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

Pharmacol Res. 2025 Jan 6:107587. doi: 10.1016/j.phrs.2025.107587. Online ahead of print.

ABSTRACT

Pulmonary fibrosis (PF) is a fatal disease with increasing incidence, poor prognosis, and unclear pathogenesis. Our previous research demonstrated the beneficial effects of the natural cyclopeptide Heterophyllin B (HB) in PF. However, the precise mechanism by which HB exerts its effects in PF remains unclear. Our study revealed HB's beneficial effects in alleviating PF symptoms and restoring the intestinal mucosal barrier. Subsequently, the microbiota-dependent antifibrotic efficacy of HB was verified using various delivery routes, antibiotic treatments, and faecal microbiota transplantation. Functionally, 16S rRNA sequencing, untargeted metabolomics, and co-incubation experiments revealed that the antifibrotic efficacy of HB was primarily contingent on the enrichment of Muribaculum intestinale and its metabolite, 3-hydroxybutyric acid. Mechanistically, indoleamine 2,3- dioxygenase 1 (IDO1)-mediated ferroptosis was identified as a pivotal process in initiating PF, and the anti-fibrotic efficacy of HB relies on suppressing IDO1-mediated ferroptosis. Conversely, IDO1 deficiency alleviated the symptoms of bleomycin-induced PF and ferroptosis in mice. Coincidentally, both IDO1 overexpression and ferroptosis were observed in the pulmonary tissue of patients with idiopathic PF. Collectively, this study revealed that HB alleviates PF by eliminating intestinal microecology and metabolism and highlights the feasibility of targeting IDO1 for PF treatment.

PMID:39778639 | DOI:10.1016/j.phrs.2025.107587

J Pain Symptom Manage. 2025 Jan 6:S0885-3924(25)00003-X. doi: 10.1016/j.jpainsymman.2024.12.023. Online ahead of print.

ABSTRACT

INTRODUCTION: Palliative care (PALC) is traditionally linked to end-of-life cancer care but also benefits advanced non-oncological diseases.

OBJECTIVES: This systematic review evaluated the impact of early PALC on quality of life (QOL), symptom management, advance care planning (ACP), and healthcare resource utilization (HRU) among non-oncological patients.

METHODS: PubMed, Web of Science, and Scopus databases were searched for randomized controlled trials and clinical studies published between January 2018 and April 2023. Participants were adult patients with non-oncological diseases exposed to PALC interventions compared to usual care. Outcomes included QOL, symptom management, ACP, and HRU. The risk of bias was assessed using Cochrane tools.

RESULTS: Seven studies were included involving 1118 patients. Early PALC positively affects pain interference and fatigue in heart failure (HF) patients and time until first readmission and days alive outside the hospital in end-stage liver disease (ESLD) patients. Benefits were noted in symptom burden for patients with Human Immunodeficiency Virus (HIV), anxiety and depression in stroke patients, and ACP in chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) patients. However, results for anxiety and depression in HF patients are inconsistent, and no significant differences in QOL were observed in HF, ESLD, IPF, and COPD. The intervention did not improve overall QOL in HIV.

CONCLUSIONS: The impact of early PALC on health outcomes in non-oncological diseases is inconsistent. Addressing barriers to early PALC integration and conducting further high-quality research are essential for optimizing care pathways and enhancing patient outcomes.

PMID:39778632 | DOI:10.1016/j.jpainsymman.2024.12.023

Sci Transl Med. 2025 Jan 8;17(780):eadk8623. doi: 10.1126/scitranslmed.adk8623. Epub 2025 Jan 8.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which repetitive epithelial injury and incomplete alveolar repair result in accumulation of profibrotic intermediate/transitional "aberrant" epithelial cell states. The mechanisms leading to the emergence and persistence of aberrant epithelial populations in the distal lung remain incompletely understood. By interrogating single-cell RNA sequencing (scRNA-seq) data from patients with IPF and a mouse model of repeated lung epithelial injury, we identified persistent activation of hypoxia-inducible factor (HIF) signaling in these aberrant epithelial cells. Using mouse genetic lineage-tracing strategies together with scRNA-seq, we found that these disease-emergent aberrant epithelial cells predominantly arose from airway-derived (Scgb1a1-CreER-traced) progenitors and exhibited transcriptional programs of Hif2a activation. In mice treated with repetitive intratracheal bleomycin, deletion of Epas1 (Hif2a) but not Hif1a, from airway-derived progenitors, or administration of the small-molecule HIF2 inhibitor PT-2385, using both prevention and rescue approaches, attenuated experimental lung fibrosis, reduced the appearance of aberrant epithelial cells, and promoted alveolar repair. In mouse alveolar organoids, genetic or pharmacologic inhibition of Hif2 promoted alveolar differentiation of airway-derived epithelial progenitors. In addition, treatment of human distal lung organoids with PT-2385 increased colony-forming efficiency, enhanced protein and transcriptional markers of alveolar type 2 epithelial cell maturation, and prevented the emergence of aberrant epithelial cells. Together, these studies showed that HIF2 activation drives the emergence of aberrant epithelial populations after repetitive injury and that targeted HIF2 inhibition may represent an effective therapeutic strategy to promote functional alveolar repair in IPF and other interstitial lung diseases.

PMID:39772774 | DOI:10.1126/scitranslmed.adk8623

Pharmaceuticals (Basel). 2024 Nov 28;17(12):1605. doi: 10.3390/ph17121605.

ABSTRACT

Background/objectives: Idiopathic pulmonary fibrosis (IPF) is a prevalent interstitial lung disease that typically progresses gradually, leading to respiratory failure and ultimately death. IPF can be treated with the tyrosine kinase inhibitor, nintedanib (NTD), owing to its anti-fibrotic properties, which ameliorate the impairment of lung function. This study aimed to formulate, optimize, and assess NTD-loaded ufasomes (NTD-UFSs) as a nanosystem for its pulmonary targeting to snowball the bioavailability and therapeutic efficacy of the drug. Methods: To investigate the influence of numerous factors on NTD-UFSs assembly and to determine the optimal formulation, Box-Behnken statistical design was implemented with the assistance of Design-Expert® software. The thin-film hydration strategy was employed to fabricate NTD-UFSs. The optimum NTD-UFSs formulation was subsequently selected and subjected to additional evaluations. Also, using a rat model, a comparative pharmacokinetic analysis was scrutinized. Results: The optimal NTD-UFSs elicited an accumulative release of 65.57% after 24 h, an encapsulation efficiency of 62.51%, a zeta potential of -36.07 mV, and a vesicular size of 364.62 nm. In addition, it disclosed remarkable stability and a continuous cumulative release pattern. In vivo histopathological studies ascertained the tolerability of NTD-UFSs administered intratracheally. According to the pharmacokinetic studies, intratracheal NTD-UFSs administration manifested a significantly higher AUC0-∞ value than oral and intratracheal NTD suspensions, by approximately 5.66- and 3.53-fold, respectively. Conclusions: The findings of this study proposed that UFSs might be a promising nanoparadigm for the non-invasive pulmonary delivery of NTD.

PMID:39770447 | DOI:10.3390/ph17121605

Medicina (Kaunas). 2024 Nov 29;60(12):1967. doi: 10.3390/medicina60121967.

ABSTRACT

Recent advances in genetics and epigenetics have provided critical insights into the pathogenesis of both idiopathic and non-idiopathic interstitial lung diseases (ILDs). Mutations in telomere-related genes and surfactant proteins have been linked to familial pulmonary fibrosis, while variants in MUC5B and TOLLIP increase the risk of ILD, including idiopathic pulmonary fibrosis and rheumatoid arthritis-associated ILD. Epigenetic mechanisms, such as DNA methylation, histone modifications, and non-coding RNAs such as miR-21 and miR-29, regulate fibrotic pathways, influencing disease onset and progression. Although no standardized genetic panel for ILD exists, understanding the interplay of genetic mutations and epigenetic alterations could aid in the development of personalized therapeutic approaches. This review highlights the genetic and epigenetic factors driving ILD, emphasizing their potential for refining diagnosis and treatment.

PMID:39768847 | DOI:10.3390/medicina60121967

J Clin Med. 2024 Dec 23;13(24):7865. doi: 10.3390/jcm13247865.

ABSTRACT

Background: The degree of exercise-induced oxygen desaturation and outcomes following antifibrotic drug therapy in asymptomatic patients with fibrosing interstitial lung disease (FILD) remain unclear. Methods: We compared clinical data, incidence of annual FILD progression, overall survival, and tolerability after initiating nintedanib between 58 patients with dyspnea and 18 patients without. Annual FILD progression was defined as >10% decrease in forced vital capacity (FVC), >15% decrease in diffusing capacity of the lungs for carbon monoxide (DLCO), developing acute exacerbations, or FILD-related death within 1 year of starting nintedanib. Outcomes between the two groups were adjusted for covariates, including age, gender, FVC, DLCO, and diagnosis of idiopathic pulmonary fibrosis, all known prognostic factors for FILD. Results: In 6-min walk test, incidence of decrease to <90% of SpO2 was significantly lower in non-dyspnea group than in dyspnea group (24% vs. 55%, p = 0.028), but incidence of >4% decreases showed no significant difference (71% vs. 89%, p = 0.11) The incidence of annual progression was significantly lower in non-dyspnea than in dyspnea group (17% vs. 53%, adjusted p = 0.026). The relative change in DLCO was significantly slower in non-dyspnea group (adjusted p = 0.036), but FVC was not (adjusted p = 0.067). Overall survival was longer in non-dyspnea group (adjusted p = 0.0089). The discontinuation rate and therapeutic period of nintedanib were not significantly different between the groups. Conclusions: Asymptomatic patients with FILD have severe exercise-induced oxygen desaturation and better outcomes after nintedanib therapy than symptomatic patients. Antifibrotic drug therapy should not be avoided solely because of a lack of symptoms.

PMID:39768788 | DOI:10.3390/jcm13247865

Cells. 2024 Dec 18;13(24):2099. doi: 10.3390/cells13242099.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is associated with a significantly increased risk of thrombotic events and mortality. This review explores the complex bidirectional relationship between pulmonary fibrosis and thrombosis, discussing epidemiological evidence, pathogenetic mechanisms, and therapeutic implications, with a particular focus on the emerging role of extracellular vesicles (EVs) as crucial mediators linking fibrosis and coagulation. Coagulation factors directly promote fibrosis, while fibrosis itself activates thrombotic pathways. Retrospective studies suggest the benefits of anticoagulants in IPF, but prospective trials have faced challenges. Novel anticoagulants, profibrinolytic therapies, and agents targeting protease-activated receptors (PARs) show promise in preclinical studies and early clinical trials. EVs have emerged as key players in the pathogenesis of interstitial lung diseases (ILDs), serving as vehicles for intercellular communication and contributing to both fibrosis and coagulation. EV-based approaches, such as EV modulation, engineered EVs as drug delivery vehicles, and mesenchymal stem cell-derived EVs, represent promising therapeutic strategies. Ongoing research should focus on optimizing risk-benefit profiles, identifying predictive biomarkers, evaluating combination strategies targeting thrombotic, fibrotic, and inflammatory pathways, and advancing the understanding of EVs in ILDs to develop targeted interventions.

PMID:39768190 | DOI:10.3390/cells13242099

Cells. 2024 Dec 12;13(24):2058. doi: 10.3390/cells13242058.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic and lethal interstitial lung disease (ILD) of unknown origin, characterized by limited treatment efficacy and a fibroproliferative nature. It is marked by excessive extracellular matrix deposition in the pulmonary parenchyma, leading to progressive lung volume decline and impaired gas exchange. The chemokine system, a network of proteins involved in cellular communication with diverse biological functions, plays a crucial role in various respiratory diseases. Chemokine receptors trigger the activation, proliferation, and migration of lung-resident cells, including pneumocytes, endothelial cells, alveolar macrophages, and fibroblasts. Around 50 chemokines can potentially interact with 20 receptors, expressed by both leukocytes and non-leukocytes such as tissue parenchyma cells, contributing to processes such as leukocyte mobilization from the bone marrow, recirculation through lymphoid organs, and tissue influx during inflammation or immune response. This narrative review explores the complexity of the chemokine system in the context of IPF and the bleomycin-induced lung fibrosis mouse model. The goal is to identify specific chemokines and receptors as potential therapeutic targets. Recent progress in understanding the role of the chemokine system during IPF, using experimental models and molecular diagnosis, underscores the complex nature of this system in the context of the disease. Despite advances in experimental models and molecular diagnostics, discovering an effective therapy for IPF remains a significant challenge in both medicine and pharmacology. This work delves into microarray results from lung samples of IPF patients and murine samples at different stages of bleomycin-induced pulmonary fibrosis. By discussing common pathways identified in both IPF and the experimental model, we aim to shed light on potential targets for therapeutic intervention. Dysregulation caused by abnormal chemokine levels observed in IPF lungs may activate multiple targets, suggesting that chemokine signaling plays a central role in maintaining or perpetuating lung fibrogenesis. The highlighted chemokine axes (CCL8-CCR2, CCL19/CCL21-CCR7, CXCL9-CXCR3, CCL3/CCL4/CCL5-CCR5, and CCL20-CCR6) present promising opportunities for advancing IPF treatment research and uncovering new pharmacological targets within the chemokine system.

PMID:39768150 | DOI:10.3390/cells13242058

Cells. 2024 Dec 12;13(24):2050. doi: 10.3390/cells13242050.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common type of fibrosis in lungs, characterized as a chronic and progressive interstitial lung disease involving pathological findings of fibrosis with a median survival of 3 years. Despite the knowledge accumulated regarding IPF from basic and clinical research, an effective medical therapy for the condition remains to be established. Thus, it is necessary for further research, including stem cell therapy, which will provide new insights into and expectations for IPF treatment. Recently, it has been reported that one of the new therapeutic candidates for IPF is adipose-derived mesenchymal stem cells (ADSCs), which have several benefits, such as easy accessibility and minimal morbidity compared to bone marrow-derived mesenchymal stem cells. Therefore, we investigated the possibility of ADSCs as a therapeutic candidate for IPF. Using human lung fibroblasts (LFs) from IPF patients, we demonstrated that human IPF LFs cocultured with ADSCs led to reduced fibrosis-related genes. Further analysis revealed that ADSCs prevented the activation of the ERK signaling pathway in IPF LFs via the upregulation of protein tyrosine phosphatase receptor-type R (PTPRR), which negatively regulates the ERK signaling pathway. Moreover, we demonstrated that intravascular administration of ADSCs improved the pathogenesis of bleomycin-induced pulmonary fibrosis with reduced collagen deposition in histology and hydroxyproline quantification and collagen markers such as the gene expression of types I and III collagen and α-smooth muscle actin (α-SMA) in a murine model. ADSC transfer was also investigated in a humanized mouse model of lung fibrosis induced via the infusion of human IPF LFs, because the bleomycin installation model does not fully recapitulate the pathogenesis of IPF. Using the humanized mouse model, we found that intravascular administration of ADSCs also improved fibrotic changes in the lungs. These findings suggest that ADSCs are a promising therapeutic candidate for IPF.

PMID:39768142 | DOI:10.3390/cells13242050