Am J Physiol Lung Cell Mol Physiol. 2025 Jan 2. doi: 10.1152/ajplung.00189.2024. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a fatal disease characterized by the TGF-β-dependent activation of lung fibroblasts, leading to excessive deposition of collagen proteins and progressive replacement of healthy lung with scar tissue. We and others have shown that TGF-β-mediated activation of the Mechanistic Target of Rapamycin Complex 1 (mTORC1) and downstream upregulation of Activating Transcription Factor 4 (ATF4) promote metabolic reprogramming in lung fibroblasts characterized by upregulation of the de novo synthesis of glycine, the most abundant amino acid found in collagen protein. Whether mTOR and ATF4 regulate other metabolic pathways in lung fibroblasts has not been explored. Here, we used RNA sequencing to determine how both ATF4 and mTOR regulate gene expression in human lung fibroblasts following TGF-β. We found that ATF4 primarily regulates enzymes and transporters involved in amino acid homeostasis as well as aminoacyl-tRNA synthetases. mTOR inhibition resulted not only in the loss of ATF4 target gene expression, but also in the reduced expression of glycolytic enzymes and mitochondrial electron transport chain subunits. Analysis of TGF-β-induced changes in cellular metabolite levels confirmed that ATF4 regulates amino acid homeostasis in lung fibroblasts while mTOR also regulates glycolytic and TCA cycle metabolites. We further analyzed publicly available single-cell RNA-seq data sets and found increased expression of ATF4 and mTOR-regulated genes in pathologic fibroblast populations from the lungs of IPF patients. Our results provide insight into the mechanisms of metabolic reprogramming in lung fibroblasts and highlight novel ATF4 and mTOR-dependent pathways that may be targeted to inhibit fibrotic processes.

PMID:39745695 | DOI:10.1152/ajplung.00189.2024

Tuberk Toraks. 2024 Dec;72(4):288-294. doi: 10.5578/tt.202404984.

ABSTRACT

INTRODUCTION: Diffuse pulmonary ossification (DPO) refers to the unusual formation of mature bone tissue within the lung parenchyma. It has been shown to be associated with a number of cardiac and chronic lung diseases. The relation between DPO and idiopathic pulmonary fibrosis (IPF) has been shown in the literature. We examined DPO, which is the supporting computed tomography (CT) finding of IPF. In this way, it was aimed to distinguish cases with an IPF-like pattern non-invasively.

MATERIALS AND METHODS: A retrospective analysis included 89 cases exhibiting a CT pattern typical of usual interstitial pneumonia (UIP). The cases were divided into two groups: One with an IPF diagnosis and the other with a nonIPF diagnosis. The presence of DPO was then assessed in each case according to the criteria outlined in the literature. Finally, the occurrence of DPO was compared between the IPF group and the non-IPF group.

RESULT: Forty-seven of 89 cases had a diagnosis of IPF (52.8%). DPO was observed in 31 patients (34.8%). Presence of DPO was detected in 28 (59.6%) patients in the IPF group. The presence of DPO was detected in 3 (7.1%) cases in the non-IPF UIP patient group. A moderate correlation was found between IPF and DPO, and a moderate correlation was found between IPF and the male sex (r= 0.549; r= 0.311, respectively).

CONCLUSIONS: DPO is an important finding to support the diagnosis of IPF.

PMID:39745228 | DOI:10.5578/tt.202404984

Ther Adv Respir Dis. 2025 Jan-Dec;19:17534666241309795. doi: 10.1177/17534666241309795.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is often regarded as the archetypal progressive fibrosing interstitial lung disease (ILD). The term "progressive pulmonary fibrosis" (PPF) generally describes progressive lung fibrosis in an individual with an ILD other than IPF. Both IPF and PPF are associated with loss of lung function, worsening dyspnea and quality of life, and premature death. Current treatments slow the decline in lung function but have side effects that may deter the initiation or continuation of treatment. There remains a high unmet need for additional therapies that can be used alone or in combination with current therapies to preserve lung function in patients with IPF and PPF. Phosphodiesterase-4 (PDE4) is an enzyme involved in the regulation of inflammatory processes. Pre-clinical studies have shown that preferential inhibition of PDE4B has anti-inflammatory and antifibrotic effects and a lower potential for gastrointestinal adverse events than pan-PDE4 inhibition. The preferential PDE4B inhibitor nerandomilast demonstrated efficacy in preserving lung function in a phase II trial in patients with IPF and is under investigation in phase III trials as a treatment for IPF and PPF.

PMID:39745090 | DOI:10.1177/17534666241309795

J Clin Invest. 2025 Jan 2;135(1):e183836. doi: 10.1172/JCI183836.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is etiologically complex, with well-documented genetic and nongenetic origins. In this Review, we speculate that the development of IPF requires two hits: the first establishes a vulnerable bronchoalveolar epithelium, and the second triggers mechanisms that reprogram distal epithelia to initiate and perpetuate a profibrotic phenotype. While vulnerability of the bronchoalveolar epithelia is most often driven by common or rare genetic variants, subsequent injury of the bronchoalveolar epithelia results in persistent changes in cell biology that disrupt tissue homeostasis and activate fibroblasts. The dynamic biology of IPF can best be contextualized etiologically and temporally, including stages of vulnerability, early disease, and persistent and progressive lung fibrosis. These dimensions of IPF highlight critical mechanisms that adversely disrupt epithelial function, activate fibroblasts, and lead to lung remodeling. Together with better recognition of early disease, this conceptual approach should lead to the development of novel therapeutics directed at the etiologic and temporal drivers of lung fibrosis that will ultimately transform the care of patients with IPF from palliative to curative.

PMID:39744946 | DOI:10.1172/JCI183836

Respir Med. 2024 Dec 30:107937. doi: 10.1016/j.rmed.2024.107937. Online ahead of print.

ABSTRACT

BACKGROUND: The relationship between serum lipid with idiopathic pulmonary fibrosis (IPF) required to be explored. We aim to evaluate the association of serum lipid levels with mortality in patients with IPF.

MATERIALS AND METHODS: This retrospective study included IPF patients with more than three years follow-up. We collected baseline demographics information, forced vital capacity (FVC)% predicted, carbon monoxide diffusion capacity (DLCO)% predicted, gender-age-physiology (GAP) index, and serum lipid levels, including Triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C). We evaluate the relationship between the serum lipid levels and the disease severity, and the mortality in IPF.

RESULTS: This study enrolled 146 patients, with the three-year survival rate of 71.23%. The median follow-up time was 46.5 months. There was no significant difference in baseline lipid levels between the survival and non-survival group. TG levels were positively correlated with DLCO% predicted (r = 0.189, p = 0.022) and negatively correlated with GAP index (r=-0.186, p=0.025). After adjusting for GAP index, smoking history, body mass index and the use of antifibrotic and lipid-lowering drug, lower TC levels (HR: 0.74, 95% CI: 0.58-0.94, p=0.013) were identified as an independent risk factor for mortality.

CONCLUSION: This study demonstrated that lower TC levels were associated with increased mortality in IPF. More investigations are required to explore the role of lipid metabolism in the pathogenesis of pulmonary fibrosis.

PMID:39743155 | DOI:10.1016/j.rmed.2024.107937

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