Sci Rep. 2025 Jan 17;15(1):2331. doi: 10.1038/s41598-025-86544-4.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal disorder of unknown etiology, characterized by interstitial fibrosis of the lungs. Bleomycin-induced pulmonary fibrosis mouse model (BLM model) is a widely used animal model to evaluate therapeutic targets for IPF. Histopathological analysis of lung fibrosis is an important method for evaluating BLM model. However, this method requires expertise in recognizing complex visual patterns and is time-consuming, making the workflow difficult and inefficient. Therefore, we developed a new workflow for BLM model that reduces inter- and intra-observer variations and improves the evaluation process. We generated deep learning models for grading lung fibrosis that were able to achieve accuracy comparable to that of pathologists. These models incorporate complex image patterns and qualitative factors, such as collagen texture and distribution, potentially identifying drug candidates overlooked in evaluations based solely on simple area extraction. This deep learning-based fibrosis grade assessment has the potential to streamline drug development for pulmonary fibrosis by offering higher granularity and reproducibility in evaluating BLM model.

PMID:39833349 | DOI:10.1038/s41598-025-86544-4

J Thorac Dis. 2024 Dec 31;16(12):8379-8388. doi: 10.21037/jtd-24-1165. Epub 2024 Dec 11.

ABSTRACT

BACKGROUND: The benefits of pulmonary rehabilitation (PR) for patients with idiopathic pulmonary fibrosis (IPF) have been limited to improving dyspnea, exercise capacity, and quality of life (QoL). This study aimed to assess the current status of PR and its effect on prognosis.

METHODS: The Nationwide Korean Health Insurance Review and Assessment Service (HIRA) database was used in this study. Annual PR implementation rate since 2016 following its coverage in the health insurance was analyzed. IPF cases were defined using the International Classification of Diseases 10th Revision (ICD-10) codes and rare intractable diseases (RID) codes. Risk of acute exacerbation (AE) and mortality of IPF patients with or without PR were analyzed.

RESULTS: Of the 4,228 patients with IPF, only 205 (4.85%) received PR. Patients in the PR group were more frequently treated with pirfenidone and systemic steroids than non-PR group. In patients treated with steroids, mortality risk increased regardless of PR application, with hazard ratio (HR) of 1.63 [95% confidence interval (CI): 1.26-2.10, P<0.001] in the PR group and 1.38 (95% CI: 1.21-1.57, P<0.001) in the non-PR group, compared to those not treated with steroids. Additionally, PR did not significant affect mortality risk in patients not receiving steroids (HR, 1.49, 95% CI: 0.87-2.54, P=0.15). Similar patterns were seen for the risk of AE.

CONCLUSIONS: PR was applied in only a minority of patients with IPF. It did not succeed in reducing the risk of AE or mortality. A prospective study targeting early-stage patients is needed to evaluate the impact of PR considering the progressive nature of IPF disease itself.

PMID:39831231 | PMC:PMC11740027 | DOI:10.21037/jtd-24-1165

J Thorac Dis. 2024 Dec 31;16(12):8528-8537. doi: 10.21037/jtd-24-1356. Epub 2024 Dec 28.

ABSTRACT

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) are at risk of lung cancer development. Antifibrotic therapy could slow disease progression of IPF, but there is limited data on its effectiveness on lung cancer. Here, we aimed to investigate lung cancer incidence and the risk of mortality of patients with IPF receiving antifibrotic therapy.

METHODS: Data from the Korean National Health Insurance service database between October 2015 and September 2021 were used. The incidence of lung cancer and all-cause mortality in the IPF cohort was analyzed depending on pirfenidone treatment. Those who were diagnosed with lung cancer prior to IPF diagnosis were excluded.

RESULTS: Among the 5,038 patients with IPF who were eligible for the study, pirfenidone was administered to 880 patients. Median follow-up duration was 4,872.8 and 23,612.1 person-years in the groups receiving and not receiving pirfenidone, respectively. The incidence of lung cancer was significantly higher in the pirfenidone group compared to non-users [2.44 vs. 1.56 per 100 person-years; risk ratio 1.56; 95% confidence interval (CI), 1.27-1.92]. However, the risk of mortality did not differ significantly between patients receiving pirfenidone and those who did not. Further analysis was conducted to assess lung cancer development and pirfenidone therapy. Among patients with lung cancer, those treated with pirfenidone demonstrated significantly improved survival compared to those not receiving pirfenidone therapy (log-rank test, P<0.001). Pirfenidone therapy was associated with a protective effect on mortality in IPF patients with lung cancer [hazard ratio, 0.61; 95% CI, 0.43-0.85].

CONCLUSIONS: Antifibrotic therapy was associated with improved survival in patients with IPF who develop lung cancer, even though the incidence of lung cancer was higher in those receiving antifibrotic treatment compared to those do not.

PMID:39831219 | PMC:PMC11740043 | DOI:10.21037/jtd-24-1356

J Thorac Dis. 2024 Dec 31;16(12):8338-8349. doi: 10.21037/jtd-23-1908. Epub 2024 Dec 20.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) has high mortality and poor prognosis, which brings enormous burdens to families and society. We conducted this meta-analysis to analyze and summarize the risk factors associated with mortality in IPF, hoping to provide reference for clinical prevention and treatment of IPF.

METHODS: We conducted a comprehensive search of PubMed, Cochrane Library, Embase, and Web of Science from inception to August 10, 2023, to include cohort studies on mortality in patients with IPF. Two researchers independently screened the studies and extracted data. The Newcastle-Ottawa Scale (NOS) was used to assess the methodological quality of studies. Hazard ratios (HRs) and 95% confidence intervals (CIs) were reported to identify risk factors for mortality in IPF. In addition, we also carried out sensitivity analysis, Begg's and Egger's tests to evaluate the heterogeneity and publication bias.

RESULTS: Eighteen studies comprising 8,408 patients were included. The meta-analysis suggested that age (HR =1.03; 95% CI: 1.01, 1.04; P<0.001), forced vital capacity (FVC) (HR =0.97; 95% CI: 0.96, 0.99; P=0.005), FVC to predicted value ratio (FVC% pred) (HR =0.98; 95% CI: 0.97, 0.99; P<0.001), diffusing capacity of the lungs for carbon monoxide to predicted value ratio (DLCO% pred) (HR =0.98; 95% CI: 0.97, 0.99; P<0.001), gender-age-physiology (GAP) index (HR =1.70; 95% CI: 1.20, 2.40; P=0.003), and lung cancer (HR =2.75, 95% CI: 1.23, 6.15; P=0.01) were mortality-related risk factors in patients with IPF. Whereas, gender, smoking, body mass index (BMI), diffusing capacity of the lungs for carbon monoxide (DLCO), C-reactive protein (CRP), 6-minute walking distance (6MWD), pulmonary hypertension, gastroesophageal reflux, and cardiovascular disease were not statistically associated with death.

CONCLUSIONS: Age, FVC, FVC% pred, DLCO% pred, GAP index, and lung cancer have been identified as potential risk factors for mortality in patients with IPF. Due to the limited number and quality of included studies, the conclusions need to be verified by further studies.

PMID:39831203 | PMC:PMC11740034 | DOI:10.21037/jtd-23-1908

Cell Rep. 2025 Jan 18;44(2):115220. doi: 10.1016/j.celrep.2024.115220. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by excess accumulation of the extracellular matrix (ECM). The role of macrophage-fibroblast crosstalk in lung fibrogenesis is incompletely understood. Here we found that fibroblast growth factor-inducible molecule 14 (Fn14), the receptor for tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is highly induced in myofibroblasts in the lungs of IPF patients and the bleomycin-induced lung fibrosis model. TWEAK-Fn14 signaling inhibits fibroblast activation and ECM synthesis and induces chemokine expression to recruit monocytes/macrophages into the lung. Fn14 deficiency increases ECM production and impairs macrophage infiltration and differentiation, leading to exacerbated lung fibrosis and impaired alveolar regeneration in a bleomycin model. Interestingly, Fn14 deficiency diminishes an injury-induced SiglecF- CD11b- MHCIIlo intermediate macrophage (IntermM) subpopulation, which promotes alveolar type II (AT2) cell proliferation in organoid cultures. These results collectively demonstrate a protective role of TWEAK-Fn14 signaling in lung fibrosis, highlighting the complexities and multilayered regulation of macrophage-fibroblast crosstalk.

PMID:39827460 | DOI:10.1016/j.celrep.2024.115220

Eur J Med Chem. 2025 Feb 15;284:117229. doi: 10.1016/j.ejmech.2024.117229. Epub 2024 Dec 30.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial lung disease for which few drugs are available in clinical practice. Here, we identified novel capsaicin analogs by combining in-house chemical library screening and further structural optimization. (E)-1-(3,4-dihydroxyphenyl)-7-phenylhept-1-en-3-one (Compound 14) was found to be the most potent in inhibiting TGF-β-induced collagen accumulation, proliferation and migration in fibroblast cells. Furthermore, compound 14 (IC50 = 0.51 ± 0.06 μM) showed over 100-fold increasing antifibrotic activity compared to capsaicin (IC50 = 53.71 ± 4.78 μM). Notably, compound 14 could target TRPV1, thereby affecting the expression of the fibrosis markers Collagen Ⅰ and α-SMA by inhibiting the TGF-β/Smads and MAPK pathways to exert antifibrotic activity in vitro. Compound 14 significantly inhibited collagen deposition in lung tissues, ameliorated alveolar structures, and increased survival rates in mice with bleomycin-induced pulmonary fibrosis. In addition, compound 14 possessed lower cytotoxicity (compared to nitedanib) and no toxicity in mice. Overall, compound 14 promise as a potential drug candidate for the treatment of IPF.

PMID:39826937 | DOI:10.1016/j.ejmech.2024.117229

Sci Rep. 2025 Jan 17;15(1):2293. doi: 10.1038/s41598-025-85338-y.

ABSTRACT

Interstitial lung disease (ILD) has shown limited treatment advancements, with minimal exploration of circulating protein biomarkers causally linked to ILD and its subtypes beyond idiopathic pulmonary fibrosis (IPF). In this study, we aimed to identify potential drug targets and circulating protein biomarkers for ILD and its subtypes. We utilized the most recent large-scale plasma protein quantitative trait loci (pQTL) data detected from the antibody-based method and ILD and its subtypes' GWAS data from the updated FinnGen database for Mendelian randomization analysis. To enhance the reliability of causal associations, we conducted external validation and sensitivity analyses, including Bayesian colocalization and bidirectional Mendelian randomization analysis. Our study identified eight plasma proteins genetically associated with ILD or its subtypes. Among these, three proteins-CDH15 (Cadherin-15), LTBR (Lymphotoxin-beta receptor), and ADAM15 (A disintegrin and metalloproteinase 15)-emerged as priority biomarkers and potential therapeutic targets, demonstrating more reliable associations by passing a series of sensitivity analyses compared to the others. Based on these findings, we propose for the first time that CDH15, ADAM15, and LTBR hold promise as novel potential circulating protein biomarkers and therapeutic targets for the diagnosis and treatment of ILD, IPF, and sarcoidosis, respectively, especially ADAM15, and these findings have the potential to provide new perspectives for advancing the research on the heterogeneity of ILD.

PMID:39824903 | DOI:10.1038/s41598-025-85338-y

Curr Treatm Opt Rheumatol. 2024 Dec;10(4):43-60. doi: 10.1007/s40674-024-00217-3. Epub 2024 Sep 16.

ABSTRACT

PURPOSE OF REVIEW: To summarize the current treatment landscape of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) in the context of the recent 2023 American College of Rheumatology/American College of Chest Physicians guideline for ILD treatment in systemic autoimmune rheumatic diseases.

RECENT FINDINGS: The guideline conditionally recommends mycophenolate, azathioprine, and rituximab for first-line RA-ILD therapy, with cyclophosphamide and short-term glucocorticoids as additional options. For RA-ILD progression after first line, mycophenolate, rituximab, nintedanib, tocilizumab, cyclophosphamide, and pirfenidone are conditionally recommended, while long-term glucocorticoids are conditionally recommended against. Only three randomized controlled trials (RCTs) enrolled patients with RA-ILD (total n=217). All other recommendations for RA-ILD were based on RCTs for other diseases or observational data. Antifibrotics might be particularly effective for patients with RA-ILD and the usual interstitial pneumonia pattern (RA-UIP). There is uncertainty of the utility of azathioprine and glucocorticoids in RA-UIP since these medications had worse outcomes compared to placebo in an RCT of patients with idiopathic pulmonary fibrosis. RA-ILD treatment decisions should consider articular activity, ILD activity, comorbidities, and potential for infection.

SUMMARY: We summarized the current treatment landscape for RA-ILD. Since only three RCTs included patients with RA-ILD, most guideline recommendations were conditional and based on low-quality evidence. This highlights the urgent need for additional high-quality RCT data for efficacy and safety of anti-inflammatory and antifibrotic medications for RA-ILD.

PMID:39822854 | PMC:PMC11735032 | DOI:10.1007/s40674-024-00217-3

J Gene Med. 2025 Jan;27(1):e70008. doi: 10.1002/jgm.70008.

ABSTRACT

BACKGROUND: The pathogenesis of idiopathic pulmonary fibrosis (IPF) remains unclear; previous studies revealed the underlying connection between IPF and diabetes, but there is no consensual opinion. This study is aimed at examining the association between Type 1 diabetes (T1D) and IPF using Mendelian randomization (MR).

METHOD: In our two-sample MR study, we selected single nucleotide polymorphisms (SNPs) that are strongly associated with T1D in a genome-wide association study (GWAS) from IEU (dataset: ebi-a-GCST005536) and obtained their corresponding effect estimates on T1D risk in an IPF GWAS from IEU (dataset: finn-b-IPF). We conducted a multivariable Mendelian randomization (MVMR) analysis to eliminate the interference of aging.

RESULT: In the outcome of inverse-variance weighted (IVW) method, T1D showed a promoting effect on IPF (odds ratio (OR): 1.132, p = 0.005). The statistics passed the MR-PRESSO test, and no outliers were observed (global test p = 0.238). MVMR study was performed, and the aging-adjusted result remains almost the same (OR = 1.132, OR_95% CI: 1.034-1.239, p = 0.007).

CONCLUSION: Our study shows a causal relation between T1D and IPF; further investigation should be conducted.

PMID:39822044 | DOI:10.1002/jgm.70008

ACS Pharmacol Transl Sci. 2024 Dec 28;8(1):256-269. doi: 10.1021/acsptsci.4c00671. eCollection 2025 Jan 10.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a debilitating, incurable, and life-threatening disease that lacks effective therapy. The overexpression of phosphodiesterase 10A (PDE10A) plays a vital role in pulmonary fibrosis (PF). However, the impact of selective PDE10A inhibitors on the tumor growth factor-β (TGF-β)/small mother against decapentaplegic (Smad) signaling pathway remains unclear. Herein, we have exploited a novel carbonyl sulfide (COS)/hydrogen sulfide (H2S)-donor hybrid PDE10A inhibitor called COS-2080 with a well-defined mechanism of H2S-releasing action. It exhibited highly potent inhibitory activity against PDE10A and excellent PDE subfamily selectivity. Moreover, COS-2080 demonstrated significant antifibrotic effects by inhibiting cell proliferation and mitigating fibroblast-to-myofibroblast transition (FMT). A dry powder inhalation formulation called COS-2080-DPI has been developed using the ultrasonic spray freeze drying (USFD) technique, demonstrating significant antifibrotic efficacy in mice with bleomycin-induced PF at a dosage approximately 600 times lower than pirfenidone. This remarkable antifibrotic efficacy of COS-2080 on TGF-β1-induced FMT could be primarily attributed to its inhibition of the Smad2/Smad3 phosphorylation. Moreover, COS-2080 effectively attenuated fibrosis in MRC-5 cells by activating the cAMP/protein kinase A (PKA)/CREB pathway and potentially increasing levels of p53 protein. Our findings suggest that effective inhibition of PDE10A potentially confers a protective effect on FMT in PF by impeding TGF-β signaling and activating the cAMP/PKA/CREB/p53 axis.

PMID:39816787 | PMC:PMC11729434 | DOI:10.1021/acsptsci.4c00671

Elife. 2025 Jan 15;13:RP95842. doi: 10.7554/eLife.95842.

ABSTRACT

Collagen-I fibrillogenesis is crucial to health and development, where dysregulation is a hallmark of fibroproliferative diseases. Here, we show that collagen-I fibril assembly required a functional endocytic system that recycles collagen-I to assemble new fibrils. Endogenous collagen production was not required for fibrillogenesis if exogenous collagen was available, but the circadian-regulated vacuolar protein sorting (VPS) 33b and collagen-binding integrin α11 subunit were crucial to fibrillogenesis. Cells lacking VPS33B secrete soluble collagen-I protomers but were deficient in fibril formation, thus secretion and assembly are separately controlled. Overexpression of VPS33B led to loss of fibril rhythmicity and overabundance of fibrils, which was mediated through integrin α11β1. Endocytic recycling of collagen-I was enhanced in human fibroblasts isolated from idiopathic pulmonary fibrosis, where VPS33B and integrin α11 subunit were overexpressed at the fibrogenic front; this correlation between VPS33B, integrin α11 subunit, and abnormal collagen deposition was also observed in samples from patients with chronic skin wounds. In conclusion, our study showed that circadian-regulated endocytic recycling is central to homeostatic assembly of collagen fibrils and is disrupted in diseases.

PMID:39812558 | DOI:10.7554/eLife.95842

Commun Biol. 2025 Jan 14;8(1):48. doi: 10.1038/s42003-024-07334-8.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an irreversible lung condition that progresses over time, which ultimately results in respiratory failure and mortality. In this study, we found that PLAC8 was downregulated in the lungs of IPF patients based on GEO data, in bleomycin (BLM)-induced lungs of mice, and in primary murine alveolar epithelial type II (pmATII) cells and human lung epithelial cell A549 cells. Overexpression of PLAC8 facilitated autophagy and inhibited apoptosis of pmATII cells and A549 cells in vitro. Moreover, inhibition of autophagy or overexpression of p53 partially abolished the effects of PLAC8 on cell apoptosis. ATII cell-specific overexpression of PLAC8 alleviated BLM-induced pulmonary fibrosis in mice. Mechanistically, PLAC8 interacts with VCP-UFD1-NPLOC4 complex to promote p53 degradation and facilitate autophagy, resulting in inhibiting apoptosis of alveolar epithelial cells and attenuating pulmonary fibrosis. In summary, these findings indicate that PLAC8 may be a key target for therapeutic interventions in pulmonary fibrosis.

PMID:39810019 | DOI:10.1038/s42003-024-07334-8

Appl Biochem Biotechnol. 2025 Jan 14. doi: 10.1007/s12010-024-05168-y. Online ahead of print.

ABSTRACT

Dysregulated circular RNAs (circRNAs) has been revealed to be involved in pulmonary fibrosis progression. Herein, this study focused on exploring the function and mechanism of circRNA Zinc Finger MYM-Type Containing 2 (circZMYM2) on idiopathic pulmonary fibrosis (IPF) using transforming growth factor (TGF)-β1-stimulated fibroblasts. Human fibroblast cell lines IMR-90 and HFL1 were stimulated with TGF-β1 to mimic fibrosis condition in vitro. Levels of genes and proteins were detected by qRT-PCR and western blotting. Cell proliferation and migration were analyzed using cell counting kit-8 assay, 5-Ethynyl-2'-deoxyuridine (EdU) and wound healing assays. The fibrosis progression was determined by the change of E-cadherin, α-smooth muscle actin (α-SMA), collagen type I α 1 (COL1A1) and collagen type III α 1 (COL3A1). The interaction between miR-199b-5p and circZMYM2 or KLF13 (Kruppel Like Factor 13) was analyzed using dual-luciferase reporter, RIP and RNA-pull-down assays. CircZMYM2 was decreased in TGF-β1-induced IMR-90 and HFL1 fibroblasts. Functionally, re-expression of circZMYM2 in IMR-90 and HFL1 cells could attenuate TGF-β1-evoked proliferation, migration and fibrosis in cells. Mechanistically, the circZMYM2/miR-199b-5p/KLF13 constituted a competing endogenous RNA (ceRNA). TGF-β1 reduced KLF13 expression and increased miR-199b-5p expression in IMR-90 and HFL1 cells. Further rescue experiments suggested that miR-199b-5p up-regulation or KLF13 knockdown reversed the anti-fibrotic effects of circZMYM2; moreover, silencing of miR-199b-5p exhibited anti-fibrotic effects, which was counteracted by KLF13 knockdown. CircZMYM2 had an anti-fibrotic effect that could suppress fibroblast activation via miR-199b-5p/KLF13 axis, pointing a novel perspective into the potential action pattern of circ_0022383 in IPF.

PMID:39808406 | DOI:10.1007/s12010-024-05168-y

Clin Exp Rheumatol. 2025 Jan 14. doi: 10.55563/clinexprheumatol/tjnyz5. Online ahead of print.

ABSTRACT

OBJECTIVES: The progressive decline in interstitial lung disease associated with non-scleroderma connective tissue disease (ILD-NSCTD) is linked to poor prognosis and frequently results in respiratory failure. Lung transplantation (LTx) offers a viable treatment option, yet its outcomes in ILD-NSCTD remain contentious, particularly across different subtypes.

METHODS: This retrospective cohort study included patients with idiopathic pulmonary fibrosis (IPF) (n=11,610) and ILD-NSCTD (n=610) listed in the United Network for Organ Sharing (UNOS) database who underwent lung transplantation between May 5, 2005, and December 31, 2022. We used the Kaplan-Meier method to evaluate cumulative survival rates and logistic regression to assess the risk of post-operative complications.

RESULTS: Compared to IPF patients, those with ILD-NSCTD are generally younger, with a lower proportion of male and white patients. After propensity matching, overall survival rates remained similar between the groups (log-rank, p=0.953). However, ILD-NSCTD was associated with a significantly higher risk of post-operative stroke (adjusted OR 1.75, 95% CI 1.12-2.74, p=0.015) and longer post-operative hospital stays (p<0.001). Subgroup analyses yielded consistent results. Finally, infection was identified as the leading cause of death.

CONCLUSIONS: Compared to IPF, patients with ILD-NSCTD have a significantly higher risk of post-operative stroke and extended hospital stays, potentially due to complications inherent to ILD-NSCTD. However, the underlying causes of these outcomes remain unclear. Despite these differences, short-term and long-term survival rates are comparable between the two groups, with consistent findings across various ILD-NSCTD subgroups. Therefore, ILD-NSCTD should not be regarded as a relative contraindication for lung transplantation. Nonetheless, the influence of extra-pulmonary complications in ILD-NSCTD patients requires further investigation.

PMID:39808303 | DOI:10.55563/clinexprheumatol/tjnyz5

Immun Inflamm Dis. 2025 Jan;13(1):e70123. doi: 10.1002/iid3.70123.

ABSTRACT

BACKGROUND: Post-coronavirus disease 19 lung fibrosis (PCLF) shares common immunological abnormalities with idiopathic pulmonary fibrosis (IPF), characterized by an unbalanced cytokine profile being associated with the development of lung fibrosis. The aim of the present study was to analyze and compare the different subsets of CD4- and CD8-T cells, along with specific cytokine expression patterns, in peripheral blood (PB) from patients affected by PCLF and IPF and healthy controls (HCs).

METHODS: One-hundred patients followed at the Rare Lung Disease Center of Siena University Hospital were enrolled. Eight HCs were recruited. PB samples were collected, and CD4- and CD8-T subsets were analyzed through flow cytometry. Multiplex bead-based LEGENDplex™ were used for cytokine quantification.

RESULTS: Higher CD8 percentages were observed in IPF than in HCs and PCLF (p = 0.020 and p = 0.007, respectively). PCLF subgroup showed higher Th-naïve, Th-effector, Tc-naïve, and Tc-reg percentages than IPF (p < 0.001; p = 0.018; p = 0.005; p = 0.017, respectively). Th-naïve and Tc-naïve inversely correlated with Tc-reg (p < 0.0001, r = -0.61 and p = 0.005, r = -0.39, respectively). Tc-naïve-PD1 and Tc-effector-PD1 percentages were higher in PCLF than IPF (p < 0.001), while Tfh-reg and Tfc-reg were significantly higher in IPF than PCLF (p < 0.001). IL-4, IL-2, TNF-α, and IL-17A were more expressed in PCLF than IPF (p < 0.001). IL-8 directly correlated with Tc-naïve percentages in PCLF (p = 0.018, r = 0.35).

CONCLUSION: A variety of immune cells is involved in the development and progression of pulmonary fibrosis confirming an immunological similarity between IPF and PCLF. T-reg cells play a key role in the worsening of the disease. High cytokine values showed a pro-fibrotic environment in PCLF patients, suggesting dysregulation of the immune system of these patients. Moreover, the immunological similarity between IPF and PCLF patients suggests that SARS-CoV2 infection may trigger the activation of biological pathways common with IPF.

PMID:39807767 | DOI:10.1002/iid3.70123

Zhongguo Zhong Yao Za Zhi. 2024 Dec;49(23):6399-6406. doi: 10.19540/j.cnki.cjcmm.20240904.402.

ABSTRACT

To investigate the therapeutic effect of Fuzheng Tongluo Granules on idiopathic pulmonary fibrosis(IPF) and its mechanism. Seventy-two SD rats were randomly divided into the control group, model group, pirfenidone group(162 mg·kg~(-1)), and low-, medium-and high-dose of Fuzheng Tongluo Granules groups(2.63, 5.25, 10.5 g·kg~(-1)). Rat model of IPF was induced by a single non-invasive tracheal intubation drip of bleomycin(BLM). The corresponding drugs were given daily by gavage after the 2nd day of modeling, and body mass was recorded. On the 28th day, the samples were collected and weighed, and the lung coefficients were calculated. The pathological changes in the lung tissue were observed by HE and Masson staining, and the hydroxyproline(HYP) content of the lung tissue was detected by alkaline hydrolysis. The contents of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and interleukin-18(IL-18) of the lung tissue were determined by ELISA. The expression of collagen type Ⅰ(collagen Ⅰ) and α-smooth muscle actin(α-SMA) was observed by immunohistochemistry. The expression levels of NOD-, LRR-and pyrin domain-containing 3(NLRP3), cysteine-requiring aspartate protease type 1(caspase-1), gasdermin D-N(GSDMD-N), and apoptosis-associated speck-like protein containing a CARD(ASC) in the lung tissue were detected by Western blot. Immunofluorescence co-localization was used to observe the expression of GSDMD and CD68. The results show that compared with the control group, the model group showed increased lung coefficient, Ashcroft score, Szapiel score, HYP, TNF-α, IL-1β, and IL-18 content in the lung tissue and elevated protein expression levels of NLRP3, caspase-1, GSDMD-N, and ASC. The expression levels of GSDMD and CD68 were increased, and there was a high degree of co-localization between GSDMD and CD68. Compared with those in the model group, the lung coefficient, Ashcroft score, and Szapiel score decreased in all drug administration groups, and the content of HYP, TNF-α, IL-1β, and IL-18 decreased. The protein expression levels of NLRP3, caspase-1, GSDMD-N, and ASC decreased, and the expression levels of GSDMD and CD68 were reduced. There was a high degree of co-localization between GSDMD and CD68. In summary, Fuzheng Tongluo Granules can effectively reduce pulmonary fibrosis and inflammation levels in rats with IPF, and the mechanism may be related to the down-regulation of the NLRP3/caspase-1/GSDMD pathway to inhibit macrophage pyroptosis.

PMID:39805786 | DOI:10.19540/j.cnki.cjcmm.20240904.402

Zhongguo Zhong Yao Za Zhi. 2024 Dec;49(24):6803-6812. doi: 10.19540/j.cnki.cjcmm.20240821.501.

ABSTRACT

This study systematically retrieved the clinical studies in the treatment of idiopathic pulmonary fibrosis(IPF) with traditional Chinese medicine(TCM) and employed evidence mapping to summarize the overall research status and deficiencies of TCM in treating IPF. CNKI, VIP, SinoMed, Wanfang, PubMed, Web of Science, Cochrane Library, and EMbase were searched for the relevant studies published from inception to February 20, 2024. The distribution characteristics of the evidence were analyzed and presented through charts combined with words. A total of 323 studies were included, including 295 randomized controlled trials(RCTs) and 28 Meta-analysis. The number of publications in this field rose with fluctuations, yet the proportion of core papers was low, and the research lacked the attention of foreign researchers. There were scant cross-regional collaboration between researchers and insufficient attention from relevant departments. The included RCT generally had low quality, with small sample sizes, short treatment courses, and insufficient attention to acute exacerbation and complications of IPF. In addition, few studies employed TCM alone, and the TCM syndromes remained to be standardized. A considerable number of outcome indicators were involved in the publications, while the majority of them failed to emphasize the disparity between primary and secondary outcome indicators. There were diverse reference standards for the comprehensive indicators among the outcome indicators, and insufficient attention was paid to long-term prognosis and health economic indicators. The included Meta-analysis concluded that TCM had potential clinical efficacy in treating IPF. However, the methodological credibility grading and the GRADE grading results of outcome indicators were low. The results suggested that TCM demonstrated certain advantages in the treatment of IPF, while the quality of the included studies was not high. In the future, clinical research protocols should be standardized and registered. Multicenter, large-sample, and follow-up clinical studies should be conducted. The research reports should refer to relevant reporting standards to improve the quality and generate high-level evidence, thus providing a reference for the clinical application of TCM in the treatment of IPF.

PMID:39805768 | DOI:10.19540/j.cnki.cjcmm.20240821.501

Chest. 2025 Jan 11:S0012-3692(25)00005-4. doi: 10.1016/j.chest.2025.01.001. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary rehabilitation (PR) is a beneficial intervention for people with interstitial lung disease (ILD), however the effect of PR on survival is unclear. This study compared the survival outcomes in people with ILD who were allocated to PR versus those who were allocated to control in two published randomised controlled trials (RCTs).

RESEARCH QUESTION: Does participation in PR impact survival among people with ILD?

STUDY DESIGN AND METHODS: The combined data from the two previous RCTs of PR in ILD were included. Time from start of PR until date of death, lung transplantation or censoring was calculated. Kaplan-Meir and Cox proportional hazard regression analysis were used to assess the impact of PR on survival. Baseline variables of age at time of PR, gender, FVC, 6-minute walk distance (6MWD), exertional nadir SpO2 and diagnosis of idiopathic pulmonary fibrosis (IPF) were included as covariates.

RESULTS: Of the 182 participants with ILD (87 IPF, 109 males, mean (SD) age 69(10), FVC%pred 76(19), TLCO%pred 48(16)), death occurred in 62%, 6% were transplanted, 20% were alive and 12% were lost to follow-up. Median survival for those who completed PR was 6.1 years (95% CI 4.4 to 7.9) compared to 4.7 years (95%CI 3.4 to 6.0) for those in the control group, however this was not significantly different (log rank p=0.7). After adjusting for baseline variables, at 5 years, completion of PR was associated a 44% lower risk of mortality (HR 0.56 (0.36-0.88), p=0.01). At 10 years, no difference in survival was observed between the PR and control group.

INTERPRETATION: Participation in PR among people with ILD may impact survival at 5 years. Along with clinical improvements following PR, the potential for a survival benefit further strengthens the importance of PR in the standard care of people with ILD.

PMID:39805518 | DOI:10.1016/j.chest.2025.01.001

Lancet Respir Med. 2025 Jan 10:S2213-2600(24)00364-3. doi: 10.1016/S2213-2600(24)00364-3. Online ahead of print.

ABSTRACT

BACKGROUND: Bronchiectasis is a disease with a global impact, but most published data come from high-income countries. We aimed to describe the clinical characteristics of patients with bronchiectasis in China.

METHODS: The Chinese Bronchiectasis Registry (BE-China) is a prospective, observational cohort enrolling patients from 111 hospitals in China. Data on demographics, comorbidities, and aetiological testing results were collected from adult patients with bronchiectasis at baseline and annual follow-up. Patients who met the inclusion criteria (age ≥18 years; received chest high-resolution CT in the past year showing bronchiectasis affecting one or more lung lobes; and clinical history consistent with bronchiectasis, including chronic cough, daily sputum production, and history of exacerbations) were included. Patients with known cystic fibrosis were excluded. To investigate variations according to different economic regions, two groups were compared based on whether per capita disposable income of residents was greater than US$5553. Clinical characteristics were compared with the European (EMBARC) registry and other national registries.

FINDINGS: Between Jan 10, 2020, and March 31, 2024, 10 324 patients from 97 centres were included in the study. Among 9501 participants with available data, the most common cause of bronchiectasis was post-infective disease (4101 [43·2%] patients), followed by idiopathic (2809 [29·6%] patients). 6676 (70·0%) of 9541 patients with available data had at least one exacerbation in the year before enrolment and 5427 (57·2%) of 9489 patients with available data were hospitalised at least once due to exacerbations. Treatments commonly used in high-income countries, such as inhaled antibiotics and macrolides, were infrequently used in China. Implementation of airway clearance in China was scarce, with only 1177 (12·2%) of 9647 patients having used at least one method of airway clearance. Compared with upper-middle-income regions, patients from lower-middle-income regions were younger (61·0 years [SD 14·0] vs 63·9 years [14·2]) with a higher proportion of pulmonary comorbidities (521 [17·8%] of 2922 patients vs 639 [8·6%] of 7402 with chronic obstructive pulmonary disease and 194 [6·6%] of 2922 patients vs 364 [4·9%] of 7402 patients with asthma), a higher tuberculosis burden (442 [16·0%] of 2768 patients vs 715 [10·6%] of 6733 patients), more severe radiological involvement (1160 [42·4%] of 2736 patients vs 2415 [35·4%] of 6816 patients with cystic bronchiectasis), more exacerbations (median 1·4 [IQR 0-2] in both groups; mean 1·4 [SD 1·6] vs 1·2 [1·4] in the previous year) and hospitalisations (1662 [60·6%] of 2743 patients vs 3765 [55·8%] of 6746 patients hospitalised at least once in the previous year), and poorer quality of life (median 57·4 [IQR 53·5-63·1] vs 58·7 [54·8-64·8] assessed by the Bronchiectasis Health Questionnaire).

INTERPRETATION: The clinical characteristics of patients with bronchiectasis in China show differences compared with cohorts in Europe and India. Bronchiectasis is more severe with a higher burden of exacerbations in lower-income regions. The management of patients with bronchiectasis in China urgently needs standardisation and improvement.

FUNDING: National Natural Science Foundation of China, Innovation Program of the Shanghai Municipal Education Commission, Program of the Shanghai Municipal Science and Technology Commission, and Program of the Shanghai Shenkang Development Center.

TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

PMID:39805296 | DOI:10.1016/S2213-2600(24)00364-3

Ann Gastroenterol. 2025 Jan-Feb;38(1):80-84. doi: 10.20524/aog.2024.0932. Epub 2024 Dec 12.

ABSTRACT

BACKGROUND: The risk of gastrointestinal (GI) cancer after lung transplantation (LTx) in sarcoidosis patients is not well defined. Given the cancer risks linked to sarcoidosis and organ transplantation, this study investigated the incidence of GI de novo malignancies (DNM), comparing LTx recipients with sarcoidosis or idiopathic pulmonary fibrosis (IPF).

METHODS: We analyzed data from the United Network for Organ Sharing registry, including adults with sarcoidosis or IPF who underwent LTx between May 2005 and December 2018. The primary outcome was the incidence of GI DNM by March 2023.

RESULTS: Of 7996 lung transplant recipients, 108 (1.35%) developed GI malignancies post-transplantation. Among these, 662 patients (9%) had sarcoidosis and 7334 (91%) had IPF. Sarcoidosis patients showed a non-significant trend toward a higher risk of GI malignancies compared to those with IPF (subhazard ratio 1.72, 95% confidence interval 0.90-3.29; P=0.099), with no observed difference in the risk of non-GI cancers.

CONCLUSIONS: The overall incidence of GI DNM following LTx is low, and sarcoidosis does not appear to increase the risk of GI cancers compared to IPF. This finding suggests that enhanced GI cancer screening beyond standard guidelines may not be warranted in this population, allowing for targeted surveillance of more prevalent malignancies in sarcoidosis patients post-LTx.

PMID:39802287 | PMC:PMC11724385 | DOI:10.20524/aog.2024.0932