Thorax. 2025 Apr 29:thorax-2024-222321. doi: 10.1136/thorax-2024-222321. Online ahead of print.

ABSTRACT

Volatile organic compounds (VOCs) in exhaled breath have shown promise as biomarkers in idiopathic pulmonary fibrosis (IPF). We analysed breath from 57 people with IPF using thermal desorption-gas chromatography-mass spectrometry to identify VOCs related to lung function change over 12 months. A LASSO regression model selected 63 VOCs associated with relative change in forced vital capacity (8 with correlation coefficient (CC) ≥0.20 on Spearman's rank analysis), and 28 associated with relative change in diffusion capacity of the lung for carbon monoxide % predicted (12 with CC ≥0.20). Secondary analyses demonstrated a correlation between VOCs and baseline lung function parameters and association with survival. This study suggests that there may be a volatile signature of prognosis in IPF that merits further validation.

PMID:40306949 | DOI:10.1136/thorax-2024-222321

J Vet Cardiol. 2025 Apr 5;59:126-132. doi: 10.1016/j.jvc.2025.04.001. Online ahead of print.

ABSTRACT

A 10-week-old female Oriental shorthair was referred due to stunted growth, weight loss, dyspnea, and reduced activity levels compared to her littermates. Thoracic radiography revealed a markedly enlarged cardiac silhouette and a diffuse unstructured interstitial pulmonary pattern, presumably due to cardiogenic pulmonary edema. Echocardiography showed marked left- and right-sided ventricular dilation, decreased contractility, and enlargement of both atria, without any identifiable congenital defects. Pleural and peritoneal effusion were also present. Based on these findings, a presumptive diagnosis of both left- and right-sided congestive heart failure due to a dilated cardiomyopathy phenotype was made. Cardiovascular pathological examination confirmed the echocardiographic findings. Additionally, mild interstitial myocardial fibrosis was present in the left ventricle, both atria, the interventricular septum, and, to a minimal extent, in the right ventricle. Moderate endocardial fibrosis was observed in the left atrium and left atrial appendage, while mild endocardial fibrosis was present in the left ventricle. Both antemortem and postmortem evaluations did not provide clear evidence of the underlying cause. Therefore, we consider this a rare case of feline juvenile idiopathic dilated cardiomyopathy with secondary reactive endocardial and myocardial fibrosis.

PMID:40305901 | DOI:10.1016/j.jvc.2025.04.001

Redox Biol. 2025 Apr 12;83:103635. doi: 10.1016/j.redox.2025.103635. Online ahead of print.

ABSTRACT

Inhibiting ferroptosis represents a promising strategy to combat ferroptosis-related diseases. Here we show that 428, a selenide-containing noscapine derivative, effectively inhibits ferroptosis in various cell lines by enhancing the stability and activity of GPX4. TRIM41 was identified as a novel E3 ubiquitin ligase of GPX4 and 428 was demonstrated to bind to the selenocysteine residue Sec46 of GPX4 via the formation of a transient and reversible Se-Se bond, thereby blocking the interaction between GPX4 and TRIM41, stabilizing GPX4 and enhancing its activity. This unique dynamic covalent binding mode was preliminarily validated by structure-activity relationship analysis and molecular docking studies. Importantly, we demonstrated that 428 treatment alleviates bleomycin-induced pulmonary fibrosis in vivo by inhibiting ferroptosis. Overall, our studies identified a novel stabilizer and activator of GPX4, offering a potential therapeutic approach for the treatment of ferroptosis-related diseases and uncovering a new mechanism for regulating GPX4 degradation.

PMID:40305884 | DOI:10.1016/j.redox.2025.103635

Ann Am Thorac Soc. 2025 Apr 30. doi: 10.1513/AnnalsATS.202503-361ED. Online ahead of print.

NO ABSTRACT

PMID:40305677 | DOI:10.1513/AnnalsATS.202503-361ED

Biomolecules. 2025 Apr 1;15(4):509. doi: 10.3390/biom15040509.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a disease with a poor prognosis and no curative therapies. Fibroblast activation by transforming growth factor β1 (TGFβ1) and disrupted metabolic pathways, including the arginine-polyamine pathway, play crucial roles in IPF development. Polyamines are agonists of the calcium/cation-sensing receptor (CaSR), activation of which is detrimental for asthma and pulmonary hypertension, but its role in IPF is unknown. To address this question, we evaluated polyamine abundance using metabolomic analysis of IPF patient saliva. Furthermore, we examined CaSR functional expression in human lung fibroblasts (HLFs), assessed the anti-fibrotic effects of a CaSR antagonist, NPS2143, in TGFβ1-activated normal and IPF HLFs by RNA sequencing and immunofluorescence imaging, respectively; and NPS2143 effects on polyamine synthesis in HLFs by immunoassays. Our results demonstrate that polyamine metabolites are increased in IPF patient saliva. Polyamines activate fibroblast CaSR in vitro, elevating intracellular calcium concentration. CaSR inhibition reduced TGFβ1-induced polyamine and pro-fibrotic factor expression in normal and IPF HLFs. TGFβ1 directly stimulated polyamine release by HLFs, an effect that was blocked by NPS2143. This suggests that TGFβ1 promotes CaSR activation through increased polyamine expression, driving a pro-fibrotic response. By halting some polyamine-induced pro-fibrotic changes, CaSR antagonists exhibit disease-modifying potential in IPF onset and development.

PMID:40305220 | DOI:10.3390/biom15040509

BMC Pulm Med. 2025 Apr 29;25(1):205. doi: 10.1186/s12890-025-03680-3.

ABSTRACT

BACKGROUND: Surgery resection would improve idiopathic pulmonary fibrosis (IPF) patients with early-stage lung cancer (LC). However, most associated studies were published from surgeons. Interstitial lung disease (ILD) physicians involved in perioperative management would be helpful for improving patients with idiopathic pulmonary fibrosis combined with lung cancer (IPF-LC). To enhance the understanding of the clinical characteristics presented by patients with IPF-LC who have undergone surgical resection, and to explore the factors linked to unfavorable prognosis, our ILD physicians conducted this study.

METHODS: We retrospectively examined clinical records of IPF-LC patients at Peking Union Medical College Hospital from January 2014 to December 2023.Data related to clinical manifestations and treatment methods were collected. Patients underwent routine follow-up through clinical assessments and telephone consultations. The demographic, clinical, and laboratory features of 12 surviving patients and 8 deceased patients were comparatively analysed.

RESULTS: There were 30 males and 2 females, aged from 49 years to 82 years. Twenty-eight patients had a history of smoking. Twenty-five patients had at least one comorbidity and emphysema was the most common. IPF was diagnosed before LC in 8 patients but none of them were prescribed with anti-fibrotic medications. Twenty-four patients were simultaneously diagnosed with LC and IPF, and 7 of them were prescribed anti-fibrotic medications. After surgery, 27 patients were pathologically diagnosed with non-small cell lung cancer and 26 patients were classified as stage I or II lung cancer. During follow-up, 8 patients died, 12 patients lost follow-up and 12 patients survived. Among the 8 deceased patients, 5 patients died from acute exacerbation of IPF, one died from cancer progression and 2 died from surgical complications. The serum Cyfra211 level was higher and the lung cancer stage was more advanced in the non-survival group than in the survival group.

CONCLUSION: Most of our IPF-LC patients were elderly males with a history of smoking and had at least one comorbidity. Most of them were diagnosed with IPF and LC simultaneously. However, only one fifth were prescribed with pirfenidone or nintedanib. Acute exacerbation of IPF was the main cause of death. Similar to the LC patients, higher serum Cyfra211 levels and more advanced lung cancer stages were associated with a poor prognosis for our enrolled IPF-LC patients.

CLINICAL TRIAL NUMBER: Not applicable.

PMID:40301827 | DOI:10.1186/s12890-025-03680-3

Transplant Proc. 2025 Apr 28:S0041-1345(25)00229-5. doi: 10.1016/j.transproceed.2025.03.026. Online ahead of print.

ABSTRACT

BACKGROUND: Lung transplantation is the optimal treatment choice, while extracorporeal membrane oxygenation (ECMO) provides cardiopulmonary support during the perioperative period of lung transplantation. Currently, there is no reported research on the ECMO withdrawal and duration of mechanical ventilation (MV) in idiopathic pulmonary fibrosis (IPF) patients undergoing lung transplantation. Therefore, this study aims to evaluate the impact of ECMO duration on prolonged mechanical ventilation (PMV) time in patients, attempting to explore the relationship between the two.

METHODS: This study included 170 patients with IPF who underwent lung transplantation under ECMO technology. The patients were divided into normal and delayed groups based on the ECMO application time of 72 hours. A multifactor logistic regression analysis was conducted to explore the independent risk factors for PMV time, and restricted cubic spline (RCS) was used to investigate the relationship between ECMO application time and MV time. Receptor operating characteristics (ROC) were further used to find the cut-off value of ECMO application time to predict PMV time.

RESULTS: In the normal group, there were 135 cases, of which 79.25% (107 cases) were males and 20.74% (28 cases) were females, whereas in the delayed group, there were 35 cases, of which 57.14% (20 cases) were males and 42.86% (15 cases) were females. In the RCS curves, there was a nonlinear correlation between the duration of ECMO application and the duration of MV, which tended to increase as the duration of ECMO application increased. According to univariate and multivariate logistic analyses, ECMO application time was an influential factor in the occurrence of PMV time, in which the OR of PMV time was 2.02 (95% CI 1.11,1.63, P = .001) when ECMO application time was ≥ 52.01 hours.

CONCLUSION: After lung transplantation, there is a nonlinear relationship between the application time of ECMO and MV time in patients with IPF. The application time of ECMO can predict well the extension of MV in patients during ICU stay. Therefore, clinicians can assess the duration of MV in patients with IPF based on the application time of ECMO, further avoiding complications related to MV.

PMID:40300905 | DOI:10.1016/j.transproceed.2025.03.026

Zhonghua Jie He He Hu Xi Za Zhi. 2025 May 12;48(5):481-486. doi: 10.3760/cma.j.cn112147-20241018-00621.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease, and its pathogenesis remains unclear. In recent years, studies have shown that complement system activation plays an important role in the process of IPF. The inhibition of complement system activation provides a new approach for IPF treatment strategies. This article reviews the recent advances of complement system activation in the molecular mechanisms in the progress of IPF, and the potential therapeutic target in drug development, providing new perspectives for the prevention and treatment of IPF.

PMID:40300875 | DOI:10.3760/cma.j.cn112147-20241018-00621

Biomedicines. 2025 Apr 17;13(4):989. doi: 10.3390/biomedicines13040989.

ABSTRACT

Increased exposure to particulate matter (PM) from air pollution causes lung inflammation and increases morbidity and mortality due to respiratory diseases. Pirfenidone is an anti-fibrotic agent used to treat idiopathic pulmonary fibrosis. Background/Objectives: In this experiment, we studied the therapeutic effects of pirfenidone on PM-induced pulmonary fibrosis. Methods: Pulmonary fibrosis was induced by the intratracheal application of 100 μg/kg PM10 mixed with 200 μL saline. After 42 days of PM10 infusion, 0.2 mL of distilled water with pirfenidone was orally administered to the pirfenidone-treated groups (200 and 400 mg/kg) every other day for a total of 15 times over 30 days. Results: The intratracheal administration of PM resulted in lung injury and a significant decrease in the number of bronchoalveolar lavage fluid cells. PM administration increased the lung injury score, level of lung fibrosis, and production of pro-inflammatory cytokines. Pirfenidone treatment effectively suppressed transforming growth factor-β-activated kinase 1 in PM-induced pulmonary fibrosis. The present changes inhibited the expressions of mitogen-activated protein kinase kinase 3 and p38, which suppressed transforming growth factor-β, ultimately alleviating lung fibrosis. PM exposure upregulated the expressions of fibronectin and type 1 collagen. PM exposure enhanced connective tissue growth factor and hydroxyproline levels in the lung tissue. The levels of these fibrosis-related factors were inhibited by pirfenidone treatment. Conclusions: These results suggest that pirfenidone is therapeutically effective against PM-induced pulmonary fibrosis.

PMID:40299673 | DOI:10.3390/biomedicines13040989

Biomedicines. 2025 Apr 14;13(4):959. doi: 10.3390/biomedicines13040959.

ABSTRACT

Background/Objectives: Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease characterized by excessive extracellular matrix (ECM) production and tissue stiffening, resulting in impaired lung function. Sodium hydrogen exchanger isoform 1 (NHE1) is a key mediator of intracellular and extracellular pH regulation, influencing fibroblast activation, motility, and proliferative pathways. This study investigates the role of NHE1 in actin stress fiber formation, fibroblast-to-myofibroblast differentiation, and cytokine secretion in IPF progression. Methods: Fibroblasts were treated with profibrotic agonists, including transforming growth factor-beta (TGFβ), lysophosphatidic acid (LPA), and serotonin (THT), in the presence or absence of the NHE1-specific inhibitor, EIPA. Actin stress fibers were visualized using phalloidin staining, while α-smooth muscle actin (α-SMA) expression and cytokine secretion (TGFβ, IL-6, and IL-8) were quantified using immunostaining and ELISA. Intracellular pH changes were measured using BCECF-AM fluorescence. Results: Profibrotic agonists induced significant actin stress fiber formation and α-SMA expression in fibroblasts, both of which were abolished by EIPA. NHE1 activity was shown to mediate intracellular alkalization, a critical factor for fibroblast activation. Cytokine secretion, including TGFβ, IL-6, and IL-8, was enhanced by agonist treatments but reduced with NHE1 inhibition. Chronic TGFβ exposure increased intracellular pH and sustained myofibroblast differentiation, which was partially reversed by EIPA. Conclusions: NHE1 is indicated to play a novel and potential role in processes supporting profibrotic agonists driving fibroblast activation and IPF progression. Targeting NHE1 could present a potential therapeutic approach to disrupt profibrotic pathways and mitigate IPF severity.

PMID:40299552 | DOI:10.3390/biomedicines13040959

Biomedicines. 2025 Mar 27;13(4):808. doi: 10.3390/biomedicines13040808.

ABSTRACT

Great progress has been made in the treatment of pulmonary arterial hypertension (WHO group 1 PAH) over the past two decades, which has significantly improved the morbidity and mortality in this patient population. Likewise, the more recent availability of antifibrotic medications for interstitial lung disease (ILD) have also been effective in slowing down the progression of disease. There is no known cure for either of these disease states. When this combination coexists, treatment can be challenging. Interstitial lung disease is a heterogenous group of chronic inflammatory and/or fibrotic parenchymal lung disorders. A subset of patients with ILD, not related to connective tissue disease, can initially present with inflammatory-predominant disease which progresses to irreversible fibrosis. This population of patients is also at risk for developing pulmonary hypertension (PH) or World Health Organization (WHO) group 3 PH. This coexistence of ILD and PH is associated with early morbidity and mortality. The early identification, diagnosis, and treatment of this combination of ILD and PH is vital. Medications available for both ILD and PH require an individualized approach with the intention of slowing down disease progression. Referral to expert centers for clinical trials and transplant evaluation is recommended. The combination of PH-ILD can be challenging to diagnose and treat effectively. Patients require a thorough clinical evaluation to enable the most accurate diagnosis. A vital part of that evaluation is the early recognition of PH. Medications can help improve disease progression along with clinical trials that will further improve our gaps in knowledge.

PMID:40299367 | DOI:10.3390/biomedicines13040808

Biomedicines. 2025 Mar 26;13(4):796. doi: 10.3390/biomedicines13040796.

ABSTRACT

Rationale: The role of the innate immune system in idiopathic pulmonary fibrosis (IPF) remains poorly understood. However, a functional myeloid compartment is required to remove dying cells and cellular debris, as well as to mediate innate immune responses against pathogens. Aberrant macrophage activity has been described in patients with post-acute sequelae of COVID fibrosis (PASC-F), and caveolin scaffolding domain (CSD) peptides have been found to attenuate inflammation and fibrosis in mouse lung injury models. Therefore, we examined, for the first time, the effects of CSD peptide LTI-2355 on the functional and synthetic properties of human myeloid cells isolated from lung explant tissue of donor lungs as well as IPF and PASC-F lung explant tissue. Methods and Results: CD45+ myeloid cells isolated from lung explant tissue from IPF and PASC-F patients exhibited an impaired capacity to clear autologous dead cells and cellular debris. The uptake of pathogen-coated bioparticles was impaired in myeloid cells from both fibrotic patient groups independent of the type of pathogen, highlighting an intrinsic functional cell impairment. LTI-2355 improved the phagocytic activity of both IPF and PASC-F myeloid cells, and this improvement was paired with decreased proinflammatory and pro-fibrotic synthetic activity. LTI-2355 was also shown to primarily target CD206-expressing IPF and PASC-F myeloid cells. Conclusions: Primary myeloid cells from IPF and PASC-F patients exhibit dysfunctional phagocytic and synthetic properties that are modulated by LTI-2355. LTI-2355 treatment of IPF myeloid cells resulted in significantly reduced sCD163, IFN-α2, IFN-γ, IL-2, IL-10, IL-12p40, and MMP-1 in the cell supernatant. This study highlights an additional mechanism of action of the CSD peptide in the treatment of IPF and progressive fibrotic lung disease.

PMID:40299362 | DOI:10.3390/biomedicines13040796

Respir Res. 2025 Apr 28;26(1):166. doi: 10.1186/s12931-025-03239-0.

ABSTRACT

BACKGROUND: Pulmonary fibrosis (PF) is a disease with a poor prognosis, and its pathogenesis is not fully understood. Identifying dysregulation of lipid metabolism in PF may provide insight and promote the development of novel therapies. The present study was designed to clarify the dysregulated lipid pathways and identify lipids correlated with treatment response.

METHODS: This research comprised two prospective cohort studies. Study 1 aimed to identify dysregulated metabolic pathways and lipids in the peripheral blood of PF patients, compared with healthy control (HC) subjects. Study 2 aimed to identify lipids associated with the decline in % forced vital capacity (%FVC) and survival in PF patients treated with the anti-fibrotic drug, nintedanib. As a preliminary ancillary experiment, we attempted to identify the lipids associated with endothelial cells and fibroblasts.

RESULTS: In Study 1, 38 lipids were identified that differed between the PF (n = 66) and HC (n = 63) groups. Compared with the HC subjects, phosphatidylcholine (PC) 36:5 was the most up-regulated and lysophosphatidylcholine (LPC) 18:0 was the most down-regulated in PF patients. Glycerophospholipid metabolism was the most enriched pathway. Plasmenyl phosphatidylethanolamine (pPE) and plasmanyl phosphatidylcholine (pPC) were determined to be endothelial-related lipids, and phosphatidylethanolamine (PE) were fibroblast-related lipids in PF. In Study 2, 10 lipids were identified that differed between the absolute decline in %FVC < 2.5% group (6 M responders, n = 14) and the decline in %FVC > 2.5% group (6 M non-responders, n = 6) after 6 M of nintedanib therapy, and 6 lipids were identified that differed between the absolute decline in %FVC < 5% group (12 M responders, n = 15) and the decline in %FVC > 5% group (12 M non-responders, n = 5) after 12 M of nintedanib therapy. Four lipids were consistently detected at 6 M and 12 M, and among them, higher levels of pPE 18:0p/22:6 at 6 M showed a poorer prognosis for 24 M survival (p < 0.05, HR = 6.547, 95% CI = 1.471-29.13). Under nintedanib therapy, pPE species were correlated with progressive fibrosis, and pPE 18:0p/22:6 was considered an endothelial-related lipid.

CONCLUSIONS: Lipidomic profiling revealed distinct pathways in PF patients. pPE species were strongly associated with the responses to nintedanib therapy. Targeting the lipids or catabolic enzymes involved in dysregulated pathways has the potential to ameliorate PF.

TRIAL REGISTRATION: Registry for UMIN, Lipidomic analysis on plasma in idiopathic pulmonary fibrosis patients. Trial registry number, UMIN000020872. Registered 3 February 2016, https://center6.umin.ac.jp/cgiopenbin/ctr/index.cgi .

PMID:40296094 | DOI:10.1186/s12931-025-03239-0

Eur J Med Res. 2025 Apr 28;30(1):341. doi: 10.1186/s40001-025-02623-2.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by recurrent injury to alveolar epithelial cells, epithelial-mesenchymal transition, and fibroblast activation, which leads to excessive deposition of extracellular matrix (ECM) proteins. However, effective preventative and therapeutic interventions are currently lacking. Ferroptosis, a unique form of iron-dependent lipid peroxidation-induced cell death, exhibits distinct morphological, physiological, and biochemical features compared to traditional programmed cell death. Recent studies have revealed a close relationship between iron homeostasis and the pathogenesis of pulmonary interstitial fibrosis. Ferroptosis exacerbates tissue damage and plays a crucial role in regulating tissue repair and the pathological processes involved. It leads to recurrent epithelial injury, where dysregulated epithelial cells undergo epithelial-mesenchymal transition via multiple signaling pathways, resulting in the excessive release of cytokines and growth factors. This dysregulated environment promotes the activation of pulmonary fibroblasts, ultimately culminating in pulmonary fibrosis. This review summarizes the latest advancements in ferroptosis research and its role in the pathogenesis and treatment of IPF, highlighting the significant potential of targeting ferroptosis for IPF management. Importantly, despite the rapid developments in this emerging research field, ferroptosis studies continue to face several challenges and issues. This review also aims to propose solutions to these challenges and discusses key concepts and pressing questions for the future exploration of ferroptosis.

PMID:40296070 | DOI:10.1186/s40001-025-02623-2

Exp Cell Res. 2025 Apr 26:114578. doi: 10.1016/j.yexcr.2025.114578. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic interstitial lung disease. With IPF, the probability of complication with lung cancer (LCA) increases considerably, and the prognosis is worse than that of simple IPF. To understand the pathological mechanisms and molecular pathways shared by these two diseases, we used the single-cell analysis from the Gene Expression Omnibus (GEO) database, and find that basal cells (BCs) and alveolar type 2 cells (AT2 cells) are important components of lung epithelial cells. Changes in molecular pathways in BCs and AT2 cells may be involved in the common pathogenesis of IPF and LCA. KRT17 and S100A14 in BCs may promote the IPF co-occurrence with LCA by mediating the EMT. WFDC2 and KRT19 may be the elements in AT2 cells that activate the EMT process to promote IPF co-occurrence with LCA. In both IPF and LCA, FN1-WNT axis may be involved in the interaction between BCs and AT2 cells. Importantly, the results of immunofluorescence colocalization experiments on tissue samples from patients with IPF and LCA were consistent with these conclusions. Basal-macrophage interactions may have also induced the IPF co-occurrence with LCA via the CYBA-ERK1/2 axis. The regulation of M2 macrophage polarization by JUN/SOD2-glycolysis axis may therefore be involved in the co-morbidity mechanism of IPF and LCA. Therefore, our results suggest that molecular changes in BCs, AT2 cells and macrophages may play important roles in the pathogenesis of IPF co-occurrence with LCA, and the cellular interactions between these cells may be critical for the progression of both diseases.

PMID:40294812 | DOI:10.1016/j.yexcr.2025.114578

Drug Dev Res. 2025 May;86(3):e70094. doi: 10.1002/ddr.70094.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive, irreversible lung disease of unknown cause, characterized by gradual thickening and scarring of lung tissue, impairing oxygen transfer into the bloodstream. As a result, symptoms such as shortness of breath, fatigue, and a persistent dry cough occur. Currently, the FDA-approved antifibrotic agents Pirfenidone and Nintedanib can slow the progression of the disease. However, these treatments cannot completely stop the loss of lung function and do not provide a significant improvement in the quality of life of patients. As fibrosis progresses, lung capacity decreases, shortness of breath increases, and general health deteriorates significantly. Therefore, new more effective, and targeted therapies that can halt the progression of IPF are urgently needed. This review addresses novel strategies to slow or halt the disease-related loss of lung function by targeting key mechanisms involved in the pathogenesis of IPF. The molecular structure-activity relationships (SARs) of synthesized compounds targeting JAK/STAT, TGF-β/Smad, Wnt/β-catenin, PI3K, JNK1, and other critical signaling pathways were examined. These targeted approaches have great potential for the development of more potent and selective therapeutic agents for the treatment of IPF. The insights provided in this review may contribute to the future development of more efficient and selective antifibrotic drugs.

PMID:40293838 | DOI:10.1002/ddr.70094

JAMA. 2025 Apr 28. doi: 10.1001/jama.2025.2680. Online ahead of print.

ABSTRACT

IMPORTANCE: Non-cystic fibrosis (CF) bronchiectasis is a chronic lung condition caused by permanent bronchial dilatation and inflammation and is characterized by daily cough, sputum, and recurrent exacerbations. Approximately 500 000 people in the US have non-CF bronchiectasis.

OBSERVATIONS: Non-CF bronchiectasis may be associated with prior pneumonia, infection with nontuberculous mycobacteria or tuberculosis, genetic conditions (eg, α1-antitrypsin deficiency, primary ciliary dyskinesia), autoimmune diseases (eg, rheumatoid arthritis, inflammatory bowel disease), allergic bronchopulmonary aspergillosis, and immunodeficiency syndromes (eg, common variable immunodeficiency). Up to 38% of cases are idiopathic. According to US data, conditions associated with non-CF bronchiectasis include gastroesophageal reflux disease (47%), asthma (29%), and chronic obstructive pulmonary disease (20%). The prevalence of non-CF bronchiectasis increases substantially with age (7 per 100 000 in individuals 18-34 years vs 812 per 100 000 in those ≥75 years) and is more common in women than men (180 vs 95 per 100 000). Diagnosis is confirmed with noncontrast chest computed tomography showing dilated airways and often airway thickening and mucus plugging. Initial diagnostic evaluation involves blood testing (complete blood cell count with differential); immunoglobulin quantification testing (IgG, IgA, IgE, and IgM); sputum cultures for bacteria, mycobacteria, and fungi; and prebronchodilator and postbronchodilator spirometry. Treatment includes airway clearance techniques; nebulization of saline to loosen tenacious secretions; and regular exercise, participation in pulmonary rehabilitation, or both. Inhaled bronchodilators (β-agonists and antimuscarinic agents) and inhaled corticosteroids are indicated for patients with bronchiectasis who have asthma or chronic obstructive pulmonary disease. Exacerbations of bronchiectasis, which typically present with increased cough and sputum and worsened fatigue, are associated with progressive decline in lung function and decreased quality of life. Exacerbations should be treated with oral or intravenous antibiotics. Individuals with 3 or more exacerbations of bronchiectasis annually may benefit from long-term inhaled antibiotics (eg, colistin, gentamicin) or daily oral macrolides (eg, azithromycin). Lung transplant may be considered for patients with severely impaired pulmonary function, frequent exacerbations, or both. Among patients with non-CF bronchiectasis, mortality is higher for those with frequent and severe exacerbations, infection with Pseudomonas aeruginosa, and comorbidities, such as chronic obstructive pulmonary disease.

CONCLUSIONS AND RELEVANCE: Non-CF bronchiectasis is a chronic lung condition that typically causes chronic cough and daily sputum production. Exacerbations are associated with progressive decline in lung function and decreased quality of life. Management involves treatment of conditions associated with bronchiectasis, airway clearance techniques, oral or intravenous antibiotics for acute exacerbations, and consideration of long-term inhaled antibiotics or oral macrolides for patients with 3 or more exacerbations annually.

PMID:40293759 | DOI:10.1001/jama.2025.2680

J Inflamm Res. 2025 Apr 23;18:5499-5517. doi: 10.2147/JIR.S505229. eCollection 2025.

ABSTRACT

AIM: To identify the molecular signature of differentially expressed genes (DEGs) associated with PANoptosis in idiopathic pulmonary fibrosis (IPF) and to interpret their immune landscape and cellular distribution characteristics.

METHODS AND RESULTS: We acquired two IPF datasets from the Gene Expression Omnibus (GEO) database to identify PANoptosis-related DGEs (PAN-DEGs), initially identifying thirty PAN-DEGs. Utilizing machine learning algorithms, we established a five-gene PANoptosis-related signature comprising IGF1, GPX3, GADD45β, SMAD7, and TIMP3, each demonstrating robust diagnostic performance. The expression of these hub genes was subsequently validated using a third GEO dataset and a bleomycin-induced pulmonary fibrosis model. Immune infiltration analysis revealed a close association of these genes with various immune cells, and single-cell RNA sequencing indicated significant expression changes in diverse pulmonary cell types, particularly endothelial cells and fibroblasts.

CONCLUSION: We identified and validated a PANoptosis-related gene signature in IPF, providing insights into their immune infiltration and potential cellular distribution. Further research is necessary to elucidate the biological functions and mechanisms of these genes in the pathogenesis of IPF.

PMID:40291456 | PMC:PMC12034268 | DOI:10.2147/JIR.S505229

Toxicol Res. 2024 Dec 28;41(3):235-244. doi: 10.1007/s43188-024-00269-6. eCollection 2025 May.

ABSTRACT

Protein kinase B (PKB/AKT) is a very important member of the protein kinase family, playing significant roles in various crucial processes including insulin-signaling, cell survival, growth, and metabolism. The carboxyl-terminal modulator protein 1 (CTMP1) inhibits PKB, primarily by attenuating its phosphorylation. Idiopathic pulmonary fibrosis (IPF) is an irreversible, chronic, progressive pulmonary disorder; the clinical treatment options are limited. Of the various experimental models, bleomycin-induced lung fibrosis is the most extensively studied. It closely resembles human lung fibrosis. We explored the impact of CTMP1 on bleomycin-induced fibrosis. In vitro experiments involved knockdown of CTMP1 in A549 cells (human alveolar epithelial cells), followed by bleomycin treatment. In vivo, lung fibrosis was induced in mice with ablated CTMP1 via intratracheal bleomycin administration at 2 mg/kg. CTMP1 deletion reduced pulmonary fibrosis and the epithelial-to-mesenchymal transition by inhibiting PKB phosphorylation. These findings suggest that CTMP1 plays a pivotal role in the regulation of lung fibrosis, offering new insights into potential therapeutic approaches for IPF patients.

SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43188-024-00269-6.

PMID:40291111 | PMC:PMC12021751 | DOI:10.1007/s43188-024-00269-6

Front Med (Lausanne). 2025 Apr 11;12:1526530. doi: 10.3389/fmed.2025.1526530. eCollection 2025.

ABSTRACT

BACKGROUND: For patients with interstitial lung diseases (ILDs) other than idiopathic pulmonary fibrosis (IPF) with a progressive pulmonary fibrosis (PPF) phenotype, current knowledge of patient experience and symptom burden is limited. This study aimed to describe the patient journey for patients with PPF and IPF in a real-world setting in Japan.

METHODS: Data were analyzed from the Adelphi Real World PPF-ILD Disease Specific Programme™, a cross-sectional survey with elements of retrospective data collection of pulmonologists and rheumatologists in Japan from April to October 2022. Participants provided data for up to 12 consecutive patients with physician-confirmed ILD with a progressive phenotype. Analyses were descriptive, except Kappa (κ) statistic was used to measure the alignment between physician- and patient-reported symptom burden in the 4 weeks prior to survey date (poor agreement: κ =<0.00; slight 0.00-0.20; fair 0.21-0.40; moderate 0.41-0.60; substantial 0.61-0.80; almost perfect 1.00).

RESULTS: A total of 63 physicians (43 pulmonologists and 20 rheumatologists) provided data on 382 patients (312 with PPF and 70 with IPF). These patients were also asked to complete a voluntary survey on their experience and symptoms. Mean time from first symptom to consultation was 14.1 months for IPF, 8.0 months for non-connective tissue disease (CTD)-associated ILDs, and 10.7 months for CTD-ILDs. Mean times from consultation to diagnosis were 7.1, 4.8, and 3.6 months, respectively. Perception of symptoms differed between physicians and patients with alignment ranging from poor (dysphagia, κ = -0.0296, p = 0.6217) to substantial (weight loss, κ = 0.6174, p = 0.001). Health-related quality of life (HRQoL) was consistently impaired in patients overall, but too few patients completed HRQoL instruments to compare IPF with other forms of ILD.

CONCLUSIONS: This real-world study expands our understanding of the patient journey for patients with PPF and IPF in Japan. Greater communication between patients and physicians is needed to shorten diagnostic delays and target treatment strategies to improve patient experience and overall outcomes.

PMID:40291022 | PMC:PMC12023007 | DOI:10.3389/fmed.2025.1526530