

CASE PRESENTATION: A 66-year-old man consulted our hospital with a chief complaint of cough. Chest computed tomography (CT) revealed multiple nodules measuring from 8mm to 20mm in diameter located in bilateral lung, along with an enlarged left hilar lymph node. CT-guided percutaneous lung biopsy confirmed the diagnosis of AFP-producing primary HAL combined with IPF. Systemic treatment according to guidelines for advanced non-small cell lung cancer resulted in a long-term survival.

CONCLUSIONS: This case report documents the first occurrence and prognosis of AFP-producing HAL in a patient with IPF. The long-term survival brought by the diagnosis and treatment model in our case may provide significant prognostic value for this rare condition.

PMID:39968074 | PMC:PMC11832387 | DOI:10.3389/fonc.2025.1487334

ACS Med Chem Lett. 2025 Jan 23;16(2):317-326. doi: 10.1021/acsmedchemlett.4c00559. eCollection 2025 Feb 13.

ABSTRACT

Lysophosphatidic acid (LPA) is a phospholipid activating different biological functions by binding to G protein-coupled receptors (LPA1-6). Among these, the role of the LPA1 receptor in modulating fibrotic processes is well-known, making it a therapeutic target for pulmonary fibrosis and other fibrotic disorders. Herein we report the search for a new class of LPA1 antagonists for the oral treatment of idiopathic pulmonary fibrosis with a focus on hepatobiliary safety. Compound 7 excelled in in vitro and in vivo efficacy, showing significant efficacy both in PD studies and in a rodent lung fibrosis model, with a promising in vitro hepatic safety profile. However, in a dose range finding (DRF) toxicity study, compound 7 did not ensure safety regarding potential hepatobiliary toxicity, leading to its development being halted.

PMID:39967626 | PMC:PMC11831564 | DOI:10.1021/acsmedchemlett.4c00559

Small. 2025 Feb 19:e2409126. doi: 10.1002/smll.202409126. Online ahead of print.

ABSTRACT

This study advances sustainable pharmaceutical research for endometriosis by developing in vitro 3D cell culture models of endometriotic pathophysiology that allow antifibrotic drug candidates to be tested. Fibrosis is a key aspect of endometriosis, yet current cell models to study it remain limited. This work aims to bridge the translational gap between in vitro fibrosis research and preclinical testing of non-hormonal drug candidates. When grown in a 3D matrix of sustainably produced silk protein functionalized with a fibronectin-derived cell adhesion motif (FN-silk), endometrial stromal and epithelial cells respond to transforming growth factor beta-1 (TGF-β1) in a physiological manner as probed at the messenger RNA (mRNA) level. For stromal cells, this response to TGF-β1 is not observed in spheroids, while epithelial cell spheroids behave similarly to epithelial cell FN-silk networks. Pirfenidone, an antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis, reverses TGF-β1-induced upregulation of mRNA transcripts involved in fibroblast-to-myofibroblast transdifferentiation of endometrial stromal cells in FN-silk networks, supporting pirfenidone's potential as a repurposed non-hormonal endometriosis therapy. Overall, endometrial stromal cells cultured in FN-silk networks-which are composed of a sustainably produced, fully defined FN-silk protein-recapitulate fibrotic cellular behavior with high fidelity and enable antifibrotic drug testing.

PMID:39967482 | DOI:10.1002/smll.202409126

Sci Rep. 2025 Feb 18;15(1):5954. doi: 10.1038/s41598-025-89770-y.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an age-related interstitial lung disease of unknown cause. Oxidative stress, an imbalance between oxidants and antioxidants, is implicated in IPF pathogenesis and prognosis but needs further study. We used transcriptome sequencing data (GSE70866) and oxidative stress-related genes from GeneCards. A prognostic risk model for IPF patients was constructed using LASSO. Functional and pathway differences were analyzed between risk score groups, along with comparisons of immune cells and functions. An IPF rat model with vitamin D3 (VD3) intervention was also established. Finally, we used IL-4 to induce M2 macrophages to explore the mechanism of action of CCL2. We identified 483 DEGs and 50 oxidative stress-related DEGs (OSDEGs). Single-factor COX regression identified 34 prognostic OSDEGs, and LASSO identified an 8-gene signature for the risk model. The high-risk group had more CD8 + T cells, macrophages, APC costimulation, and cytokine-cytokine receptor activity. CCL2 was significantly correlated with macrophages in IPF. VD3 inhibited the TGF-β signaling pathway and reduced macrophage M2 infiltration in the rat model. In the IL-4 induced M2 macrophage model, we found that M2 macrophages produced more CCL2, and the production of CCL2 was significantly reduced after VD3 intervention. We established prognostic markers of eight oxidative stress-related genes. The risk score effectively predicts adverse outcomes in IPF. VD3 may alleviate IPF by reducing macrophage infiltration and inhibiting the TGF-β signaling pathway.

PMID:39966531 | DOI:10.1038/s41598-025-89770-y

Cell Biochem Biophys. 2025 Feb 19. doi: 10.1007/s12013-025-01696-4. Online ahead of print.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a severe, rapidly advancing disease that drastically diminishes life expectancy. Without treatment, it can progress to lung cancer. The precise etiology of IPF remains unknown, but inflammation and damage to the alveolar epithelium are widely thought to be pivotal in its development. Research has indicated that activating the NLRP3 inflammasome is a crucial mechanism in IPF pathogenesis, as it triggers the release of pro-inflammatory cytokines such as IL-1β, IL-18, and TGF-β. These cytokines contribute to the myofibroblast differentiation and extracellular matrix (ECM) accumulation. Currently, treatment options for IPF are limited. Only two FDA-approved medications, pirfenidone and nintedanib, are available. While these drugs can decelerate disease progression, they come with a range of side effects and do not cure the disease. Additional treatment strategies primarily involve supportive care and therapy. Emerging research has highlighted that numerous flavonoids derived from traditional medicines can inhibit the critical regulators responsible for activating the NLRP3 inflammasome. These flavonoids show promise as potential therapeutic agents for managing IPF, offering a new avenue for treatment that targets the core inflammatory processes of this debilitating condition.

PMID:39966334 | DOI:10.1007/s12013-025-01696-4

JCI Insight. 2025 Feb 18:e177072. doi: 10.1172/jci.insight.177072. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive scarring and loss of lung function. With limited treatment options, patients succumb to the disease within 2 to 5 years. The molecular pathogenesis of IPF regarding the immunologic changes that occur is poorly understood. We characterize a role for non-canonical aryl-hydrocarbon receptor signaling (ncAHR) in dendritic cells (DCs) that leads to production of IL-6 and increased IL-17+ cells, promoting fibrosis. TLR9 signaling in myofibroblasts is shown to regulate production of TDO2 which converts tryptophan into the endogenous AHR ligand kynurenine. Mice with augmented ncAHR signaling were created by crossing floxed AHR exon-2 deletion mice (AHRΔex2) with mice harboring a CD11c-Cre. Bleomycin (blm) was used to study fibrotic pathogenesis. Isolated CD11c+ cells and primary fibroblasts were treated ex-vivo with relevant TLR agonists and AHR modulating compounds to study how AHR signaling influenced inflammatory cytokine production. Human datasets were also interrogated. Inhibition of all AHR signaling rescued fibrosis, however, AHRΔex2 mice treated with blm developed more fibrosis and DCs from these mice were hyperinflammatory and profibrotic upon adoptive transfer. Treatment of fibrotic fibroblasts with TLR9 agonist increased expression of TDO2 and fibrotic fibroblasts activated IL-6 production in CD103+ DCs. Study of human samples corroborates the relevance of these findings in IPF patients. We also, for the first time, identify that AHR exon-2 floxed mice retain capacity for ncAHR signaling.

PMID:39964756 | DOI:10.1172/jci.insight.177072

Drug Dev Ind Pharm. 2025 Feb 18:1-18. doi: 10.1080/03639045.2025.2468811. Online ahead of print.

ABSTRACT

OBJECTIVE: This review aims to explore innovative therapeutic strategies, with a particular focus on recent advancements in drug delivery systems using bioinspired nanomaterials such as solid lipid nanoparticles (SLNs) and nanostructured lipid carriers (NLCs) for the Idiopathic pulmonary fibrosis (IPF).

SIGNIFICANCE OF THE REVIEW: Current treatments for IPF, including the FDA-approved anti-fibrotic agents pirfenidone and nintedanib, primarily aim to slow disease progression rather than reverse fibrosis. Bioinspired nanomaterials like SLNs and NLCs have shown promise in enhancing the efficacy of anti-fibrotic agents by improving drug solubility, stability, and targeted delivery. These systems not only minimize systemic side effects but also maximize therapeutic impact in lung tissues, offering a new hope for improved patient management and outcomes in this debilitating disease.

KEY FINDINGS: SLNs facilitate sustained drug release and have demonstrated potential in delivering phosphodiesterase type 5 inhibitors effectively to lung cells. NLCs, on the other hand, exhibit superior biocompatibility and controlled release properties, making them suitable for pulmonary applications. Studies indicate that both SLNs and NLCs can enhance the bioavailability of drugs like ciprofloxacin and montelukast, thereby improving treatment outcomes in pulmonary conditions.

CONCLUSIONS: The integration of nanotechnology into anti-fibrotic therapy represents a significant advancement in addressing the challenges posed by IPF. By leveraging the unique properties of SLNs and NLCs, there is potential to overcome the limitations of current treatments and provide new therapeutic options that offer better management and improved outcomes for patients suffering from this debilitating disease.

PMID:39963904 | DOI:10.1080/03639045.2025.2468811

Minerva Med. 2025 Feb 17. doi: 10.23736/S0026-4806.25.09643-0. Online ahead of print.

ABSTRACT

BACKGROUND: Early diagnosis of idiopathic pulmonary fibrosis (IPF) is fundamental to slow disease progression; multidisciplinary teams (MDTs) play a central role in posing the final diagnosis of IPF, thus aiming to improve patient outcomes. However, the practical implementation of MDTs in clinical real-life settings may be hindered by the lack of local expertise or time constraints, with the diagnosis being made without the support of complementary professional health care figures. This study aims to evaluate the impact of MDT meetings on the latency between the symptom onset and the final diagnosis of IPF.

METHODS: Patients referred to a regional center for IPF between January 2019 and August 2019 were included. The length of time to pose a definite diagnosis by means of MDT evaluation was compared with that of patients diagnosed elsewhere (no MDT evaluation) in an observational case-control investigation.

RESULTS: Among 24 IPF patients, those evaluated by MDT (M/F: 14/2, age: 69.8±8.2 yrs) showed a time interval from the first outpatient visit to the definite diagnosis of 3±2.3 months; on the other hand, patients in the control group (M/F: 7/1, age: 76.9±7.7 yrs) showed a time interval of 12.8±9.4 months (P=0.02). The time elapsed between the onset of symptoms and the definite diagnosis was 11.1±5.3 months for patients evaluated within the MDT, compared to 33.8±21.5 months for the control group (P=0.02).

CONCLUSIONS: These exploratory findings confirm the essential role of the MDT in the early diagnosis of IPF, thus discouraging the acquisition of diagnosis solely on individual basis. The current findings highlight the need for the implementation of MDTs in clinical practice to optimize patient care.

PMID:39960753 | DOI:10.23736/S0026-4806.25.09643-0

J Inflamm Res. 2025 Feb 11;18:1993-2009. doi: 10.2147/JIR.S489210. eCollection 2025.

ABSTRACT

BACKGROUND: Studies suggest that immune and inflammation processes may be involved in the development of idiopathic pulmonary fibrosis (IPF); however, their roles remain unclear. This study aims to identify key genes associated with immune response and inflammation in IPF using bioinformatics.

METHODS: We identified differentially expressed genes (DEGs) in the GSE93606 dataset and GSE28042 dataset, then obtained differentially expressed immune- and inflammation-related genes (DE-IFRGs) by overlapping DEGs. Two machine learning algorithms were used to further screen key genes. Genes with an area under curve (AUC) of > 0.7 in receiver operating characteristic (ROC) curves, significant expression and consistent trends across datasets were considered key genes. Based on these key genes, we carried out nomogram construction, enrichment and immune analyses, regulatory network mapping, drug prediction, and expression verification.

RESULTS: 27 DE-IFRGs were identified by intersecting 256 DEGs, 1793 immune-related genes, and 1019 inflammation-related genes. Three genes (RNASE3, S100A12, S100A8) were obtained by crossing two machine algorithms (Boruta and LASSO),which had good diagnostic performance with AUC values. These key genes were all enriched in the same pathways, such as GOCC_azurophil_granule, IL-12 signalling and production in macrophages is the pathway with the strongest role for key genes. Six distinct immune cells, including naive CD4 T cells, T cells CD4 memory resting, T cells regulatory (Tregs), Monocytes, Macrophages M2, Neutrophils were identified. Real-time quantitative polymerase chain reaction (RT-qPCR) results were consistent with the training and validation sets, and the expression of these key genes was significantly upregulated in the IPF samples.

CONCLUSION: This study identified three key genes (RNASE3, S100A12 and S100A8) associated with immune response and inflammation in IPF, providing valuable insights into the diagnosis and treatment of IPF.

PMID:39959639 | PMC:PMC11829586 | DOI:10.2147/JIR.S489210