ACS Nano. 2025 Jan 1. doi: 10.1021/acsnano.4c11113. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterized by persistent tissue injury, dysregulated wound healing, and extracellular matrix (ECM) deposition by myofibroblasts (MFs) through the fibroblast-to-myofibroblast transition (FMT). Implicit in the FMT process are changes in the ECM and cellular topology, but their relationship with the lung fibroblast phenotype has not been explored. We engineered topological mimetics of alignment cues (anisotropy/isotropy) using lung decellularized ECM micropattern arrays and investigated the effects of cellular topology on cellular fates in MRC-5 lung fibroblasts. We found that isotropic MRC-5 cells presented changes of the cytoskeleton, increased cell-cell adhesions and a multicellular architecture with increased overlap, changes in actin-myosin development, and enhanced focal adhesion and cell junction with random alignment. Besides, anisotropic fibroblasts were activated into a regular phenotype with an ECM remodeling profile. In contrast, isotropic fibroblasts developed a highly invasive phenotype expressing molecules, including CD274/programmed death-ligand 1 (PD-L1), cellular communication network factor 2 (CCN2)/connective tissue growth factor (CTGF), hyaluronan synthase 2 (HAS2), and semaphorin 7A (SEMA7A), but with downregulated matrix genes. Moreover, isotropic fibroblasts also showed higher expressions of Ki-67 and cyclin D1 (CCND1), resistance to apoptosis/senescence, and decreased autophagy. The topology regulated the cellular heterogeneity and resulted in positive feedback between changes in the cellular phenotype and the ECM structure, which may aggravate fibrosis and lead to a priming of malignant microenvironment during carcinogenesis. Using the versatile platform of micropattern array, we can not only visualize the interaction mechanism between cells and the ECM but also select potential clinical targets for diagnosis and therapeutics.

PMID:39742460 | DOI:10.1021/acsnano.4c11113

Front Oncol. 2024 Dec 17;14:1488157. doi: 10.3389/fonc.2024.1488157. eCollection 2024.

ABSTRACT

BACKGROUND: Interstitial lung diseases (ILDs) comprise a family of heterogeneous entities, primarily characterised by chronic scarring of the lung parenchyma. Among ILDs, idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial pneumonitis, associated with progressive functional decline leading to respiratory failure, a high symptom burden, and mortality. Notably, the incidence of lung cancer (LC) in patients already affected by ILDs-mainly IPF-is significantly higher than in the general population. Moreover, these cases are often neglected and deprived of active oncologic treatments.

METHODS: We here aim to identify variables predictive of outcome (mortality) in a multicentre retrospective cohort of ILD associated with lung cancer, collected from 2018 to the end of 2023. Overall, 73 cases were identified, and exhaustive clinicopathologic data were available for 55 patients. Among them, 42 had IPF. The entire dataset was then analysed by using the JMP partition algorithm (JMP-Statistical Discoveries, from SAS), which can choose the optimum splits from many possible trees, making it a powerful modelling and data discovery tool.

RESULTS: The average age at lung cancer diagnosis was 71.4 years, whereas the average age at IPF diagnosis was 69.5 years. The average Charlson Comorbidity Index was 4.6. Female patients constituted 28.3% (15) of the evaluated cases. The most frequent tumour histotype was adenocarcinoma (45.2%), and in more than 60% of the cases (67.9%), cancer was diagnosed at an early stage (TNM I-II-IIIA). A significant gender difference emerges regarding the overall patient survival, and quite unexpectedly, surgical approach to IPF-associated LC and the detection of serum autoantibodies are among the strongest outcome predictors.

CONCLUSIONS: The analysis performed is descriptive and successfully identifies key features of this specific and rare cancer population. IPF-associated LC emerges as a unique malignant disease defined by specific gender and histopathologic clinical and molecular parameters, which might benefit from active treatments.

PMID:39741973 | PMC:PMC11685083 | DOI:10.3389/fonc.2024.1488157

Eur J Radiol. 2024 Dec 22;183:111899. doi: 10.1016/j.ejrad.2024.111899. Online ahead of print.

ABSTRACT

OBJECTIVE: To assess whether CT style conversion between different CT vendors using a routable generative adversarial network (RouteGAN) could minimize variation in ILD quantification, resulting in improved functional correlation of quantitative CT (QCT) measures.

METHODS: Patients with idiopathic pulmonary fibrosis (IPF) who underwent unenhanced chest CTs with vendor A and a pulmonary function test (PFT) were retrospectively evaluated. As deep-learning based ILD quantification software was mainly developed using vendor B CT, style-converted images from vendor A to B style were generated using RouteGAN. Quantification was performed in both original and converted images. Measurement variability in QCT between original and converted images was evaluated using the concordance correlation coefficient (CCC). Two radiologists visually evaluated quantification accuracy using original and converted images. Correlations between CT parameters and PFT measures were assessed.

RESULTS: Total 112 patients (mean age, 61; 82 men) were studied. Measurement variability between original and converted CT was a CCC of 0.20 for reticulation, 0.72 for honeycombing, and 0.59 for ground-glass opacity. The median visual accuracy scores were higher for the quantification using converted compared with the original images (P < 0.001). Correlation between fibrosis score increased significantly after CT conversion for both forced vital capacity (original vs. converted; -0.35 vs. -0.50; P = 0.005) and diffusing capacity of the lung for carbon monoxide (-0.50 vs. -0.66; P < 0.001).

CONCLUSION: The improved accuracy in deep learning based ILD quantification after applying GAN-based CT style conversion can result in the improved functional correlation of QCT measurements in patients with IPF.

PMID:39740598 | DOI:10.1016/j.ejrad.2024.111899

Biochem Biophys Res Commun. 2024 Dec 19;745:151220. doi: 10.1016/j.bbrc.2024.151220. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease with limited therapeutic options. In this study, we identified Complement Factor H (CFH) as a critical regulator in the pathogenesis of IPF, contributing to fibrotic progression through autocrine regulation of complement component C3 and suppression of macrophage phagocytosis. Transcriptomic analysis of IPF lung tissues revealed upregulation of CFH and enrichment of pro-fibrotic pathways, including M2 macrophage infiltration. Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning further validated CFH as a key gene associated with macrophage polarization and fibrotic remodeling. Functional studies demonstrated that CFH deficiency in mouse models attenuated bleomycin-induced pulmonary fibrosis, as evidenced by reduced collagen deposition, improved lung function, and decreased macrophage infiltration. Mechanistically, CFH deficiency enhanced macrophage efferocytosis and autophagy, reducing macrophage-mediated inflammation and fibrosis. Moreover, siRNA-loaded liposomes targeting CFH mitigated pulmonary fibrosis in vivo, further supporting the therapeutic potential of CFH modulation. These findings highlight CFH as a promising therapeutic target for IPF and underscore the importance of complement regulation in macrophage-driven fibrosis.

PMID:39740399 | DOI:10.1016/j.bbrc.2024.151220

Sci Rep. 2024 Dec 30;14(1):31855. doi: 10.1038/s41598-024-83187-9.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal disease defined by a progressive decline in lung function due to scarring and accumulation of extracellular matrix (ECM) proteins. The SOCS (Suppressor Of Cytokine Signaling) domain is a 40 amino acid conserved domain known to form a functional ubiquitin ligase complex targeting the Von Hippel Lindau (VHL) protein for proteasomal degradation. Here we show that the SOCS conserved domain operates as a molecular tool, to disrupt collagen and fibronectin fibrils in the ECM associated with fibrotic lung myofibroblasts. Our results demonstrate that fibroblasts differentiated using TGFβ, followed by transduction with the SOCS domain, exhibit significantly reduced levels of the contractile myofibroblast-marker, α-SMA. Furthermore, in support of its role to retard differentiation, we find that lung fibroblasts expressing the SOCS domain present with significantly reduced levels of α-SMA and fibrillar fibronectin after differentiation with TGFβ. We show that adenoviral delivery of the SOCS domain in the fibrotic phase of experimental lung fibrosis in mice, significantly reduces collagen accumulation in disease lungs. These data underscore a novel function for the SOCS domain and its potential in ameliorating pathologic matrix deposition in lung fibroblasts and experimental lung fibrosis.

PMID:39738247 | DOI:10.1038/s41598-024-83187-9

Front Immunol. 2024 Dec 16;15:1450688. doi: 10.3389/fimmu.2024.1450688. eCollection 2024.

ABSTRACT

Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are the leading cause of mortality among patients with IPF. There is still a lack of effective treatments for AE-IPF, resulting in a hospitalization mortality rate as high as 70%-80%. To reveal the complicated mechanism of AE-IPF, more attention has been paid to its disturbed immune environment, as patients with IPF exhibit deficiencies in pathogen defense due to local immune dysregulation. During the development of AE-IPF, the classical stimulatory signals in adaptive immunity are inhibited, while the nonclassical immune reactions (Th17) are activated, attracting numerous neutrophils and monocytes to lung tissues. However, there is limited information about the specific changes in the immune response of AE-IPF. We summarized the immune mechanisms of AE-IPF in this review.

PMID:39737178 | PMC:PMC11682984 | DOI:10.3389/fimmu.2024.1450688

J Inflamm Res. 2024 Dec 24;17:11605-11629. doi: 10.2147/JIR.S490457. eCollection 2024.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease. PANoptosis, a unique inflammatory programmed cell death, it manifests as the simultaneous activation of signaling markers for pyroptosis, apoptosis, and necroptosis. However, research on the role of PANoptosis in the development of IPF is currently limited. This study was aimed to explore the role of PANoptosis in IPF.

METHODS: In this study, we first identified PANDEGs using the GEO database. Exploring potential biological functions and immune cell infiltration abundance through GO/KEGG enrichment analysis and Immune infiltration analysis. Through machine learning and experimental validation, we identified four diagnostic genes and four prognostic genes associated with PANoptosis, leading to the development of a diagnostic and prognostic model for IPF. Our single-cell analysis further explored the role of these PANoptosis prognostic genes. Additionally, the L1000FWD application was used to identify small molecule drugs, based on the four PANoptosis prognostic genes, and confirmed their efficacy through molecular docking.

RESULTS: 104 PANoptosis differentially expressed genes were identified from IPF and normal tissues. Enrichment analysis indicated that these genes were associated with immune-inflammatory response pathway. We developed a diagnostic and prognostic models based on PANoptosis related genes. The diagnostic model included AKT1, PDCD4, PSMA2, and PPP3CB. Conversely, the prognostic model included TNFRSF12A, DAPK2, UACA, and DSP. External dataset validation and qPCR showed the reliability of most of the conclusions. Additionally, potential therapeutic drugs, including Metergoline, Candesartan, and Selumetinib, were identified based on four prognostic genes. Molecular docking shows that these drugs have good binding ability with their targets.

CONCLUSION: Importantly, our findings provide scientific evidence for the diagnosis and prognostic biomarkers of IPF patients, as well as small molecule therapeutic drugs.

PMID:39737099 | PMC:PMC11682943 | DOI:10.2147/JIR.S490457

Cureus. 2024 Nov 27;16(11):e74611. doi: 10.7759/cureus.74611. eCollection 2024 Nov.

ABSTRACT

Pulmonary fibrosis (PF) is a medical condition that affects the lungs and causes scarring due to the deposition of excess fibrotic tissue. This is often preceded by various causes and can lead to long-term health consequences. The treatment of PF using mesenchymal stem cells (MSCs) to correct lung damage and decrease inflammation is a current focus of research. MSCs are beneficial in inhibiting the immune response and inducing more efficient repair processes, therefore having the potential to be useful in various settings. This review aims to identify the current utilization of MSCs in treating PF in adults. A systematic search was conducted according to the Joanna Briggs Institute Reviewers Manual using Ovid Medline, Embase, and Web of Science to identify studies. Following PRISMA guidelines, eligible peer-reviewed studies that used MSCs to treat adults with PF were identified. The initial search produced 1,836 articles after removing duplicates. Twenty-nine articles met the inclusion criteria. A final analysis of the articles further narrowed the number to eight articles that met all criteria and were relevant to the scoping review's objective. Four studies utilized bone marrow-derived MSCs, two utilized umbilical-derived MSCs, one utilized placenta-derived MSCs, and one utilized adipose-derived MSCs. Of these studies, five administered treatments via an intravenous infusion, two used an endobronchial infusion, and the last utilized an intratracheal approach. The use of MSCs in the treatment of PF in adults was found to be safe with the most common adverse effect reported being fever and chills which resolved a few hours after administration. Although the research regarding MSC use in the treatment of idiopathic PF is relatively new, our results summarize the current sources, route of administration, and current adverse effects. We have shown that future studies with larger sample sizes should be performed to determine long-term outcomes and overall efficacy before clinical practice guidelines become implemented.

PMID:39735115 | PMC:PMC11678155 | DOI:10.7759/cureus.74611

Sci Rep. 2024 Dec 28;14(1):30680. doi: 10.1038/s41598-024-77328-3.

ABSTRACT

Quantitative assessment of the extent of radiological alterations in interstitial lung diseases is a promising field of application that goes beyond the limitations of qualitative scoring. Analysis of density histograms, i.e., skewness, kurtosis, and mean lung attenuation, is among the most studied approaches. We recently proposed their integration in a single parameter, the computerized integrated index (CII), to reduce their redundancy. The CII has proven effective in detecting subclinical lung involvement, correlates with lung function/disease activity, and predicts mortality in systemic sclerosis patients. Seventy-three newly diagnosed and therapy-naive IPF patients (M = 50; median age: 70.2 years) were prospectively enrolled from January 2014 to December 2022, and followed till December 2023. At baseline, all underwent lung function testing and volumetric high resolution chest CT. Density histograms were analyzed with an open-source automatic platform (Slicer 3D) and CII derived by means of Principal Component Analysis, as previously described. During a median follow-up of 5.8 years, 39 (53.4%) subjects died. Median overall survival (OS) was 4.9 years (95% CI 3.7 years-not estimable). The CII was significantly associated with OS (HR 0.49; 95% CI 0.35-0.68; P < 0.001) and correlated with lung function (r = 0.41; 95% CI 0.19 to 0.60; P < 0.001 for FVC, and r = 0.62; 95% CI 0.44 to 0.75; P < 0.001 for DLCOsb). Patients stratification according to CII tertile, showed a consistent reduction in the hazard of death. After adjusting for body mass index, smoking, GAP stage, and anti-fibrotic therapy, the CII preserved a significant association with the hazard of death (HR 0.35; 95% CI 0.2-0.63; P < 0.001). CII is a proxy marker of IPF severity worthy of use for prognostication purposes in daily practice.

PMID:39730381 | DOI:10.1038/s41598-024-77328-3

J Am Dent Assoc. 2024 Dec 24:S0002-8177(24)00636-6. doi: 10.1016/j.adaj.2024.11.002. Online ahead of print.

ABSTRACT

BACKGROUND: Dentists can be exposed to dust and nanoparticles from teeth, dental composites, and metal alloys generated during dental procedures, and exposure to dust can cause respiratory diseases, including pulmonary fibrosis. The authors describe mortality from nonmalignant respiratory diseases (NMRDs) among dentists in the United States.

METHODS: The authors submitted information on US dentists who died from 1979 through 2018 to a centralized US death records database to obtain underlying causes of death. Decedent data that met records-matching criteria were analyzed using the Life Table Analysis System software (National Institute for Occupational Safety and Health) to calculate proportionate mortality ratios (PMRs), indirectly standardized for age, sex, race, and 5-year calendar period with 95% CIs, for NMRD and a group of International Classification of Diseases, Ninth and Tenth Revision codes approximating idiopathic pulmonary fibrosis.

RESULTS: Among 21,928 dentist decedents with complete race information, 1,583 deaths (7.2%) resulted from NMRD. Proportionate mortality for dentist decedents was significantly lower than the general population for NMRD overall (PMR, 0.66; 95% CI, 0.62 to 0.69), chronic obstructive pulmonary disease (PMR, 0.44; 95% CI, 0.41 to 0.48), and pneumonia (PMR, 0.73; 95% CI, 0.67 to 0.81) but significantly higher than the general population for the pulmonary fibrosis group (PMR, 1.57; 95% CI, 1.37 to 1.80).

CONCLUSIONS: Dentists had decreased proportionate mortality for most NMRD and increased proportionate mortality for underlying causes of death associated with pulmonary fibrosis.

PRACTICAL IMPLICATIONS: Existing engineering controls that reduce inhalational exposures during dental procedures might be inadequate. Improved characterization of these exposures could help inform more effective engineering controls.

PMID:39729055 | DOI:10.1016/j.adaj.2024.11.002

Curr Issues Mol Biol. 2024 Dec 4;46(12):13746-13766. doi: 10.3390/cimb46120821.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, deathly disease with no recognized effective cure as yet. Furthermore, its diagnosis and differentiation from other diffuse interstitial diseases remain a challenge. Circulating miRNAs have been measured in IPF and have proven to be an adequate option as biomarkers for this disease. These miRNAs, released into the circulation outside the cell through exosomes and proteins, play a crucial role in the pathogenic pathways and mechanisms involved in IPF development. This review focuses on the serum/plasma miRNAs reported in IPF that have been validated by real-time PCR and the published evidence regarding the fibrotic process. First, we describe the mechanisms by which miRNAs travel through the circulation (contained in exosomes and bound to proteins), as well as the mechanism by which miRNAs perform their function within the cell. Subsequently, we summarize the evidence concerning miRNAs reported in serum/plasma, where we find contradictory functions in some miRNAs (dual functions in IPF) when comparing the findings in vitro vs. in vivo. The most relevant finding, for instance, the levels of miRNAs let-7d and miR-21 reported in the serum/plasma in IPF, correspond to those found in studies in lung fibroblasts and the murine bleomycin model, reinforcing the usefulness of these miRNAs as future biomarkers in IPF.

PMID:39727949 | DOI:10.3390/cimb46120821

Cell Mol Life Sci. 2024 Dec 27;82(1):30. doi: 10.1007/s00018-024-05548-x.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a prevalent interstitial lung disease with high mortality. CD38 is a main enzyme for intracellular nicotinamide adenine dinucleotide (NAD+) degradation in mammals. It has been reported that CD38 participated in pulmonary fibrosis through promoting alveolar epithelial cells senescence. However, the roles of endothelial CD38 in pulmonary fibrosis remain unknown. In the present study, we observed that the elevated expression of CD38 was related to endothelial-to-mesenchymal transition (EndMT) of lung tissues in IPF patients and bleomycin (BLM)-induced pulmonary fibrosis mice and also in human umbilical vein endothelial cells (HUVECs) treated with BLM. Micro-computed tomography (MCT) and histopathological staining showed that endothelial cell-specific CD38 knockout (CD38EndKO) remarkably attenuated BLM-induced pulmonary fibrosis. In addition, CD38EndKO significantly inhibited TGFβ-Smad3 pathway-mediated excessive extracellular matrix (ECM), reduced Toll-like receptor4-Myeloid differentiation factor88-Mitogen-activated protein kinases (TLR4-MyD88-MAPK) pathway-mediated endothelial inflammation and suppressed nicotinamide adenine dinucleotide phosphate oxidases1 (NOX1)-mediated oxidative stress. Furthermore, we demonstrated that 3-TYP, a SIRT3-specific inhibitor, markedly reversed the protective effect of HUVECsCD38KD cells and 78 C, a CD38-specific inhibitor, on BLM-induced EndMT in HUVECs. Therefore, we concluded that CD38EndKO significantly ameliorated BLM-induced pulmonary fibrosis through inhibiting ECM, endothelial inflammation and oxidative stress, further alleviating EndMT in mice. Our findings suggest that endothelial CD38 may be a new therapeutic target for the prevention and treatment of pulmonary fibrosis clinically.

PMID:39725783 | DOI:10.1007/s00018-024-05548-x

Thorax. 2024 Dec 25:thorax-2024-222636. doi: 10.1136/thorax-2024-222636. Online ahead of print.

ABSTRACT

INTRODUCTION: Acute exacerbation of interstitial lung disease (AE-ILD) often results in death and poses significant challenges in clinical management. While corticosteroids are frequently employed, the optimal regimen and their clinical efficacy remain uncertain. To address this knowledge gap, we undertook a systematic review to evaluate the impact of steroid therapy on clinical outcomes in patients experiencing AE-ILD.

METHOD: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, we systematically searched multiple databases, identifying 12 454 articles. After removing duplicates and screening titles and abstracts, 447 articles were selected for full-text review. Ultimately, nine studies met inclusion criteria, comparing high-dose corticosteroids with low-dose or non-steroidal interventions in treating AE-ILD. Key outcomes included in-hospital and long-term mortality, as well as AE recurrence.

RESULTS: Analysis of nine studies (total n=18 509) revealed differential treatment effects based on the ILD subtype. In non-idiopathic pulmonary fibrosis (IPF) ILD, high-dose corticosteroid therapy (>1.0 mg/kg prednisolone) demonstrated improved survival (adjusted HR 0.221, 95% CI 0.102 to 0.480, p<0.001) and reduced 90-day mortality. Early tapering of high-dose corticosteroids (>10% reduction within 2 weeks) reduced in-hospital mortality (adjusted HR 0.37, 95% CI 0.14 to 0.99). Higher cumulative doses in the first 30 days (5185±2414 mg/month vs 3133±1990 mg/month) were associated with lower recurrence rates (adjusted HR 0.61, 95% CI 0.41 to 0.90, p=0.02). In IPF patients, however, high-dose therapy showed inconsistent benefits, with some studies reporting increased mortality risk (OR 1.075, 95% CI 1.044 to 1.107, p<0.001).

CONCLUSION: This review emphasises the potential benefits of individualised treatment approaches for AE-ILD but highlights the need for caution in making definitive recommendations. Although high-dose corticosteroids may show promise, particularly in non-IPF cases, the current evidence is inconsistent, and the lack of robust supporting literature makes it difficult to draw firm conclusions. Further research through randomised controlled trials is necessary to refine and optimise therapeutic strategies for AE-ILD.

PMID:39721758 | DOI:10.1136/thorax-2024-222636

EClinicalMedicine. 2024 Dec 5;79:102966. doi: 10.1016/j.eclinm.2024.102966. eCollection 2025 Jan.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, deadly lung disease with several factors, including respiratory tract infections (RTI), for disease worsening. There's no comprehensive data on RTI incidence in IPF patients across different therapies, including antifibrotic (nintedanib or pirfenidone), investigative or placebo treatments.

METHODS: A systematic search of databases Medline, EMBASE, Cochrane Central, Web of Science and Scopus was conducted on September 30th 2024 (PROSPERO registration number: CRD42023484213). Only randomized controlled trials of drugs intended for IPF treatment in adults and reporting RTI incidence were included. Pooled risk ratio with 95% confidence interval (CI), risk of bias, GRADE and CINEMA assessments were conducted along with subgroup analyses for upper and lower RTI and for different antifibrotic doses.

FINDINGS: A total of 27 trials of different drugs aimed for IPF therapy were pooled in a pairwise meta-analysis, 11,542 patients were analyzed with an overall number of 4156 RTI events, representing an average incidence of 38.4 ± 23.5%. Most therapies did not affect RTI risk in IPF, although single trials with everolimus and trimethoprim/sulfamethoxazole showed a significant decrease compared to placebo. For antifibrotics, RTI incidence was similar with pirfenidone treatment compared to nintedanib (RR: 0.98 CI: [0.71; 1.36]) and compared to placebo (RR: 0.88 CI: [0.69; 1.10]) and nintedanib compared to placebo (RR: 0.89 CI: [0.71; 1.12]).

INTERPRETATION: RTIs are frequently reported adverse events in IPF patients over a one-year period, with different investigated treatments showing no profound impact compared to placebo. Future clinical trials should focus on targeting treatable traits like RTIs.

FUNDING: None.

PMID:39720602 | PMC:PMC11665700 | DOI:10.1016/j.eclinm.2024.102966

PNAS Nexus. 2024 Dec 7;4(1):pgae551. doi: 10.1093/pnasnexus/pgae551. eCollection 2025 Jan.

ABSTRACT

Investigating the molecular, cellular, and tissue-level changes caused by disease, and the effects of pharmacological treatments across these biological scales, necessitates the use of multiscale computational modeling in combination with experimentation. Many diseases dynamically alter the tissue microenvironment in ways that trigger microvascular network remodeling, which leads to the expansion or regression of microvessel networks. When microvessels undergo remodeling in idiopathic pulmonary fibrosis (IPF), functional gas exchange is impaired and lung function declines. We integrated a multiscale computational model with independent experiments to investigate how combinations of biomechanical and biochemical cues in IPF alter cell fate decisions leading to microvascular remodeling. Our computational model predicted that extracellular matrix (ECM) stiffening reduced microvessel area, which was accompanied by physical uncoupling of endothelial cell (EC) and pericytes, the cells that comprise microvessels. Nintedanib, an Food and Drug Administration-approved drug for treating IPF, was predicted to further potentiate microvessel regression by decreasing the percentage of quiescent pericytes while increasing the percentage of pericytes undergoing pericyte-myofibroblast transition in high ECM stiffnesses. Importantly, the model suggested that YAP/TAZ inhibition may overcome the deleterious effects of nintedanib by promoting EC-pericyte coupling and maintaining microvessel homeostasis. Overall, our combination of computational and experimental modeling can predict and explain how cell decisions affect tissue changes during disease and in response to treatments.

PMID:39720203 | PMC:PMC11667245 | DOI:10.1093/pnasnexus/pgae551

Respir Res. 2024 Dec 24;25(1):442. doi: 10.1186/s12931-024-03075-8.

ABSTRACT

BACKGROUND: The composite physiologic index (CPI) was developed to estimate the extent of interstitial lung disease (ILD) in idiopathic pulmonary fibrosis (IPF) patients based on pulmonary function tests (PFTs). The CALIPER-revised version of the CPI (CALIPER-CPI) was also developed to estimate the volume fraction of ILD measured by CALIPER, an automated quantitative CT postprocessing software. Recently, artificial intelligence-based quantitative CT image analysis software (AIQCT), which can be used to quantify the bronchial volume separately from the ILD volume, was developed and validated in IPF. The aim of this study was to develop AIQCT-derived CPI formulas to quantify CT abnormalities in IPF and to investigate the associations of these CPI formulas with survival.

METHODS: The first cohort included 116 patients with IPF. In this cohort, ILD, bronchial, and hyperlucent volumes on CT were quantified using AIQCT. New CPI formulas were developed based on PFTs to estimate the volume fraction of ILD (ILD-CPI), the sum of the ILD and bronchial volume fractions (ILDB-CPI), and the sum of the ILD, bronchial and hyperlucent volume fractions (ILDBH-CPI). The associations of the original CPI, the CALIPER-CPI and the AIQCT-derived CPIs with survival were analyzed in the first cohort and in a second cohort of patients with IPF (n = 72).

RESULTS: In the first cohort, over a median observation time of 92.8 months, 79 patients (68.1%) died, and one patient (0.9%) underwent living-donor lung transplantation. The original CPI, the CALIPER-CPI, and all AIQCT-derived CPIs were associated with overall survival (hazard ratios: 1.07-1.22). The C-index of the ILDB-CPI (0.759) was the highest among all AIQCT-derived CPIs and was comparable to that of the original CPI (0.765) and the CALIPER-CPI (0.749). The C-index of the ILDBH-CPI (0.729) was lower than that of the other CPI variables. The second cohort yielded similar C-indices as the first cohort for the original CPI (0.738), CALIPER-CPI (0.757) and ILDB-CPI (0.749).

CONCLUSIONS: The ILDB-CPI can predict the outcomes of IPF patients with a similar performance to that of the original CPI and the CALIPER-CPI. Adding the hyperlucent volume to the CPI formula did not improve its predictive accuracy for mortality.

TRIAL REGISTRATION: None (no health care interventions were performed).

PMID:39719582 | DOI:10.1186/s12931-024-03075-8

RMD Open. 2024 Dec 23;10(4):e004704. doi: 10.1136/rmdopen-2024-004704.

ABSTRACT

Interstitial lung disease (ILD) associated with rheumatoid arthritis or with connective tissue diseases such as systemic sclerosis can be collectively named systemic autoimmune rheumatic disease-associated ILDs (SARD-ILDs) or rheumatic musculoskeletal disorder-associated ILDs. SARD-ILDs result in substantial morbidity and mortality, and there is a high medical need for effective therapies that target both fibrotic and inflammatory pathways in SARD-ILD. Phosphodiesterase 4 (PDE4) hydrolyses cyclic AMP, which regulates multiple pathways involved in inflammatory processes. PDE4 is overexpressed in peripheral blood monocytes from patients with inflammatory diseases. However, clinical data on pan-PDE4 inhibition in fibrotic conditions are lacking. The PDE4B subtype is highly expressed in the brain, lungs, heart, skeletal muscle and immune cells. As such, inhibition of PDE4B may be a novel approach for fibrosing ILDs such as idiopathic pulmonary fibrosis (IPF) and SARD-ILD. Preclinical data for PDE4B inhibition have provided initial evidence of both anti-inflammatory and antifibrotic activity, with reduced potential for gastrointestinal toxicity compared with pan-PDE4 inhibitors. In a proof-of-concept phase II trial in patients with IPF, nerandomilast (BI 1015550), the only PDE4B inhibitor currently in clinical development, prevented a decline in lung function over 12 weeks compared with placebo. The potential clinical benefit of PDE4B inhibition is now being investigated in the phase III setting, with two trials evaluating nerandomilast in patients with IPF (FIBRONEER-IPF) or with progressive pulmonary fibrosis other than IPF (FIBRONEER-ILD). Here, we review the preclinical and clinical data that provide rationale for PDE4B inhibition as a treatment strategy in patients with SARD-ILD.

PMID:39719300 | DOI:10.1136/rmdopen-2024-004704

Naunyn Schmiedebergs Arch Pharmacol. 2024 Dec 24. doi: 10.1007/s00210-024-03744-x. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe and progressive lung disorder with an average survival rate of 3 to 5 years. IPF presents a significant challenge in clinical management, necessitating novel therapeutic approaches. Nanostructured lipid carriers (NLCs) have proven to be promising vehicles for targeted drug delivery to the lung tissues. This research focuses on formulating and evaluating umbelliferone (UMB)-loaded NLCs for the treatment of IPF. UMB-NLC was formulated using the hot emulsion ultrasonication method and was characterized. The formulation was then tested for its efficacy in a bleomycin-induced IPF mice model. Leukocyte infiltration and interleukin-6 were estimated in the bronchoalveolar lavage fluid (BALF). Various antioxidant activities were also assessed for the formulation, followed by histopathological analysis. Furthermore, an in silico mechanistic approach using network pharmacology was carried out to obtain genes of interest. Particle size analysis revealed a mean size of 174.9 ± 3.66 nm for UMB-NLC, ideal for lung tissue targeting. Zeta potential measurements indicated good stability (-34.3 ± 1.35 mV) for long-term storage. Fourier transform infrared spectroscopy (FTIR) confirmed the successful encapsulation of UMB within the lipid matrix of NLCs. X-ray diffraction (XRD) and differential scanning calorimetry (DSC) demonstrated the amorphous state of UMB-NLC, indicating enhanced solubility and bioavailability. Field emission scanning electron microscopy (FESEM) revealed uniform, spherical particles in the nanometer range. Drug entrapment efficiency (EE%) and loading capacity (DL%) were found to be 85.03 ± 2.36% and 17.01 ± 0.48%, respectively, indicating efficient drug incorporation. In vitro release study showed uniform sustained drug release over 48 h, indicating the potential for prolonged therapeutic effect. In vivo studies using UMB-NLC demonstrated significant improvements in bleomycin-induced IPF. A restoration in body weight and lung/body-weight (L/B) ratio was observed compared to disease controls. BALF analysis revealed reduced leukocyte infiltration and decreased inflammatory cytokine IL-6 levels (**p < 0.01). Biochemical assays showed enhanced antioxidant status and reduced oxidative stress in lung tissues. Hydroxyproline content (HPO, **p < 0.01), malondialdehyde (MDA, ***p < 0.001), and total protein content (**p < 0.01) were significantly reduced, while glutathione (GSH, ***p < 0.001), superoxide dismutase (SOD, **p < 0.01), and catalase (CAT, **p < 0.01) were elevated. Histopathological analysis confirmed the attenuation of lung fibrosis with maintained alveolar architecture and reduced fibrotic deposition. Furthermore, network pharmacology identified UMB targets and IPF-related genes with a Venn diagram, and cytoHubba analysis revealed key hub genes. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment demonstrated UMB's involvement in IPF-related pathways, highlighting its therapeutic potential. Therefore, UMB-NLC may exhibit promising therapeutic potential in the treatment of IPF, offering targeted drug delivery, enhanced bioavailability, and improved efficacy in alleviating pulmonary inflammation and fibrosis.

PMID:39718612 | DOI:10.1007/s00210-024-03744-x

Adv Ther. 2024 Dec 23. doi: 10.1007/s12325-024-03079-2. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial pneumonia, which is characterised by progressive worsening of dyspnoea and lung function. Nintedanib treatment is recommended to slow IPF disease progression. The aim of this post-marketing surveillance (PMS) study was to evaluate the safety and effectiveness of nintedanib over 24 months in patients with IPF in a real-world setting in Japan.

METHODS: This prospective, non-interventional, all-case PMS study of nintedanib included Japanese patients with IPF who started nintedanib between 7 October 2015 and 2 May 2023. The primary outcome was to determine the proportion of patients with adverse drug reactions (ADRs), and the secondary outcome was the adjusted absolute change from baseline in forced vital capacity (FVC) at 24 months.

RESULTS: In total, 5717 patients from 1013 institutions were included in the safety analysis (mean ± standard deviation age 71.7 ± 8.1 years, 78.1% male, 70.8% current or former smokers). Most patients (83.9%) had initiated nintedanib at a dose of 150 mg capsules twice daily. At 24 months, 2841 patients (64.8%) had discontinued nintedanib, mainly due to adverse events (44.0%), ADRs (24.1%) or insufficient effectiveness (5.7%). The most common ADRs were diarrhoea (35.5%), hepatic function abnormal (14.4%), decreased appetite (9.9%), liver disorders (7.8%) and nausea (5.8%). The adjusted absolute mean change in FVC from baseline to 24 months was - 212.3 mL (95% confidence interval - 235.3, - 189.3).

CONCLUSION: This is the largest prospective study to investigate patients with IPF who were treated with nintedanib. The safety and effectiveness of nintedanib treatment in this real-world setting of Japanese patients with IPF was similar to that reported in previous studies. Nintedanib effectively slowed the progression of IPF. No new safety concerns were identified, and the need for appropriate management of hepatic disorders and diarrhoea (as per the approved product information) was confirmed.

STUDY REGISTRATION: ClinicalTrials.gov (NCT02607722)/European Union electronic register of Post-Authorisation Studies (EUPAS10891).

PMID:39714546 | DOI:10.1007/s12325-024-03079-2

Clin Radiol. 2024 Nov 29;81:106759. doi: 10.1016/j.crad.2024.106759. Online ahead of print.

ABSTRACT

AIM: Idiopathic pulmonary fibrosis (IPF) is a debilitating and fatal lung disease. Changes in body composition potentially correlate with outcomes in patients with IPF.

MATERIALS AND METHODS: Patients with IPF on antifibrotic treatment attending a single institution were identified and retrospectively evaluated (n=84). Three groups were formed based on antifibrotic treatment: pirfenidone group, nintedanib group and pirfenidone-nintedanib switch group. Morphomic analysis of muscle quantity (cross-sectional area in cm2) and quality (density in Hounsfield Units) on thoracic computed tomography (CT) was performed using a web-based morphomic segmentation tool. Bilateral erector spinae and pectoralis muscles were measured at pre-defined vertebral levels.

RESULTS: All three treatment groups showed a statistically significant decline in forced vital capacity (FVC), diffusion capacity of the lung for carbon monoxide (DLCO), pectoral muscle cross sectional area (PMA), and erector spinae muscle cross-sectional area (ESMA). Muscle density did not change significantly. Differences existed in analytic morphomics between treatment groups. Patients with a pretreatment body mass index (BMI) below 30 were found to have a significantly greater loss of PMA when treated with nintedanib instead of pirfenidone. FVC and DLCO did not differ between treatment groups.

CONCLUSION: There were no direct correlations between pulmonary function and morphomic parameters in our entire group of IPF patients. However, between different treatment groups, the rate of muscle bulk loss differed. This is an important consideration for clinicians when deciding on an antifibrotic agent of choice.

PMID:39709732 | DOI:10.1016/j.crad.2024.106759