Cough is a prevalent symptom in patients with interstitial lung disease (ILD), often significantly impacting quality of life (QoL). However, there is limited data on cough's burden and its effects on QoL in patients with progressive pulmonary fibrosis (PPF).

This study aimed to evaluate the impact of cough burden on QoL among a cohort of patients with PPF PATIENTS AND METHOD: This multicenter, cross-sectional cohort study focused on PPF. Cough severity and its impact on QoL were assessed using the Visual Analogue Scale (VAS) and Leicester Cough Questionnaire (LCQ) scores RESULTS: Of the 248 patients included, 136 (54.8%) had PPF due to rheumatic diseases, and 193 (77.8%) reported experiencing cough. Patients with fibrotic nonspecific interstitial pneumonia had the highest cough frequency (p=0.019). Correlations between cough measures and other variables were generally weak. The mean total LCQ score was 16.1±4.7, with correlations between age and LCQ sub-scores. LCQ total scores positively correlated with FVC (%) (r=0.202, p=0.002), DLCO (%) (r=0.255, p<0.001), and 6MWT distance (r=0.277, p=0.001). VAS scores showed a negative correlation with DLCO, FVC (%), FVC (L), and 6MWT distance. No factor was significantly associated with cough presence in logistic regression, but longer antifibrotic treatment duration and higher LCQ scores were linked to lower VAS scores in linear regression.

Cough is highly prevalent in PPF patients and significantly impacts health-related QoL, underscoring the need for targeted management of this symptom in PPF.

Maimendong decoction (MMDD) originates from the ancient Chinese medical text Synopsis of the Golden Chamber and is a well-established remedy for treating lung diseases. It has demonstrated efficacy in the long-term clinical management of idiopathic pulmonary fibrosis (IPF); however, its underlying mechanisms remain unclear.

This study investigates whether MMDD alleviates IPF by reducing type 2 alveolar epithelial cell (AEC2) senescence and enhancing mitochondrial autophagy. It also explores whether these effects are mediated through the PTEN-induced putative kinase 1 (PINK1)/Parkinson juvenile disease protein 2 (Parkin) pathway.

An IPF mouse model was established with bleomycin (BLM). Mice were administered MMDD, pirfenidone (PFD), or saline for 7 or 28 days. Body weight, lung coefficient, and lung appearance were monitored, and lung tissue pathology was assessed. The expression levels of p53, p21, p16, SA-β-gal activity, and senescence-associated secretory phenotype (SASP) markers were measured. Ultrastructural changes in AEC2 mitochondria were analyzed using transmission electron microscopy. Protein levels of autophagy markers sequestosome-1 and light chain 3 were assessed. The protein levels of PINK1, Parkin, and phosphorylated Parkin were further assessed using network pharmacology analysis and molecular docking technology.

MMDD alleviated BLM-induced IPF by improving body weight, lung appearance, and histopathological features. It reduced AEC2 senescence markers, including p53, p21, p16, SA-β-gal, and SASP, while enhancing mitochondrial autophagy and repairing mitochondrial damage. Network pharmacology and molecular docking identified PINK1 as a major target, and Western blot (WB) analysis confirmed that MMDD regulates the PINK1/Parkin signaling pathway in the treatment of IPF.

MMDD regulates the PINK1/Parkin signaling pathway, alleviates AEC2 senescence, and enhances mitochondrial autophagy, providing significant therapeutic potential for IPF treatment.

A subset of idiopathic pulmonary fibrosis cases has a familial component. Telomeric mutations, such as those in the Regulator of Telomere Elongation Helicase 1 (RTEL1) gene, have been associated with lung fibrosis and a minority of dyskeratosis congenita (DC) cases.We present the case of a A male in his 50s with pulmonary fibrosis, cryptogenic hepatic cirrhosis, chronic anaemia and thrombocytopenia, lacy skin hyperpigmentation, dystrophic nails and canities. Family history included pulmonary fibrosis in two brothers. Genetic testing identified a RTEL1 mutation (c.3730T>C, p.Cys1244Arg) in heterozygosity, linked to a few cases of pulmonary fibrosis and DC. This mutation was confirmed in one brother and two sons. The patient was started on pirfenidone and referred for respiratory rehabilitation, haematological and transplant evaluations.Recognising family history and extrapulmonary manifestations in familial pulmonary fibrosis can expedite diagnosis, treatment and genetic counselling. Early detection of DC allows timely management of bone marrow failure and malignancy screening.

The approach for the diagnosis and treatment of interstitial lung diseases (ILDs) has changed in recent years, mainly for the identification of new entities, such as interstitial lung abnormalities (ILAs) and progressive pulmonary fibrosis (PPF). Clinicians and radiologists are facing new challenges for the screening, diagnosis, prognosis, and follow-up of ILDs. The detection and classification of ILAs or the identification of fibrosis progression at high-resolution computed tomography (HRCT) is difficult, with high inter-reader variability, particularly for non-expert radiologists. In the last few years, various software has been developed for ILD evaluation at HRCT, with excellent results, equal to or more reliable than humans. AI tools can classify ILDs, quantify the extent, analyze the features hidden from the human eye, predict prognosis, and evaluate the progression of the disease. More advanced tools can incorporate clinical and radiological data to obtain personalized prognosis, with the potential ability to steer treatment decisions. To step forward and implement in daily practice such tools, more collaboration is required to collect more homogeneous clinical and radiological data; furthermore, more robust, prospective trials, with the new AI-derived biomarkers compared with each other, are needed to demonstrate the real reliability of the computer-aided evaluation of ILDs.

Diquat (DQ) is a potent herbicide known for its significant toxicity to humans and animals, often resulting in severe pulmonary fibrosis, a serious and potentially life-threatening complication of DQ poisoning. Currently, there are no effective pharmacological treatments for this condition. Crocin-I, a primary bioactive component derived from crocin, possesses notable antioxidant and anti-inflammatory properties; however, its potential to inhibit DQ-induced pulmonary fibrosis has not been fully explored. This study aimed to elucidate the underlying mechanisms and therapeutic effects of crocin-I on DQ-induced pulmonary fibrosis.

C57BL/6 mice exposed to DQ served as a model of pulmonary fibrosis. Pathological characteristics were assessed with hematoxylin and eosin staining, and collagen deposition was measured using Masson's trichrome staining. The expression of epithelial-mesenchymal transition markers was measured using Western blotting and quantitative real-time polymerase chain reaction. Additionally, proteins associated with the SIRT3/FOXO3a signaling pathway were analyzed through Western blotting and quantitative real-time polymerase chain reaction.

Administration of crocin-I at a dosage of 40 mg/kg significantly reduced pulmonary fibrosis, as indicated by decreased collagen deposition. Furthermore, treatment with crocin-I enhanced the expression of SIRT3 and FOXO3a, leading to altered levels of EMT-associated markers, specifically decreased E-cadherin and increased vimentin and α-SMA.

These findings suggest that crocin-I activates the SIRT3/FOXO3a pathway and alleviates DQ-induced pulmonary fibrosis, highlighting its potential as a therapeutic agent for lung injury and paving the way for further research into its clinical applications.

Lily flowers are widely used in China for lung nourishment; however, their active ingredients remain unknown. To address this question, we isolated a novel polysaccharide (L005-B) from the flowers of Lilium lancifolium. Its backbone is comprised of Glcp, Galp, and 1,2-linked α-Rhap. The branch is composed of Xyl and T-α-Glcp residues substituted at the C-4 position of Rhap, along with portions of Glcp, Galp, Araf, and GlcpA residues substituted at the C-4 position of glucose or the C-3 position of galactose. Bioactivity study showed that L005-B alleviated fibrosis-associated protein (fibronectin, collagen, α-SMA) expression in TGF-β1-induced human fibroblast cells (MRC-5). Moreover, L005-B significantly inhibited the epithelial-mesenchymal transition of the human alveolar type II epithelial cell. More importantly, L005-B dramatically improved bleomycin-induced histopathological changes and attenuated the pulmonary index and hydroxyproline contents. Taken together, our findings revealed that L005-B may serve as a promising leading compound for the development of novel antipulmonary fibrosis therapeutics.

High symptom burden and psychosocial needs in chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) warrant palliative care. We assessed the use of specialist palliative care (SPC) and its association with the use of emergency department (ED) and hospital inpatient days in COPD and ILD.

A retrospective cohort study of all Finnish decedents who died of COPD (n = 1189) or ILD (n = 382) in 2019. Data was gathered from the registries of the Finnish Institute of Health and Welfare. Demographics, the use of SPC, the use of ED, and hospital inpatient days during the last six months of life were evaluated.

During the last six months of life, ILD patients used more ED (92 % vs. 84 %, p < 0.001) and spent more time at the hospital (median of 19 vs. 12 days, p < 0.001) compared to COPD. Overall, 12 % and 8 % of the ILD and COPD patients had contact with SPC, respectively (p = 0.012). During the last month of life, SPC reduced the use of ED both in COPD (57 % vs. 68 %, p = 0.036) and ILD (58 % vs. 74 %, p = 0.021), as well as the number of days spent in secondary care hospitals in ILD (median of 0 vs. 2 days, p = 0.011). Also in multivariate analysis, SPC reduced the use of ED. Most patients (72 %) died in a hospital.

ILD patients received more SPC than COPD patients, yet the numbers were low in both patient groups. Using acute hospital resources was common during the last months of life, but SPC reduced this.

Patients with idiopathic pulmonary fibrosis (IPF) may experience insomnia and use hypnotics. However, the effect of the use of hypnotics on their clinical course remains unclear.

Is the use of hypnotics associated with an increased risk of mortality in patients with IPF?

This study included 99 patients with IPF from the Hamamatsu hospital-based cohort and 123 patients with IPF from the Seirei hospital-based cohort, as well as 30,218 patients with IPF from the National Database of Health Insurance Claims and Specific Health Checkups of Japan (the NDB cohort). To analyze the association of hypnotics use with outcomes avoiding immortal time bias, multivariable Cox models with time-dependent covariates and target trial emulation with a new user design were used for the hospital- and NDB-based cohorts.

In the cohorts studied, the 3-year cumulative incidence of new use of hypnotics following the IPF diagnosis ranged from 13.4% to 24.1%. In both hospital-based cohorts, the continuous use of hypnotics was associated with an increased risk of all-cause mortality and disease progression. In the NDB cohort, the continuous use of hypnotics was also associated with an increased risk of all-cause mortality. Subgroup analysis found associations between the continuous use of hypnotics and increased mortality regardless of sex and comorbidities, excluding certain subpopulations.

This study found that continuous use of hypnotics was associated with an increased risk of mortality in patients with IPF. Given the relatively high cumulative incidence of hypnotics use in this population, there is an urgent need to reassess the appropriate use of hypnotics for patients with IPF.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a complex and heterogeneous disease. Given this, we reasoned that differences in genetic profiles may be associated with unique clinical and radiologic features. Computational image analysis, sometimes referred to as radiomics, provides objective, quantitative assessments of radiologic features in subjects with pulmonary fibrosis. Objectives: To determine if the genetic risk profile of patients with IPF identifies unique computational imaging phenotypes. Methods: Participants with IPF were included in this study if they had genotype data and computed tomography (CT) scans of the chest available for computational image analysis. The extent of lung fibrosis and the likelihood of a usual interstitial pneumonia (UIP) pattern were scored automatically using two separate, previously validated deep learning techniques for CT analysis. UIP pattern was also classified visually by radiologists according to established criteria. Results: Among 329 participants with IPF, MUC5B and ZKSCAN1 were independently associated with the deep learning-based UIP score. None of the common variants were associated with fibrosis extent by computational imaging. We did not find an association between MUC5B or ZKSCAN1 and visually assessed UIP pattern. Conclusions: Select genetic variants are associated with computer-based classification of UIP on CT in this IPF cohort. Analysis of radiologic features using deep learning may enhance our ability to identify important genotype-phenotype associations in fibrotic lung diseases.

Rationale: In the United States, ambulatory oxygen is recommended for patients with idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) who experience symptomatic exertional hypoxemia. Ambulatory oxygen need is often determined by submaximal hall walk testing; however, this may fail to accurately characterize exertional hypoxemia in some patients. Objectives: Assess for differences in ambulatory oxygen needs between patients with IPF and COPD who completed a ramped treadmill protocol exercise test (RTPET) and correlate oxygen flow rates determined at highest-level (HL) exertion with lung function and exercise parameters. Oxygen need is defined as the flow rate needed to maintain oxygen saturation ⩾90% in patients who desaturate to ⩽88%. Methods: We conducted a retrospective review of RTPET results for patients with IPF and COPD who also recently completed spirometry. The RTPET has three phases: rest, submaximal usual pace (UP) walking at 0% treadmill grade for 3 minutes, and HL walking at the UP walk speed with increasing treadmill grade by 2% every 2 minutes. Patients with IPF were part of a clinical registry, whereas patients with COPD were identified based on diagnosis coding and spirometry (forced expiratory volume in 1 s/forced vital capacity < 0.70). The RTPET for both groups was completed based on a pulmonologist's referral. Results: We included 329 patients with IPF and 2,343 patients with COPD. A greater proportion of patients with IPF required ambulatory oxygen to maintain saturation ⩾90% at HL exertion. After adjusting for demographic covariates and exercise parameters, patients with IPF required higher ambulatory oxygen flow rates than subjects with COPD with similar diffusion capacity of carbon monoxide values. Of patients who did not require oxygen with submaximal UP testing, 49% with IPF and 24% with COPD required oxygen at HL exertion. Conclusions: The RTPET identified higher oxygen flow needs at HL exertion in patients with IPF versus patients with COPD; however, in both diseases, there was a significant proportion of patients who were only found to have exertional desaturation at HL exertion. Reliance on submaximal testing may fail to meet the needs of patients with IPF and COPD. Further studies are needed to determine if oxygen prescriptions targeting the highest level of desaturation improve clinical outcomes, symptoms, or quality of life.

The molecular link between endoplasmic reticulum stress (ERS) and idiopathic pulmonary fibrosis (IPF) remains elusive. Our study aimed to uncover core mechanisms and new therapeutic targets for IPF. By analyzing gene expression profiles from the Gene Expression Omnibus (GEO) database, we identified 1519 differentially expressed genes (DEGs) and 11 ERS-related genes (ERSRGs) diagnostic for IPF. Using weighted gene co-expression network analysis (WGCNA) and differential expression analysis, key genes linked to IPF were pinpointed. CIBERSORT was used to assess immune cell infiltration, while the Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed to explore biological mechanisms. In three GEO datasets (GSE150910, GSE92592, and GSE124685), the receiver operating characteristic (ROC) curve analysis showed area under the ROC curve (AUC) > 0.7 for all ERSRGs. The Connectivity Map (CMap) database was used to predict small molecules modulating IPF signatures. The molecular docking energies of mirdametinib with protein targets ranged from - 5.1643 to - 8.0154 kcal/mol, while those of linsitinib ranged from - 5.6031 to - 7.902 kcal/mol. Molecular docking and animal experiments were performed to validate the therapeutic potential of identified compounds, with mirdametinib showing specific effects in a murine bleomycin-induced pulmonary fibrosis model. In vitro experiments indicated that mirdametinib may alleviate pulmonary fibrosis by reducing ERS via the PI3K/Akt/mTOR pathway. Our findings highlight 11 ERSRGs as predictors of IPF and demonstrate the feasibility of bioinformatics in drug discovery for IPF treatment.

Patients with Amyotrophic Lateral Sclerosis (ALS) exhibit altered patterns of respiratory rate and heart rhythm that are directly related to autonomic nervous system (ANS) activity. This study aimed to analyze the role of the ANS in respiratory function, cognition, functionality, and antioxidant capacity in patients with ALS through a predictive model that assesses the mediating activity of respiration. This quantitative, observational, analytical, and cross-sectional clinical study was conducted using a sample of 75 patients diagnosed with ALS. ANS activity, respiratory function, cognition, functionality, and antioxidant capacity were also measured. Using these values, a structural equation model was developed using AMOS V.23 software. The mediational predictive model showed that increased sympathetic nervous system (SNS) activity, in turn, increased respiratory function, whereas the role of the parasympathetic nervous system in respiration was very weak and had the opposite effect. Furthermore, SNS activity increased respiratory function values, which, in turn, improved functional capacity, cognition, and antioxidant power in patients with ALS, with respiratory function playing a mediating role. The mediating effect of respiratory function was observed primarily between ANS and functional disability. For oxidative stress, respiratory function showed a high mediating effect, such that greater respiratory function corresponded to greater antioxidant capacity. Additionally, for cognitive activity, a moderate direct effect of the ANS was observed; however, it was greatly enhanced by respiratory disability. Finally, differences were only found based on sex, with respiratory capacity and antioxidant power being higher in men.

BackgroundBreathlessness is a distressing and prevalent symptom in fibrotic interstitial lung disease. Dyspnea management requires systematic assessment including patients' lived experiences; however, most dyspnea tools are point-in-time numerical severity scales. The Edmonton Dyspnea Inventory was developed to assess severity at rest, during activities of daily living and self-reported activities. It enables documentation of crisis dyspnea episodes and triggers clinicians to guide action plans and dyspnea management. This study is part of a larger project to validate the tool. The purpose was to describe patient perceptions of assessment of breathlessness of patient use of the tool.MethodsPatients with fibrotic interstitial lung disease were invited to share their perceptions and experiences of breathlessness and the tool. Focus groups were led on Zoom©, with patient-participants in their homes. Data were analysed with inductive content analysis for development of themes.ResultsThirteen patients participated in 2 focus groups. There were 4 major themes, each with minor themes: physicians need to explicitly ask about breathlessness; the tool conveys breathlessness and disease progression; the tool increases self-awareness of breathlessness and complexity; and the tool helps prevent crises and manage breathlessness. Patient-participants perceived the tool provided the needed language and means to focus and relay their breathlessness to others.ConclusionPatient-participants reported the tool was easy to understand and integrate in daily living. They recommended its use for general and specialized practitioners. Developed to assess breathlessness, the tool may provide a framework to promote patient self-awareness, describe individual progression, and tailor breathlessness self-management.

Idiopathic pulmonary fibrosis (IPF) is a fatal, progressive lung disease characterized by extensive scarring and thickening of lung tissue that leads to respiratory failure. Early and accurate diagnosis is crucial for monitoring disease progression and assessing therapeutic efficacy. While imaging modalities such as radiological X-rays and high-resolution computed tomography (HRCT) are commonly employed, magnetic resonance imaging (MRI) offers significant advantages, including superior soft tissue contrast and the absence of ionizing radiation. However, in lung MRIs are hindered by short transverse relaxation times, low proton density, and motion artifacts which is addressed herein by developing theranostic platform combining MRI imaging with targeted drug delivery using melanin nanoparticles conjugated with nintedanib (MNP-NIN). Chelation with ferric ions (MNP-NIN-Fe³⁺) enhanced MRI visibility enabling non-invasive imaging and drug tracking. MNP-NIN and MNP-NIN-Fe³ ⁺ nanoparticles were built with mean diameters of 189 ± 44 nm and 182 ± 35 nm, respectively and demonstrating successful NIN conjugation. Controlled NIN release followed zero-order kinetics over 36 days. MNP conjugation reduced cytotoxicity in BEAS-2B and A549 cells improving the drug's safety. MRI experiments conducted with a 7.0 T animal scanner demonstrated enhanced imaging contrast with MNP-NIN-Fe solutions compared to saline underscoring their potential for localized visualization and tracking within lung tissues. By integrating MRI diagnostics and targeted drug delivery, the MNP-NIN-Fe³ ⁺ system offers a promising solution to overcome current challenges in IPF management. This theranostic platform addresses the limitations of conventional imaging techniques while providing an innovative strategy for reducing drug-related systemic side effects and improving therapeutic efficacy.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and irreversible fatal disease, the prevalence of which has been increasing in recent years. Nonradiographic and noninvasive early diagnosis of pulmonary fibrosis could improve prognosis but is a formidable challenge. As one of the fundamental microenvironmental parameters, viscosity is relevant to various pathological states, such as acute inflammation. Nevertheless, the potential biological roles of viscosity during the IPF process have been relatively underexplored. To address this issue, herein, we developed a new viscosity-responsive probe (JZ-2), which displayed high sensitivity and selectivity for viscosity, as well as excellent characteristics for targeting mitochondria. JZ-2 was successfully applied to map the changes in mitochondrial viscosity in cells caused by various stimuli, such as nystatin and lipopolysaccharide. Besides, JZ-2 was capable of differentiating cancer cells from normal cells and even tissues. More importantly, JZ-2 has been demonstrated to be sufficiently sensitive for tumor detection and early identification of IPF in vivo, revealing a significant increase in the viscosity of lung fibrosis tissues. Thus, JZ-2 is expected to be a swift and reliable diagnostic modality for the prediction of IPF progression in clinical settings.

Idiopathic pulmonary fibrosis (IPF) remains an incurable form of interstitial lung disease with sub-optimal treatments that merely address adverse symptoms or slow fibrotic progression. Here, inhalable hsa-miR-30a-3p-loaded liposomes (miR-30a) for the treatment of bleomycin-induced pulmonary fibrosis in mice are presented. It was previously found that exosomes (Exo) derived from lung spheroid cells are therapeutic in multiple animal models of pulmonary fibrosis and are highly enriched for hsa-miR-30a-3p. The present study investigates this miRNA as a singular factor to treat IPF. Liposomes containing miR-30a mimic can be delivered to rodents through dry powder inhalation. Inhaled miR-30a and Exo consistently lead to improved pulmonary function across six consecutive pulmonary function tests and promote de-differentiation of profibrotic myofibroblasts. The heterogenous composure of Exo also promotes reparative alveolar type I and II cell remodeling and vascular wound healing through broad transforming growth factor-beta signaling downregulation, while miR-30a targets myofibroblast de-differentiation through CNPY2/PERK/DDIT3 signaling. Overall, inhaled miR-30a represses the epithelial-mesenchymal transition of myofibroblasts, providing fibrotic attenuation and subsequent improvements in pulmonary function.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease characterized by the disruption of the alveolar and interstitial architecture due to extracellular matrix deposition. Emerging evidence suggests that genetic susceptibility plays a crucial role in IPF development. This study explores the role of human leukocyte antigen (HLA) alleles and haplotypes in IPF susceptibility and progression within the genetically distinct Sardinian population. Genotypic data were analyzed for associations with disease onset and progression, focusing on allele and haplotype frequencies in patients exhibiting slow (S) or rapid (R) progression. While no significant differences in HLA allele frequencies were observed between IPF patients and controls, the HLA-DRB1*04:05 allele and the extended haplotype (HLA-A*30:02, B*18:01, C*05:01, DQA1*05:01, DQB1*02:01, DRB1*03:01) were associated with a slower disease progression and improved survival (log-rank = 0.032 and 0.01, respectively). At 36 months, carriers of these variants demonstrated significantly better pulmonary function, measured with single-breath carbon monoxide diffusing capacity (DLCO%p) (p = 0.005 and 0.02, respectively). Multivariate analysis confirmed these findings as being independent of confounding factors. These results highlight the impact of HLA alleles and haplotypes on IPF outcomes and underscore the potential of the Sardinian genetic landscape to illuminate immunological mechanisms, paving the way for predictive biomarkers and personalized therapies.

Human bronchial epithelial cell-derived extracellular vesicles have demonstrated the ability to attenuate fibroblasts activation. However, the specific key effector cell populations mediating this inhibitory effect remain unidentified. Airway basal stem cells (BSCs), which serve as progenitor cells for bronchial epithelial cells, play a critical role in fibrotic remodeling processes and possess significant therapeutic potential. This study aimed to characterize BSC-derived extracellular vesicles (BSC-EVs) and investigate their regulatory influence on fibroblasts behavior.

Airway BSCs were collected through bronchoscopic brushing and differential centrifugation. Fibroblasts were subsequently treated with BSC-EVs at various concentrations to evaluate their dose- and time-dependent effects in vitro. The proteomic composition of BSC-EVs was analyzed using four-dimensional data-independent acquisition quantitative mass spectrometry (4D-DIA). Moreover, a bleomycin-induced pulmonary fibrosis model was established to evaluate the safety and preliminary efficacy of BSC-EVs.

We successfully isolated and identified BSC-EVs, which expressed the nucleus-specific marker TP63, indicative of BSCs, but lacked the BSC marker KRT5. Our findings demonstrated that BSC-EVs enhanced fibroblasts proliferation and migration in a dose-dependent manner. Importantly, BSC-EVs significantly attenuated fibroblasts activation and promoted fibroblasts senescence. Utilizing 4D-DIA quantitative proteomics, we revealed that BSC-EVs modulate extracellular matrix remodeling processes and regulate the expression of key proteins, including collagen I/III and matrix metalloproteinases. Animal models utilizing intratracheal administration of BSC-EVs demonstrate efficient reduction of collagen deposition.

This study offers an extensive characterization of BSC-EVs, adhering to the guidelines set forth by MISEV2023. The findings underscore the significant therapeutic potential of BSC-EVs in the management of fibrotic diseases.

Advances in the understanding of idiopathic pulmonary fibrosis (IPF) and international cooperation have led to the publication and subsequent updates of international practice guidelines. The impact of these guidelines, especially significant updates occurring after 2011, on IPF epidemiology and clinical practices remains relatively unexplored.

This retrospective nationwide population-based study utilized the Whole-Population Datafiles (WPD) of Taiwan's National Health Insurance Research Database that contained basic demographics, complete claim data, and causes of death for all insured persons. We refined the code-based definition to identify IPF cases from the WPD between 2011 and 2019. Independent validation confirmed the high accuracy of this definition. We analyzed the annual standardized rates of IPF incidence, prevalence, overall and IPF-specific all-cause mortality. Additionally, we examined trends in the prescription of selected medications and the proportions of patients with respiratory failure receiving invasive (IMV) and non-invasive (NIV) mechanical ventilation.

We included 4359 incident cases of IPF. From 2011 to 2019, the annual standardized incidence rates increased from 1.66 (95% confidence interval [CI], 1.36-1.97) to 11.35 (95% CI, 10.65-12.04) per 100,000 standard population, and the annual standardized prevalence rates increased from 1.98 (95% CI, 1.65-2.31) to 27.25 (95% CI, 26.17-28.33) per 100,000 standard population. The standardized IPF-specific all-cause mortality and respiratory failure rates remained stable. Male and older patients received IPF diagnoses more frequently, and experienced higher mortality rates, compared to their female and younger counterparts. Most deaths were attributed to respiratory causes, without significant seasonal variation. Changing trends in the management of IPF mirrored with the evolving guideline recommendations, and showed diminishing roles of immunosuppressants, growing usage of antifibrotics, and NIV usage surpassing IMV.

Our findings reflected the longitudinal impact of the recently evolving guideline recommendations on IPF epidemiology and real-world management.

Prognostic factors in patients with newly diagnosed idiopathic interstitial pneumonia (IIP) have rarely been analyzed using prospective data. This study investigated prognostic factors in patients with IIP.

Central interstitial lung disease (ILD) experts established the diagnoses for fibrotic ILD. Prognostic factors using baseline data, including the pathological confidence level of usual interstitial pneumonia (UIP) assessed on a 0%-100% linear analog scale by high-resolution CT (HRCT), pulmonary function tests, and patient-reported outcomes were investigated.

Overall, 866 eligible patients were registered. Patients with unclassifiable idiopathic interstitial pneumonia (n = 272) survived longer than those with idiopathic pulmonary fibrosis (IPF) (n = 469) (hazard ratio [HR] = 0.67; [95% confidence interval [CI]: 0.47-0.95]; P = 0.022); however, IPF as IIPs classification was not a significant prognostic factor at diagnosis (P = 0.577). UIP pattern on HRCT, age, body mass index, forced vital capacity, diffusing capacity of the lungs for carbon monoxide, and St. George's Respiratory Questionnaire were risk factors for survival (P < 0.05). Patients with proposed progressive pulmonary fibrosis (PPF) had poorer prognoses than those without proposed PPF (HR = 5.63; [95% CI: 3.17-10.00]; P < 0.001). Patients with progressive fibrosing ILD (PF-ILD) had poorer prognoses than those without PF-ILD (HR = 7.85; [95% CI: 3.38-18.3]; P < 0.001).

A prospective registry of patients with newly diagnosed IIP provided evidence that the UIP pattern on HRCT by analog scale was a prognostic predictor. Proposed PPF and PF-ILD were valuable for discriminating prognosis. (JIPS Registry, ClinTrials.gov, NCT03041623).

Novel non-invasive machine learning algorithms may improve accuracy and reduce the need for biopsy when diagnosing idiopathic pulmonary fibrosis (IPF). We conducted a cost-effectiveness analysis of diagnostic strategies for IPF.

We developed a decision analytic model to evaluate diagnostic strategies for IPF in the United States. To assess the full spectrum of costs and benefits, we compared four interventions: a machine learning diagnostic algorithm, a genomic classifier, a biopsy-all strategy, and a treat-all strategy. The analysis was conducted from the health sector perspective with a lifetime horizon. The primary outcome measures were costs, Quality-Adjusted Life-Years (QALYs) gained, and Incremental Cost-Effectiveness Ratios (ICERs) based on the average of 10,000 probabilistic runs of the model.

Compared to a biopsy-all strategy the machine learning algorithm and genomic classifer reduced diagnostic-related costs by $14,876 and $3,884, respectively. Use of the machine learning algorithm consistently reduced diagnostic costs. When including downstream treatment costs and benefits of anti-fibrotic treatment, the machine learning algorithm had an ICER of $331,069 per QALY gained compared to the biopsy-all strategy. The genomic classifier had a higher ICER of $390,043 per QALY gained, while the treat-all strategy had the highest ICER of $3,245,403 per QALY gained. Results were sensitive to changes in various input parameters including IPF treatment costs, sensitivity and specificity of novel screening tools, and the rate of additional diagnostics following inconclusive results. High treatment costs were found to drive overall cost regardless of the diagnostic method. As treatment costs lowered, the supplemental diagnostic tools became increasingly cost-effective.

Novel tools for diagnosing IPF reduced diagnostic costs, while overall incremental cost-effectiveness ratios were high due to treatment costs. New IPF diagnosis approaches may become more favourable with lower-cost treatments for IPF.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease of unknown aetiology. Evidence on the progression of idiopathic pulmonary fibrosis (IPF) following the introduction of antifibrotic therapies still indicates a generally poor prognosis. IPF is associated with both respiratory and non-respiratory comorbidities, which can worsen symptoms and impact overall survival. Background/Objectives: The study aimed to investigate the effect of these comorbidities on the early and permanent discontinuation of pirfenidone or nintedanib in IPF patients. Methods: In this single-centre retrospective study, 101 patients diagnosed with IPF according to ATS/ERS/JRS/ALAT guidelines were treated with AFT. Clinical data were collected at 12 months prior to and up to 24 months following treatment initiation, including age, gender, smoking history, and the presence of respiratory and non-respiratory comorbidities. Results: The data showed that 21 patients (20.8%) discontinued treatment within the first 12 months. Additionally, pre-treatment comorbidities were not statistically correlated with the suspension of antifibrotic treatment. Among the overall cohort, 77 patients (76.2%) had at least one comorbidity and 27 (26.7%) had three or more comorbidities. Notably, 24 (23.8%) had respiratory comorbidities, while 75 (74.3%) had non-respiratory comorbidities. Conclusions: This real-life study emphasises the complexities involved in managing IPF, particularly regarding adherence to treatment when significant comorbidities are present. The evidence suggests that in patients with IPF, pre-treatment respiratory or non-respiratory conditions do not affect AFT discontinuation.

Background: Fibrosing interstitial lung diseases can evolve into acute exacerbations, which significantly impact morbidity and mortality. Currently, no routinely used clinical biomarkers can discern the potential progression in these patients. This study aims to analyze different biological markers used in routine clinical practice as possible predictive biomarkers for patients with acute fibrosing interstitial lung disease exacerbation. Methods: We conducted a retrospective, single-center study including patients diagnosed with acute exacerbation of fibrosing interstitial lung disease who required hospitalization between 2018 and 2019 at Vall d'Hebron Hospital, Spain. Patient demographics, clinical data, respiratory function, and comorbidities were collected at baseline. The primary outcome was survival at 30 days, 90 days, and 365 days, using Kaplan-Meier survival analysis and Cox regression. Results: Twenty-nine patients were included (mean age 70.4 years). At the 3-month follow-up, patients with ischemic heart disease showed higher survival rates (p = 0.02). Identifying an infection as the etiology of the exacerbation was associated with worse one-year survival rates compared to idiopathic cases (p = 0.03). Elevated levels of leukocytes (p < 0.01), neutrophils (p < 0.01), and fibrinogen (p = 0.03) were predictors of mortality. Additionally, patients who received a cumulative dose of corticosteroids between 501 and 1000 mg during the exacerbation showed higher one-year survival (p < 0.01). Conclusions: Routine clinical markers can help predict outcomes in AE-f-ILD. Further multicenter studies should validate these findings and assess the role of therapies in its management.

Respiratory muscle dysfunction in patients with idiopathic pulmonary fibrosis (IPF) is a big challenge for treatment and rehabilitation. To quantitatively assess diaphragm and chest wall dysfunction using dynamic Magnetic Resonance Imaging (Dyn-MRI) in patients with IPF.

Ninety-six patients with IPF and 50 gender- and age-matched controls were prospectively included and underwent D-MRI with a dynamic fast spoiled gradient-recalled echo sequence. Respiratory muscles function were assessed with thoracic anterior-posterior (AP), left-right (LR), cranial-caudal (CC) metrics. Moreover, lung area ratios, height (DH), and area (DA) of diaphragm curvature between end-inspiration and end-expiration during both quiet and deep breathing.

During quiet breathing, the functional metrics of the diaphragm and chest wall were comparable between IPF patients and controls. However, during deep breathing, IPF patients exhibited significantly reduced ratios of AP, CC, and lung area compared to controls. Moreover, the median ratios of DH and DA were higher in IPF patients than in controls (DH: 0.96 vs. 0.81, p < 0.001; DA: 1.00 vs. 0.90, p < 0.001). Furthermore, the ratios of AP, CC, and lung area during deep breathing were found to correlate with pulmonary function, total lung volume, and 6-minute walk distance.

D-MRI demonstrated dysfunction in the diaphragm and chest wall among IPF patients, with respiratory muscle dysfunction showing a correlation with the severity of disease.

This article presents a prospective observational study that does not include the outcomes of any healthcare interventions on human participants. The study was registered on September 11, 2018, under the registration number NCT03666234.

Idiopathic pulmonary fibrosis (IPF) is a kind of interstitial lung disease (ILD). It has a high incidence rate and mortality. Its pathogenesis remains unclear. So far, no effective methods have been found for the early diagnosis of IPF. Ferroptosis has been reported to be critical in the initiation and progression of IPF. Therefore, our aim was to identify the hub gene related to ferroptosis co-expressed in the peripheral blood and pulmonary tissue of patients with IPF. Sequencing data were obtained from the Gene Expression Omnibus database. A comprehensive analysis was conducted on the differentially expressed genes (DEGs) to extract ferroptosis-related differentially expressed genes (FRDEGs). The results showed that ferroptosis-related signal paths were highly enriched in IPF, and 10 FRDEGs were identified.The hub gene was predicted through protein-protein interactions (PPI) and Cytoscape. The diagnostic utility of the hub gene was proven by enzyme-linked immunosorbent assay (ELISA) in serum and by immunohistochemistry (IHC) in pulmonary tissues. The results of ELISA indicated that the levels of ATM in the serum of patients with IPF were significantly lower than the normal levels. In contrast, the results of IHC showed that the expression of ATM in the pulmonary tissues of IPF patients exhibited a notably elevated trend. The immune status was assessed by the CIBERSORT method and so was the relevance between ATM and immune cells. These findings unveiled significant differences in various immune cell types in peripheral blood and pulmonary tissue between the IPF group and the control group. Furthermore, ATM was associated with various immune cells. This study suggests that as a ferroptosis-related gene, ATM assumes a pivotal role in the diagnosis and treatment of IPF. This discovery presents a novel approach for the clinical diagnosis and therapy of IPF.

Idiopathic Pulmonary Fibrosis (IPF) is a chronic, progressive disease of unknown origin. Establishing the epidemiology of IPF has been challenging due to diagnostic complexity, poor survival, low prevalence, and heterogeneity of ascertainment methodologies.

This research aimed to estimate the rates of IPF in central and western Pennsylvania and to pilot the use of capture recapture (CR) methods to estimate the disease incidence.

We identified adults ≥ 30 years old diagnosed with IPF (by ICD-9/10 coding) between 2013 to 2021 from two health systems (UPMC Health System and Penn State Health) participating in the PaTH Clinical Research Network. We extracted information on patients' sex, race, date of birth and 3-digit zip code from electronic health records (EHR). Incidence rate of IPF among Pennsylvania residents was calculated using three case definitions (broad and two restricted) and piloted the use of CR in estimating IPF incidence.

IPF incidence rates were 8.42, 6.95 and 4.4 per 100,000 person-years for the unrestricted (n = 3148), partially restricted (n = 2598) and fully restricted (n = 1661) samples, respectively. Low case overlap between two sites resulted in a highly inflated estimate of IPF incidence, using the CR methodology.

The rate of IPF in central and western Pennsylvania was similar to previously published statistics. The application of CR to IPF epidemiology could be further investigated in health systems with greater overlap of patients utilizing more than one system.

Pulmonary fibrosis (PF) is an interstitial chronic lung disease characterized by interstitial inflammation and extracellular matrix deposition, resulting in progressive lung dysfunction and ultimate respiratory failure. However, lacking of precise and noninvasive tracers for fibrotic lesions limits timely diagnosis and treatment. Here, we identified LyP-1, a cyclic peptide, as a specific and sensitive tracer for PF detection using PET/CT imaging. FITC-LyP-1 selectively recognized fibrotic regions in bleomycin-induced PF mice, indicating its targeting capability. The colocalization of FITC-LyP-1 with extracellular collagen I within the fibrotic lesions validated its specificity, and further analysis revealed several potential target molecules. In the in vivo application studies, radiolabeled [68Ga]Ga-LyP-1 showed significantly increased lung uptake in PF mice, specifically enriching fibrotic regions on PET/CT imaging. Notably, compared to CT imaging that showed increased mean lung density throughout the phases after bleomycin-administration, lung uptake of [68Ga]Ga-LyP-1 was only increased in the later phase, indicating that LyP-1 recognizes the fibrous changes rather than the inflammatory cells in vivo. These results suggest that the new radiotracer [68Ga]Ga-LyP-1 specifically detects the extracellular matrix in fibrotic lungs. LyP-1 shows promise as a noninvasive tracer for assessing human pulmonary fibrosis, offering potential for improved diagnostic accuracy and timely intervention.

Idiopathic pulmonary fibrosis (IPF), a progressive lung disease characterized by scarring and worsening lung function, has a poor prognosis. A recent systematic review estimated that 21% of IPF deaths might be attributable to occupational exposures. To describe IPF mortality among U.S. residents aged ≥15 years who were ever employed, by industry and occupation, CDC conducted an exploratory analysis of 2020-2022 multiple cause-of-death data. During 2020-2022, a total of 67,843 (39,712 [59%] male and 28,131 [41%] female) decedents had IPF, suggesting that during this 3-year period, 8,340 IPF deaths in males and 5,908 deaths in females might have been associated with occupational exposures. By industry group, the highest proportionate mortality ratios among males were among those employed in utilities (1.15) and among females, were among those employed in public administration (1.12). By occupation group, the highest IPF mortality rates among males were among community and social services workers (1.23) and among females among farming, fishing, and forestry workers (1.24). Estimates of elevated IPF mortality among workers in specific industries and occupations warrant confirmation, control of known exposure-related risk factors, and continued surveillance to better understand the full range of occupational exposures that might increase risk for developing IPF.

Background: Patients suffering from idiopathic pulmonary fibrosis (IPF) may experience acute exacerbation (AE-IPF), which frequently results in acute respiratory failure (ARF) requiring hospitalization. Objective: This study aims to determine if survival has improved over the last decade in patients hospitalized for ARF consequent to AE-IPF, in view of the progress recently made in pharmacological and supportive treatment strategies. Methods: This was an observational retrospective single-center study. The data of 14 patients admitted to an Intermediate Respiratory Care Unit (IRCU) between 1 January 2004 and 31 December 2013 (group A) were compared with those of 26 patients admitted between 1 January 2014 and 31 December 2023 (group B). This study's primary endpoint was survival following IRCU admission. Results: Survival time was significantly longer in the second group of patients compared to the first one [median survival time: 134 (31-257) vs. 25.5 (20-50) days; p < 0.001]. Group B patients also had a lower IRCU mortality rate (6/26 vs. 10/14; p = 0.003) and a significantly shorter stay in the IRCU [6 (1-60) vs. 14 (1-43) days; p = 0.039]. Conclusions: Innovative pharmacologic treatments and supportive therapeutic strategies are able to prolong survival and reduce the risk of in-hospital mortality in patients with AE-IPF hospitalized for ARF.

Lung compliance, a biomarker of pulmonary fibrosis, is generally measured globally. Hyperpolarized 129Xe gas MRI offers the potential to evaluate lung compliance regionally, allowing for visualization of changes in lung compliance associated with fibrosis.

To assess global and regional lung compliance in a rat model of pulmonary fibrosis using hyperpolarized 129Xe gas MRI.

Prospective.

Twenty Sprague-Dawley male rats with bleomycin-induced fibrosis model (N = 10) and saline-treated controls (N = 10).

7-T, fast low-angle shot (FLASH) sequence.

Lung compliance was determined by fitting lung volumes derived from segmented 129Xe MRI with an iterative selection method, to corresponding airway pressures. Similarly, lung compliance was obtained with computed tomography for cross-validation. Direction-dependencies of lung compliance were characterized by regional lung compliance ratios (R) in different directions. Pulmonary function tests (PFTs) and histological analysis were used to validate the pulmonary fibrosis model and assess its correlation with 129Xe lung compliance.

Shapiro-Wilk tests, unpaired and paired t-tests, Mann-Whitney U and Wilcoxon signed-rank tests, and Pearson correlation coefficients. P < 0.05 was considered statistically significant.

For the entire lung, the global and regional lung compliance measured with 129Xe gas MRI showed significant differences between the groups, and correlated with the global lung compliance measured using PFTs (global: r = 0.891; regional: r = 0.873). Additionally, for the control group, significant difference was found in mean regional compliance between areas, eg, 0.37 (0.32, 0.39) × 10-4 mL/cm H2O and 0.47 (0.41, 0.56) × 10-4 mL/cm H2O for apical and basal lung, respectively. The apical-basal direction R was 1.12 ± 0.09 and 1.35 ± 0.13 for fibrosis and control groups, respectively, indicating a significant difference.

Our findings demonstrate the feasibility of using hyperpolarized gas MRI to assess regional lung compliance.

2 TECHNICAL EFFICACY: Stage 1.

Anti-neutrophil cytoplasmic antibody (ANCA) seropositivity strongly correlates to ANCA-associated vasculitis. Patients with idiopathic interstitial pneumonias (IIPs) without systemic vasculitis are sometimes ANCA-positive. Radiological and pathological differences between patients with myeloperoxidase (MPO)-ANCA-positive and those with proteinase 3 (PR3)-ANCA-positive IIPs remain unclear. To determine whether high-resolution computed tomography (HRCT) features and pathology findings differ by ANCA subtype in ANCA-positive IIP patients in a national database. Clinical, radiological, and pathological data were examined along with a web-based multidisciplinary discussion.

We reviewed records of 10 MPO-ANCA-positive and 9 PR3-ANCA-positive IIP patients who underwent HRCT and surgical lung biopsy between April 2009 and March 2014. Pulmonologists, chest radiologists, and pathologists evaluated HRCT scans and pathological findings independently. Patterns were classified using ATS/ERS/JRS/ALAT 2011 guidelines for idiopathic pulmonary fibrosis.

HRCT patterns were definite usual interstitial pneumonia (UIP) (n = 8; 42.1%), possible UIP (n = 6; 31.6%), and inconsistent with UIP (n = 5; 26.3%). Pathological patterns were definite UIP (n = 5; 26.3%), probable UIP (n = 8; 42.1%), possible UIP (n = 4; 21.1%), and not UIP (n = 2; 10.5%). HRCT and pathological patterns did not differ between MPO-ANCA-positive and PR3-ANCA-positive IIPs. Radiological features were reticulation (n = 13; 68.4%), nodules (n = 12; 63.1%), honeycombing (n = 10; 52.6%), and increased attenuation around honeycombing (n = 7; 36.8%). Pathological findings were cysts (n = 12; 63.1%), lymphoid follicles with germinal centers (n = 11; 57.9%), and peribronchiolar wall lymphocytic infiltration (n = 11; 57.9%).

HRCT and pathological patterns did not differ between MPO-ANCA-positive and PR3-ANCA-positive IIPs. This absence of significant differences suggests a similar mechanism underlying both types of interstitial pneumonia.

High-resolution computed tomography (HRCT) is essential in clinical evaluation and management of interstitial lung diseases (ILDs). Quantitative analysis can assist in both accurate diagnosis and longitudinal assessment. The aim was to verify the role of automatic quantitative analysis of HRCT images in the diagnosis and classification of ILD.

Retrospective single-center study evaluating patients undergoing investigation for fibrosing ILD between 2010 and 2019. HRCT images were re-evaluated, ILD patterns were classified according to the 2018 ATS/ERS/JRS/ALAT consensus. Demographic and clinical variables, distribution of fibrosis and honeycombing pattern, and variables obtained from the quantitative analysis performed by YACTA scientific program were compared between ILD groups according to the 2018 ATS/ERS/JRS/ALAT consensus and to the radiological patterns of idiopathic interstitial pneumonia (IIP), using ANOVA, Kruskal-Wallis H test or Pearson's chi-squared test.

481 patients (mean age 57.7 ± 14 years, 277 women, 204 men) were evaluated. Patients with radiological pattern of usual interstitial pneumonia (UIP) exhibited lower lung volumes, higher mean lung densities (UIP group, -698.8 ± 66.3; probable UIP group, -743.8 ± 47.9; alternative diagnosis to UIP, -712.7 ± 73.7; p = 0.01), and higher absolute vascular lung volumes. Among tomographic patterns of IIP, bronchiolocentric interstitial pneumonia demonstrated smaller lung volume and higher lung density. Collagen vascular disease was the most prevalent.

This study demonstrated that, in a large dataset of exams, the fully automated quantitative analysis of HRCTs is an objective method, which can help in the diagnostic workup of ILDs.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease characterized by dyspnea and loss of lung function. Transforming growth factor-β (TGF-β) activation mediated by αv integrins is central to the pathogenesis of IPF. Bexotegrast (PLN-74809) is an oral, once-daily, dual-selective inhibitor of αvβ6 and αvβ1 integrins under investigation for the treatment of IPF. Positron emission tomography (PET) using an αvβ6-specific PET tracer could confirm target engagement of bexotegrast in the lungs of participants with IPF. Objectives: This Phase 2 study evaluated αvβ6 receptor occupancy in the lung as assessed by changes from baseline in αvβ6 PET tracer uptake, after single-dose administration of bexotegrast to participants with IPF. Methods: In this open-label, single-center study, adults with IPF received up to two single doses of bexotegrast, ranging from 60 to 320 mg with or without background IPF therapy (pirfenidone or nintedanib). At baseline and approximately 4 hours after each orally administered bexotegrast dose, a 60-minute dynamic PET-computed tomography scan was conducted after administration of an αvβ6-specific PET probe ([18F]FP-R01-MG-F2). αvβ6 receptor occupancy by bexotegrast was estimated from the changes in PET tracer uptake after bexotegrast administration. Pharmacokinetics, safety, and tolerability of bexotegrast were also assessed. Results: Eight participants completed the study. Total and unbound plasma bexotegrast concentrations increased in a dose-dependent manner, and regional PET volume of distribution values decreased in a dose- and concentration-dependent manner. The data for volume of distribution fit a simple saturation model, producing an unbound bexotegrast half maximal effective concentration estimate of 3.32 ng/ml. Estimated maximum receptor occupancy was 35%, 53%, 71%, 88%, and 92% after single 60-, 80-, 120-, 240-, and 320-mg doses of bexotegrast, respectively. No treatment-emergent adverse events related to bexotegrast were reported. Conclusions: Dose and concentration-dependent αvβ6 receptor occupancy by bexotegrast was observed by PET imaging, supporting once-daily 160- to 320-mg dosing to evaluate efficacy in clinical trials of IPF. Clinical trial registered with www.clinicaltrials.gov (NCT04072315).