Int J Gen Med. 2025 Jan 6;18:21-32. doi: 10.2147/IJGM.S498350. eCollection 2025.

ABSTRACT

OBJECTIVE: To evaluate the effectiveness and safety of traditional Chinese medicine (TCM) ion introduction therapy in the treatment of patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF).

METHODS: This study adopts a prospective cohort study design, with 60 AE-IPF patients as the research subjects. Divided into an exposed group and a non exposed group, with 30 cases in each group, based on the frequency of TCM ion introduction treatment as the exposure factor. Follow-up for 1 year to observe the acute exacerbation of the patient. The main indicator is the annual incidence of acute exacerbation, and the secondary indicators are hospitalization time, readmission rate, time to first acute exacerbation, mortality rate, all-cause mortality rate, inflammatory indicators, quality of life, etc.

RESULTS: 51 patients completed a one-year clinical observation, including 27 in the exposed group and 24 in the non exposed group. Compared to the non exposed group, significant differences were observed in the annual incidence of acute exacerbation [incidence rate ratios (IRR) = 0.556, 95% CI: 0.315, 0.980; P = 0.035] and hospitalization time (P = 0.040), readmission rate (IRR = 0.533, 95% CI: 0.288, 0.988; P = 0.037), time to first acute exacerbation (P = 0.045), and quality of life (P < 0.05). However, there was no statistically significant difference in mortality rate and all-cause mortality rate between the two groups (P > 0.05).

CONCLUSION: Compared to the non exposed group, TCM ion introduction can reduce the annual incidence of acute exacerbation of IPF patients. Hospitalization time, readmission rate, time to first acute exacerbation, quality of life improved, but mortality rate and all-cause mortality rate did not improve.

PMID:39801926 | PMC:PMC11721691 | DOI:10.2147/IJGM.S498350

Expert Rev Respir Med. 2025 Jan 12. doi: 10.1080/17476348.2025.2453657. Online ahead of print.

ABSTRACT

INTRODUCTION: Interstitial lung disease (ILD) is a broad group of conditions characterized by fibrosis of the lung parenchyma. Idiopathic pulmonary fibrosis (IPF) is the most common subvariant. IPF is marked by considerable symptom burden of dyspnea, cough and fatigue that is often refractory to optimal disease-directed treatment.

AREAS COVERED: In this narrative review, we searched MEDLINE for articles related to the current evidence regarding management of chronic dyspnea, cough, and fatigue as three of the most prevalent and distressing symptoms associated with IPF and other ILDs. Each symptom shares common features of multi-factorial etiology and a lack of safe and effective pharmacological therapies. Both corticosteroids and opioids have been utilized in this context, yet there is insufficient evidence of therapeutic benefit and considerable risk of harms. Whilst some may benefit from symptom-directed pharmacological management, usage must be carefully monitored. Use of non-pharmacological strategies, such as breathing techniques and speech therapy represent low risk and low-cost option, yet broader validation of these therapies' effectiveness is needed.

EXPERT OPINION: Symptom management in IPF and other ILDs requires an iterative and individualized approach. Leveraging the expertise of multidisciplinary teams within an integrated care setting is an important opportunity to maximize health outcomes.

PMID:39800565 | DOI:10.1080/17476348.2025.2453657

Exp Eye Res. 2025 Jan 10:110238. doi: 10.1016/j.exer.2025.110238. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease linked to aging. This study investigates potential connections between IPF and age-related eye problems using a bleomycin-induced IPF mouse model. Intratracheal administration of bleomycin induces rapid lung injury in mice, followed by IPF with characteristics of cellular senescence. IPF-injured mice had reduced amplitudes of scotopic ERG and immunostaining of visual arrestin, suggesting declined rod-related visual function. Interestingly, the mice's eyes also showed increased susceptibility to Staphylococcus aureus infections, reminiscent of the aging eyes. To determine whether an early onset of aging contributes to the eye disorders, we examined complement and senescence markers in the retina. In bleomycin-injury IPF mice, DNA damage-related senescence marker γH2AX was found in the retinal out nuclear layer where photoreceptors are located. Additionally, IPF mice displayed elevated levels of C3b, a complement fragment resulting from C3 activation that occurs frequently in aging eyes. These findings underscore the potential of IPF as a valuable mouse model for investigating early-onset age-related ocular disorders.

PMID:39800285 | DOI:10.1016/j.exer.2025.110238

J Clin Med. 2025 Jan 6;14(1):291. doi: 10.3390/jcm14010291.

ABSTRACT

Chronic cough is a distressing and prevalent symptom in interstitial lung disease (ILD), significantly impairing quality of life (QoL) and contributing to disease progression, particularly in idiopathic pulmonary fibrosis (IPF). It is associated with physical discomfort, psychological distress, and social isolation and is often refractory to conventional therapies. The pathophysiology of cough in ILD is complex and multifactorial, involving neural hypersensitivity, structural lung changes, inflammatory processes, and comorbid conditions such as gastroesophageal reflux disease (GERD). Evaluating cough in ILD relies on subjective and objective tools to measure its severity, frequency, and impact on daily life, although standardization of these measures remains challenging. Management strategies span pharmacological interventions, including neuromodulators such as opiates, antifibrotic agents, pharmacologic and surgical GERD treatments, and non-pharmacological approaches like behavioral therapies, cough suppression techniques, and pulmonary rehabilitation and physiotherapy. Emerging treatments, such as P2X3 receptor antagonists and airway hydration therapies, offer promising avenues but require further investigation through robust clinical trials. This review aims to demonstrate the importance of addressing cough in ILD as a significant symptom and present objective and subjective methods of quantifying coughs, while providing insights into effective and emerging therapeutic options. By highlighting these potential therapies, we hope to guide healthcare practitioners in considering them through a thorough evaluation of benefits and risks on a case-by-case basis, with relevance both in the U.S. and internationally.

PMID:39797373 | DOI:10.3390/jcm14010291

J Clin Med. 2025 Jan 3;14(1):247. doi: 10.3390/jcm14010247.

ABSTRACT

Background: Antibodies against Ku have been described in patients with various connective tissue diseases. The objective of this study was to describe the clinical, functional, and imaging characteristics of interstitial lung disease in patients with anti-Ku antibodies. Methods: This single-center, retrospective observational study was conducted at a tertiary referral institution. Patients with positive anti-Ku antibodies and interstitial lung disease identified between 2007 and 2022 were included. Clinical, immunological, functional, and imaging data were systematically reviewed. Results: Nineteen patients (ten females) with a mean age of 59 ± 12.6 years were included. The most frequent associated diagnosis was systemic sclerosis (42%), followed by rheumatoid arthritis (26%), Sjögren syndrome, undifferentiated connective tissue disease, and overlap between systemic sclerosis and idiopathic inflammatory myopathy (scleromyositis). Imaging revealed frequent septal and intralobular reticulations and ground-glass opacities, with nonspecific interstitial pneumonia as the predominant pattern (53%). The mean forced vital capacity was 82% ± 26 of the predicted value, and the mean diffusing capacity for carbon monoxide was 55% ± 21. Over the first year of follow-up, the mean annual forced vital capacity decline was 140 mL/year (range: 0-1610 mL/year). The overall survival rate was 82% at 5 years and 67% at 10 years. Conclusions: Most patients with interstitial lung disease and anti-Ku antibodies presented with dyspnea, a mild-to-moderate restrictive ventilatory pattern, and reduced diffusing capacity for carbon monoxide. The CT pattern was heterogeneous but was consistent with nonspecific interstitial pneumonia in half of the patients.

PMID:39797328 | DOI:10.3390/jcm14010247

Int J Mol Sci. 2025 Jan 4;26(1):382. doi: 10.3390/ijms26010382.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disorder. In response to transforming growth factor-β (TGF-β), normal lung cells proliferate and differentiate into myofibroblasts, which are instrumental in promoting disease progression. Small interfering RNA (siRNA) targeting heat shock protein 47 (HSP47) has been demonstrated to alleviate IPF by blocking collagen synthesis and secretion. Exosomes (EXOs) have been investigated for drug delivery due to their superior carrier properties. However, their loading efficiency has been a limiting factor in widely application as drug carriers. In this study, an ultrasonic microfluidic method was employed to enhance the loading efficiency of siHSP47 into EXOs, achieving 31.1% efficiency rate. EXOs were isolated from human embryonic kidney cells (293F) and loaded with siHSP47 (EXO-siHSP47). The findings indicated that EXO-siHSP47 penetrated the collagen barrier and effectively silenced HSP47 expression in activated fibroblasts in vitro. Western blotting and immunofluorescence analyses confirmed that EXO-siHSP47 significantly reduced the secretion and deposition of extracellular matrix (ECM) proteins. Wound healing and Transwell migration assays demonstrated that EXO-siHSP47 inhibited fibroblast differentiation and migration. In conclusion, 293F-derived EXOs loaded with siHSP47 present a promising therapeutic strategy for IPF.

PMID:39796239 | DOI:10.3390/ijms26010382

Eur J Med Res. 2025 Jan 10;30(1):20. doi: 10.1186/s40001-024-02256-x.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis, nomogram model for its prognosis and acute exacerbation was constructed.

METHODS: Two hundred and sixty eight patients with IPF were grouped with different severity according to fibrosis area, serum Club cell secretory protein 16(CC16) was compared between these groups. All patients were randomly divided into training and testing sets. COX regression and LASSO algorithm were used to screen featured characteristics. Then nomogram models were constructed, ROC curve, calibration curve and decision curve analysis(DCA) were conducted to evaluate the performance of model. Expression of CC16 were detected in fibrotic human lung tissues, bronchoalveolar lavage fluid (BALF) and Bleomycin(BLM)-treated mouse lung tissues and serums.

RESULTS: Serum CC16 gradually increased with the severity of fibrosis, and was especially high in AE-IPF group. CC16 and diffusion capacity for carbon monoxide (DLCO) were screened as characteristic variables to construct nomogram model for IPF prognosis. The survival was significantly lower in high-risk group scored by the model. The area under ROC curves(AUCs) for 1-year and 2-year mortality prediction were 0.866 and 0.916, respectively. This model performed better than gender-age-physiology (GAP) index for predicting 2-year and 3-year mortality. Another nomogram model for acute exacerbation of IPF based on CC16, Krebs von den Lungen-6(KL-6) and DLCO was developed, the AUC was 0.815. Expression of CC16 obviously up-regulated in fibrotic lung tissues, BALF and BLM-treated mice lung tissues and serums.

CONCLUSIONS: The nomogram model based on CC16 performed good predictive ability for prognosis and acute exacerbation of IPF.

PMID:39794841 | DOI:10.1186/s40001-024-02256-x

Gene. 2025 Jan 9:149223. doi: 10.1016/j.gene.2025.149223. Online ahead of print.

NO ABSTRACT

PMID:39794204 | DOI:10.1016/j.gene.2025.149223

Ecotoxicol Environ Saf. 2025 Jan 9;289:117679. doi: 10.1016/j.ecoenv.2025.117679. Online ahead of print.

ABSTRACT

AIM: Identifying the common functional single-nucleotide polymorphisms (SNPs) that can both affect the susceptibility to idiopathic pulmonary fibrosis (IPF) and silicosis.

METHODS: We first integrated the genome-wide association studies (GWASs) of IPF and silicosis to obtain the shared SNPs. Following this, functional expression quantitative trait locus (eQTL)-SNPs were identified by the GTEx database. This was followed by the validation of the correlation between these eQTL-SNPs and silicosis susceptibility through an additional case-control study including 194 silicosis cases and 235 healthy controls.

RESULTS: A total of 10 eQTL-SNPs that may affect silicosis susceptibility (P < 0.05) were obtained after the integration of the GWASs of IPF and silicosis, and a series of rigorous selection principles. Subsequently, the results of integrating the validation stage and the screening stage indicated that the variant T allele of rs1620530 located in the MAD1L1 (additive model: OR= 1.56, 95 % CI = 1.21-2.01, P = 0.001) and the variant G allele of rs2070063 located in the SERTAD2 (additive model: OR= 1.60, 95 % CI = 1.24-2.06, P < 0.001) were associated with increased silicosis susceptibility. The joint analysis indicated the risk of developing silicosis was higher in individuals who carried more unfavorable alleles of rs1620530 and rs2070063.

CONCLUSIONS: The rs1620530 and rs2070063 may affect the silicosis susceptibility by regulating the expression of the MAD1L1 and SERTAD2, respectively. Further biological experiments are warranted to elucidate the underlying biological mechanisms between these two SNPs and the increased susceptibility to silicosis.

PMID:39793288 | DOI:10.1016/j.ecoenv.2025.117679

JAMA Health Forum. 2025 Jan 3;6(1):e244874. doi: 10.1001/jamahealthforum.2024.4874.

ABSTRACT

IMPORTANCE: The prevalence of pharmacies owned by integrated insurers and pharmacy benefit managers (PBMs), or insurer-PBMs, is of growing regulatory concern. However, little is known about the role of these pharmacies in Medicare, in which pharmacy network protections may influence market dynamics.

OBJECTIVE: To evaluate the prevalence of insurer-PBM-owned pharmacies and the extent to which insurer-PBMs steer patients to pharmacies they own in Medicare.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used Medicare Part D claims data on prescription fills for a 20% random sample of US beneficiaries enrolled from January 1 through December 31, 2021. Data were analyzed from March to November 2024.

EXPOSURES: Prescription fills.

MAIN OUTCOMES AND MEASURES: The main outcome was the share of spending filled by insurer-PBM-owned pharmacies overall, by pharmacy type (specialty and nonspecialty), and by drug class. For the top 100 specialty and nonspecialty molecules by claim volume, 2 quantities were identified for 4 major insurer-PBMs (Cigna, CVS, Humana, and UnitedHealth Group): share of the index firm's insurer claims filled by its owned pharmacies and share of other firms' insurer claims filled by the index firm's owned pharmacies. Differences between these quantities were assessed to evaluate the degree to which insurer-PBMs steered patients to their own pharmacies.

RESULTS: Among 10 455 726 patients (54.8% women; mean [SD] age, 71.8 [10.7] years), 34.1% of all pharmacy and 37.1% of specialty pharmacy spending occurred through Cigna, CVS, Humana, or UnitedHealth Group pharmacies. Among specialty molecules, market shares varied by drug class (antivirals: 18.5%; antipsychotics: 29.5%; cancer: 32.5%; disease-modifying antirheumatic drugs: 41.1%; multiple sclerosis: 64.8%; pulmonary arterial hypertension and idiopathic pulmonary fibrosis: 89.7%). Across molecule-firm combinations, a 19.8 (95% CI, 18.0-21.6)-percentage point and 13.9 (95% CI, 13.1-14.7)-percentage point greater share of claims were filled at insurer-PBM-owned pharmacies than would be expected without steering for specialty and nonspecialty categories, respectively.

CONCLUSIONS AND RELEVANCE: This cross-sectional study found that insurer-PBM firms represented an important portion of the Medicare Part D market, especially for certain drug classes, and that insurer-PBM firms steered patients to their own pharmacies, despite certain pharmacy network protections in Medicare. These findings underscore the need to understand the impacts of insurer-PBM and pharmacy integration on medication access and costs for Medicare patients.

PMID:39792403 | DOI:10.1001/jamahealthforum.2024.4874

ACS Nano. 2025 Jan 10. doi: 10.1021/acsnano.4c15130. Online ahead of print.

ABSTRACT

For idiopathic pulmonary fibrosis (IPF), interleukin 11 (IL-11) is a pivotal cytokine that stimulates the transformation of fibroblasts into myofibroblasts, thus accelerating the progression of pulmonary fibrosis. Here, we develop an innovative inhalable small interfering RNA (siRNA) delivery system termed PEI-GBZA, which demonstrates impressive efficiency in loading siIL-11 targeting IL-11 (siIL-11) and substantially suppresses the differentiation of fibroblasts into myofibroblasts and epithelial-mesenchymal transition (EMT), reduces neutrophil and macrophage recruitment, and ultimately relieves the established fibrotic lesions in the IPF model. PEI-GBZA is prepared by modifying low-molecular-weight polyethylenimine (PEI) with 4-guanidinobenzoic acid (GBZA). The resulting PEI-GBZA may effectively encapsulate siIL-11 through a variety of interactions such as hydrophobic, hydrogen bonding, and electrostatic interactions, creating stable carrier/siIL-11 nanoparticles (PEI-GBZA/siIL-11 NPs). Upon inhalation, PEI-GBZA/siIL-11 NPs demonstrate effective retention in fibrotic lesions, leading to a marked mitigation of disease progression in a bleomycin-induced pulmonary fibrosis model. Impressively, this inhalation therapy exhibits negligible systemic toxicity. This work provides a universal and noninvasive RNA therapeutic delivery platform that holds significant promise for respiratory diseases. The potential for clinical application of this platform is substantial, offering a frontier for the treatment of IPF and potentially other pulmonary disorders.

PMID:39791575 | DOI:10.1021/acsnano.4c15130

BMC Pulm Med. 2025 Jan 9;25(1):11. doi: 10.1186/s12890-024-03433-8.

ABSTRACT

BACKGROUND: This study aims to compare Lung Ultrasound (LUS) findings with High-Resolution Computerized Tomography (HRCT) and Pulmonary Function Tests (PFTs) to detect the severity of lung involvement in patients with Usual Interstitial Pneumonia (UIP) and Non-Specific Interstitial Pneumonia (NSIP).

METHODS: A cross-sectional study was conducted on 35 UIP and 30 NSIP patients at a referral hospital. All patients underwent LUS, HRCT, and PFT. LUS findings such as B-lines, pleural fragmentation, and pleural thickening were compared with HRCT-based lung involvement and PFT parameters.

RESULTS: In UIP patients, B-lines > 18 and pleural fragmentation significantly differentiated between < 50% and > 50% HRCT involvement. A logistic regression model showed that B-lines > 18 (OR = 39, p = 0.04) and pleural fragmentation (OR = 22, p = 0.037) independently predicted > 50% HRCT involvement. ROC analysis of the model revealed 84.2% sensitivity and 84.5% specificity. Furthermore, the crude number of B-lines (OR = 1.2, p = 0.038) and > 50% HRCT involvement (OR = 9.5, p = 0.045) independently predicted severe DLCO impairment, with a sensitivity of 94.7% and specificity of 84.5%. Linear regression showed that each additional B-line was associated with a 0.4% decrease in DLCO (Beta = -0.377, p = 0.043), independent of patient diagnosis. In NSIP patients, no significant correlation was observed between LUS findings and > 50% HRCT involvement (p > 0.05), though B-line numbers and pleural thickening increased in cases with severe DLCO impairment (p < 0.05).

CONCLUSIONS: LUS shows promise as a sensitive, radiation-free alternative to HRCT in monitoring the severity of UIP. It is particularly valuable in predicting the extent of lung involvement and severe DLCO impairment in UIP patients but has limited application in NSIP.

PMID:39789530 | DOI:10.1186/s12890-024-03433-8

Lung. 2025 Jan 9;203(1):25. doi: 10.1007/s00408-024-00778-z.

ABSTRACT

PURPOSE: In the INBUILD trial in patients with progressive pulmonary fibrosis (PPF), nintedanib slowed the decline in forced vital capacity (FVC) versus placebo, with a safety profile characterised mainly by gastrointestinal events. INBUILD-ON, the open-label extension of INBUILD, assessed the safety of nintedanib during longer-term treatment. Data on FVC were collected.

STUDY DESIGN AND METHODS: Adverse events and changes in FVC in INBUILD-ON were assessed descriptively in all patients and in two subgroups: patients who received nintedanib in INBUILD and continued nintedanib in INBUILD-ON ("continued nintedanib" group) (n = 212) and patients who received placebo in INBUILD and initiated nintedanib in INBUILD-ON ("initiated nintedanib" group) (n = 222). Changes in FVC were based on observed values.

RESULTS: Median exposure to nintedanib in INBUILD-ON was 22.0 months. Diarrhoea was the most frequent adverse event. Amongst patients who had diarrhoea, 90.0% experienced only events of mild or moderate severity. Adverse events led to discontinuation of nintedanib at a rate of 16.7 per 100 patient-years. Serious and fatal adverse events were reported at rates of 37.2 and 9.5 per 100 patient-years. Mean (SE) changes in FVC from baseline to week 48 were - 71.6 (16.1) mL [- 128.5 (25.5) mL in continued nintedanib group (n = 106), - 14.8 (18.2) mL in initiated nintedanib group (n = 106)].

CONCLUSION: The safety profile of nintedanib in INBUILD-ON was consistent with that in INBUILD. Change in FVC in INBUILD-ON was consistent with decline in FVC in the nintedanib group of INBUILD. These results support the use of nintedanib in the long-term treatment of PPF.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT03820726; registered January 29, 2019.

PMID:39789408 | DOI:10.1007/s00408-024-00778-z

Sci Rep. 2025 Jan 9;15(1):1479. doi: 10.1038/s41598-025-85135-7.

ABSTRACT

Automated tools for quantification of idiopathic pulmonary fibrosis (IPF) can aid in ensuring reproducibility, however their complexity and costs can differ substantially. In this retrospective study, two automated tools were compared in 45 patients with biopsy proven (12/45) and imaging-based (33/45) IPF diagnosis (mean age 74 ± 9 years, 37 male) for quantification of pulmonary fibrosis in CT. First, a tool that identifies multiple characteristic lung texture features was applied to measure multi-texture fibrotic lung (MTFL) by combining the amount of ground glass, reticulation, and honeycombing. Opacity-based fibrotic lung (OFL) was measured by a second tool that performs a simpler binary classification of tissue into either normal or opacified lung and was originally developed for quantifying pneumonia. Differences in quantification of MTFL and OFL were assessed by Mann-Whitney U-test and Pearson correlation (r). Also, correlation with spirometry parameters (percent predicted total lung capacity (TLC), percent predicted vital capacity (VC), percent predicted forced expiratory volume in 1 s (FEV1), diffusing capacity of the lungs for carbon monoxide (DLCO), partial pressure of oxygen (PO2) and carbon dioxide (PCO2)) were assessed by r. The prognostic values for 3-year patient survival of OFL, LSS and MTFL were investigated by multivariable Cox-proportional-hazards (CPH) models including sex, age and TLC and including sex, age and VC. Also, Kaplan-Meier analysis with log rank test between subgroups separated by median OFL and MTFL were conducted. No significant difference between OFL and MTFL was observed (median and interquartile range: OFL = 29% [20-38%], MTFL = 31% [19-45%]; P = 0.44). For OFL significant correlation was observed to MTFL (r = 0.93, P < 0.01) and VC (r=-0.50, P = 0.03). For MTFL no significant correlation to spirometry parameters was found. The total time for one analysis was lower for the automated MTFL (MTFL: 313 ± 25s vs. OFL: 612 ± 61s, P < 0.001). Both analyses were significant predictors in the multivariable CPH analysis including TLC (hazard-ratios: MTFL 1.03 [1.01-1.06], P = 0.02; OFL 1.03 [1.00-1.06], P = 0.03). No parameter was a significant predictor in the CPH models including VC (hazard-ratios: MTFL 1.01 [0.98-1.04], P = 1; OFL 1.01 [0.97-1.05], P = 1). OFL showed significance in Kaplan-Meier analysis (MTFL: P = 0.17; OFL: P = 0.03). Using a simple opacity-based quantification of pulmonary fibrosis in IPF patients displayed similar results and prognostic value compared to a more complex multi-texture based analysis.

PMID:39789082 | DOI:10.1038/s41598-025-85135-7

Eur Respir J. 2025 Jan 9:2400615. doi: 10.1183/13993003.00615-2024. Online ahead of print.

ABSTRACT

RATIONALE: Although a relationship between the Gas6/AXL pathway and pulmonary fibrosis (PF) has been suggested, the precise mechanisms and clinical implications of the AXL pathway in idiopathic pulmonary fibrosis (IPF) are still unclear.

METHODS: Constitutive and conditional AXL-knockout mice were generated and injected with bleomycin (BLM) to induce pulmonary fibrosis. The expression of AXL and macrophage subtypes in BLM-injected mice and patients with IPF was analysed using flow cytometry. The therapeutic effects of the AXL inhibitors were examined.

RESULTS: AXL-deficient mice were resistant to BLM-induced pulmonary fibrosis and had a lower degree of M2-like macrophage differentiation than wild-type mice. Interestingly, AXL expression in monocytes was enhanced according to the progression of BLM-induced pulmonary fibrosis (PF), and these results were especially prominent in Ly6Chigh monocytes. Gene silencing or inhibitor treatment with AXL inhibited the differentiation of M2-like macrophages during bone marrow-derived macrophage (BMDMs) differentiation. These results were confirmed through experiments using AXLfl/flLysMCre+ mice and systems with depletion and reconstitution of macrophages. In line with these results, patients with severe IPF had higher AXL expression in monocytes, high GAS6 levels, and an enhanced population of M2-like macrophages than those with mild IPF. Lastly, treatment with AXL inhibitors ameliorated BLM-induced PF and improved survival rate.

CONCLUSIONS: The AXL pathway in classical monocytes contributed to PF progression through the induction of M2-like macrophage differentiation. Therefore, targeting AXL may be a promising therapeutic option for PF.

PMID:39788632 | DOI:10.1183/13993003.00615-2024

FASEB J. 2025 Jan 15;39(1):e70306. doi: 10.1096/fj.202402813R.

ABSTRACT

Obstructive sleep apnea (OSA) is increasingly recognized for its link to idiopathic pulmonary fibrosis (IPF), though the underlying mechanisms remain poorly understood. Histone lysine demethylase 6B (KDM6B) may either prevent or promote organ fibrosis, but its specific role in IPF is yet to be clarified. This study aimed to investigate the function and mechanisms of KDM6B in IPF and the exacerbating effects of OSA. We assessed KDM6B levels in lung tissues from IPF patients, IPF mouse models, and a dual-hit model combining OSA-associated intermittent hypoxia (IH) with bleomycin (BLM) or TGF-β1. We evaluated pulmonary fibrosis, myofibroblast activation, and oxidative stress. KDM6B levels were elevated in lung tissues from IPF patients and BLM-treated mice, as well as in TGF-β1-stimulated myofibroblasts. Importantly, IH significantly worsened BLM-induced pulmonary fibrosis and TGF-β1-induced myofibroblast activation, further amplifying KDM6B expression both in vivo and in vitro. Inhibition of KDM6B reduced pulmonary fibrosis and decreased fibroblast activation and migration in IPF and dual-hit models. Mechanistically, KDM6B inhibition led to decreased NOX4 expression and reduced oxidative stress. KDM6B plays a critical role in promoting pulmonary fibrosis and mediating the exacerbating effects of OSA on this condition. Our findings identify KDM6B as a novel potential therapeutic target for IPF.

PMID:39781582 | DOI:10.1096/fj.202402813R

Int J Biol Sci. 2025 Jan 1;21(2):685-707. doi: 10.7150/ijbs.105826. eCollection 2025.

ABSTRACT

Pulmonary fibrosis (PF) is a high-mortality lung disease with limited treatment options, highlighting the need for new therapies. Cyclin-dependent kinase 8 (CDK8) is a promising target due to its role in regulating transcription via the TGF-β/Smad pathway, though CDK8 inhibitors have not been thoroughly studied for PF. This study aims to evaluate the potential of E966-0530-45418, a novel CDK8 inhibitor, in mitigating PF progression and explores its underlying mechanisms. We discovered that CDK8 is upregulated in lung tissues from idiopathic pulmonary fibrosis patients and in a bleomycin-induced PF mouse model. Our study further revealed that E966-0530-45418 inhibits PF progression by attenuating the activity of the transcription factor Smad3, which is involved in TGF-β1/Smad signaling, along with RNA polymerase II to downregulate fibrosis-associated protein expression in alveolar epithelia and lung fibroblasts and consequently mitigate myofibroblast differentiation and collagen deposition. E966-0530-45418 also blocks STAT3 signaling to obstruct M2 macrophage polarization, further suppressing PF progression. Moreover, E966-0530-45418 administration ameliorated lung function deterioration and lung parenchymal destruction in the bleomycin-induced PF mouse model. These findings indicate that E966-0530-45418 holds promise as a pioneering CDK8 inhibitor for treating PF.

PMID:39781457 | PMC:PMC11705631 | DOI:10.7150/ijbs.105826

Ther Adv Rare Dis. 2025 Jan 6;6:26330040241311621. doi: 10.1177/26330040241311621. eCollection 2025 Jan-Dec.

ABSTRACT

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening systemic hyperinflammatory syndrome, rarely associated with bone marrow failure (BMF). Telomere biology disorders (TBD) are caused by inherited defects in telomerase processes and can have heterogeneous presentations including idiopathic pulmonary fibrosis, cirrhosis, and BMF. We report a case of a 10-year-old male from Lima, Peru, who presented with HLH as the initial manifestation of a TBD. He experienced fever, gastrointestinal symptoms, and mucocutaneous involvement. Initial laboratory analyses revealed pancytopenia and elevated inflammatory markers. Despite symptomatic and antibiotic treatment, his clinical condition persisted leading to a suspicion of Kawasaki disease and, subsequently, HLH. Immunomodulatory treatment was initiated with a good clinical response. Bone marrow aspiration revealed severe hypocellular bone marrow and cytophagocytosis. Genetic studies identified a pathogenic variant in the TERC gene (n.110_113del), which was also found in the patient's mother and brother. HLH as the initial manifestation of BMF is rare. This case highlights the importance of considering TBD in children with BMF of unclear etiology and the value of genetic testing in such cases.

PMID:39780848 | PMC:PMC11705338 | DOI:10.1177/26330040241311621

BMC Pulm Med. 2025 Jan 8;25(1):9. doi: 10.1186/s12890-024-03459-y.

ABSTRACT

BACKGROUND: Acute exacerbation (AEx) of interstitial pneumonia is the most common lethal adverse event related to the pharmacological treatment of patients with lung cancer complicated with interstitial pneumonia. Although small cell lung cancer (SCLC) is linked to poor prognosis, it exhibits good response to chemotherapy. Few previous research studies have investigated the safety and efficacy of treatment for advanced SCLC complicated with idiopathic interstitial pneumonia (IIP). We conducted a single-arm phase II study to evaluate the safety and efficacy of carboplatin plus etoposide for the treatment of patients with SCLC complicated with IIP.

METHODS: Chemotherapy-naïve patients with advanced SCLC complicated with IIP were enrolled. Patients received carboplatin every 21-28 days at a dose of area under the curve 4-6 on day 1 and etoposide at a dose of 80-100 mg/m2 on days 1-3.

RESULTS: Thirty-one patients were enrolled between December 2009 and December 2022. A median of four cycles of carboplatin plus etoposide were administered. Acute exacerbation of idiopathic interstitial pneumonia was not observed; the rate of AEx was 0% (95% confidence interval [CI]: 0-9.6%, p = 0.038). The objective response rate was 83.9% (95% CI: 82.5-85.2). The median progression-free survival and overall survival were 5.9 (95% CI: 4.7-6.8) months and 14.0 (95% CI: 7.6-27.6) months, respectively. The 1-year survival rate was 61% (95% CI 41-76).

CONCLUSIONS: The carboplatin plus etoposide treatment was tolerable and effective in SCLC patients complicated with IIP.

PMID:39780119 | DOI:10.1186/s12890-024-03459-y

J Cell Mol Med. 2025 Jan;29(1):e70321. doi: 10.1111/jcmm.70321.

ABSTRACT

Pulmonary fibrosis is a pathological manifestation that occurs upon lung injury and subsequence aberrant repair with poor prognosis. However, current treatment is limited and does not distinguish different disease stages. Here, we aimed to study the differential functions of Axl, a receptor tyrosine kinase expressing on both macrophages and fibroblasts, in the whole course of pulmonary fibrosis. We used mice with Axl total knockout, conditionally knockout in macrophages or fibroblasts, or treating with Axl inhibitors in inflammation or fibrosis stages to examine the effect of temporary dysfunction of Axl on bleomycin (BLM)-induced pulmonary fibrosis. Primary bone marrow-derived monocytes and primary fibroblasts from mice were used for cell-type-specific studies. Lung tissue and plasma samples were collected from idiopathic pulmonary fibrosis (IPF) patients and healthy controls to assess the Axl levels. We found that Axl inhibited the M1 polarisation of macrophages; inhibition of Axl during acute phase exacerbated inflammatory response and subsequent pulmonary fibrosis. On the other hand, Axl promoted the proliferation and invasion of the fibroblasts, partially by accelerating the focal adhesion turnover; inhibiting Axl during the fibrotic phase significantly alleviated pulmonary fibrosis. Consistently, phosphorylated Axl levels increased in fibrotic foci in the lung sample of IPF patients. In contrast, the soluble Axl (sAxl) level decreased in their plasma as compared to healthy controls. These results indicate that Axl may sequentially and differentially regulate macrophages and fibroblasts in acute and fibrosis phases, implying the necessity of a stage-specific treatment for pulmonary fibrosis. In addition, the activated Axl on fibroblasts may be reflected by the lowered plasma sAxl level, which may act as a biomarker for IPF. Trial Registration: ClinicalTrials.gov identifier: NCT03730337.

PMID:39779468 | DOI:10.1111/jcmm.70321