Crit Care. 2023 Oct 18;27(1):398. doi: 10.1186/s13054-023-04682-5.

ABSTRACT

BACKGROUND: Although patients with interstitial pneumonia pattern (ILD-UIP) and acute exacerbation (AE) leading to severe acute respiratory failure may require invasive mechanical ventilation (MV), physiological data on lung mechanics during MV are lacking. We aimed at describing the physiological effect of lung-protective ventilation in patients with AE-ILD-UIP compared with primary ARDS.

METHODS: Partitioned lung and chest wall mechanics were assessed in a series of AE-ILD-UIP patients matched 1:1 with primary ARDS as controls (based on BMI and PaO2/FiO2 ratio). Three PEEP levels (zero = ZEEP, 4-8 cmH2O = PEEPLOW, and titrated to achieve positive end-expiratory transpulmonary pressure PL,EE = PEEPTITRATED) were used for measurements.

RESULTS: Ten AE-ILD-UIP patients and 10 matched ARDS were included. In AE-ILD-UIP median PL,EE at ZEEP was - 4.3 [- 7.6- - 2.3] cmH2O and lung elastance (EL) 44 [40-51] cmH2O/L. At PEEPLOW, PL,EE remained negative and EL did not change (p = 0.995) versus ZEEP. At PEEPTITRATED, PL,EE increased to 0.8 [0.3-1.5] cmH2O and EL to 49 [43-59] (p = 0.004 and p < 0.001 compared to ZEEP and PEEPLOW, respectively). ΔPL decreased at PEEPLOW (p = 0.018) and increased at PEEPTITRATED (p = 0.003). In matched ARDS control PEEP titration to obtain a positive PL,EE did not result in significant changes in EL and ΔPL.

CONCLUSIONS: In mechanically ventilated AE-ILD-UIP patients, differently than in patients with primary ARDS, PEEP titrated to obtain a positive PL,EE significantly worsened lung mechanics.

PMID:37853480 | PMC:PMC10585808 | DOI:10.1186/s13054-023-04682-5

Thorax. 2023 Oct 18:thorax-2023-220483. doi: 10.1136/thorax-2023-220483. Online ahead of print.

NO ABSTRACT

PMID:37852777 | DOI:10.1136/thorax-2023-220483

BMC Cancer. 2023 Oct 17;23(1):992. doi: 10.1186/s12885-023-11520-y.

ABSTRACT

BACKGROUND: We aim to identify the multifaceted risk factors that can affect the development of severe radiation pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) treated with curative high-dose radiotherapy with or without concurrent chemotherapy.

METHODS: We retrospectively reviewed the medical records of 175 patients with stage-I-III NSCLC treated with curative thoracic X-ray radiotherapy at the Korea University Guro Hospital between June 2019 and June 2022. Treatment-related complications were evaluated using the Common Terminology Criteria for Adverse Events (version 4.03).

RESULTS: The median follow-up duration was 15 months (range: 3-47 months). Idiopathic pulmonary fibrosis (IPF) as an underlying lung disease (P < 0.001) and clinical stage, regarded as the concurrent use of chemotherapy (P = 0.009), were associated with a high rate of severe RP. In multivariate analyses adjusting confounding variables, the presence of IPF as an underlying disease was significantly associated with severe RP (odds ratio [95% confidence interval] = 48.4 [9.09-347]; P < 0.001). In a subgroup analysis of stage-I-II NSCLC, the incidence of severe RP in the control, chronic obstructive pulmonary disease (COPD), and IPF groups was 3.2%, 4.3%, and 42.9%, respectively (P < 0.001). The incidence of severe RP was 15.2%, 10.7%, and 75.0% in the control, COPD, and IPF groups, respectively (P < 0.001) in the stage-III NSCLC group.

CONCLUSIONS: This study revealed that IPF as an underlying lung disease and the concurrent use of chemotherapy are associated with a high rate of severe RP. In contrast, COPD did not increase the risk of pulmonary toxicity after receiving curative high-dose radiotherapy.

PMID:37848850 | DOI:10.1186/s12885-023-11520-y

Sci Rep. 2023 Oct 17;13(1):17616. doi: 10.1038/s41598-023-45027-0.

ABSTRACT

Approximately one-third of fibrosing interstitial lung diseases exhibit progressive pulmonary fibrosis (PPF), a clinicopathological condition distinct yet resembling idiopathic pulmonary fibrosis (IPF). PPF in ANCA-positive ILD (ANCA-ILD) is poorly documented. To clarify incidence, predictors of PPF in ANCA-ILD, and their prognostic impact, 56 patients with ANCA-ILD were followed for ≥ 1 year (April 2004 to April 2021). PPF was defined per ATS/ERS/JRS/ALAT PPF 2022 guideline. We compared PPF and non-PPF in 38 patients with pulmonary function tests and ≥ 1 year follow up. ANCA-ILD (19 male, 19 female; mean age 72 years) comprised 21 patients with microscopic polyangiitis ILD (MPA-ILD) and 17 with ANCA-positive IP without systemic vasculitis (ANCA-IP). PPF occurred in 15/38 (39.5%) overall, and 27% of patients with MPA-ILD and 53% with ANCA-IP. Patient characteristics did not differ between PPF and non-PPF, however, the survival was significantly worse in patients with PPF than those with non-PPF. On multivariate regression analysis, higher age, higher serum SP-D level, and lower baseline %FVC were associated with PPF. In ANCA-ILD, 39.5% of patients demonstrated PPF, which is associated with increased mortality. Predictors of PPF were older age, higher SP-D, and lower baseline %FVC.

PMID:37848575 | DOI:10.1038/s41598-023-45027-0

Int J Hyperthermia. 2023;40(1):2270793. doi: 10.1080/02656736.2023.2270793. Epub 2023 Oct 17.

ABSTRACT

PURPOSE: This study aimed to retrospectively evaluate the safety and feasibility of computed tomography (CT)-guided synchronous percutaneous core-needle biopsy (CNB) and microwave ablation (MWA) for stage I non-small cell lung cancer (NSCLC) in patients with idiopathic pulmonary fibrosis (IPF).

METHODS: From January 2019 to January 2023, nineteen stage I NSCLC patients with IPF underwent CT-guided synchronous percutaneous CNB and MWA in this study. The technical success rate, complications, local tumor progression (LTP) and overall survival (OS) were observed, and the effect of synchronous percutaneous CNB and MWA were evaluated.

RESULTS: The technical success rate of synchronous percutaneous CNB and MWA was 100%. With a median follow-up time of 20.36 months, the median OS was 25 months (95% CI: 21.79, 28.20). The six-, twelve- and eighteen-month OS rates were 94.73%, 89.47% and 57.89%, respectively. The six-, twelve- and eighteen-month LTP rates were 0%, 10.52% and 31.57%, respectively. Major complications including pneumothorax, bronchopleural fistula and pneumonia occurred in 26.32% (5/19) patients. None of the patients died during the procedure.

CONCLUSIONS: According to the results of the current study, CT-guided synchronous percutaneous CNB and MWA appears to be a safe and effective for stage I NSCLC in patients with IPF and providing an alternative therapeutic option for local control of pulmonary malignancy in high-risk patients.

PMID:37848399 | DOI:10.1080/02656736.2023.2270793

Ann Am Thorac Soc. 2023 Oct 17. doi: 10.1513/AnnalsATS.202306-561OC. Online ahead of print.

ABSTRACT

RATIONALE: Standing from a sitting position is an important activity of daily living. The five-repetition sit-to-stand test (5STS) is a simple physical performance test that measures the fastest time taken to stand five times from a chair with arms folded. It can be measured in most healthcare settings, including the home where traditional field walking tests may not be possible. The 5STS has been validated in community-dwelling older adults and people with COPD, but data in idiopathic pulmonary fibrosis (IPF) are limited.

OBJECTIVE: The aims of this cohort study were to establish the construct validity, responsiveness to pulmonary rehabilitation (PR) and minimal important difference (MID) of the 5STS in IPF.

METHODS: In 149 people with IPF, we compared 5STS to measures of lung function, exercise capacity, quadriceps strength, breathlessness and health-related quality of life. Responsiveness and effect sizes were determined by measuring 5STS before and after PR. The MID was estimated using anchor- and distribution-based methods.

RESULTS: The 5STS correlated significantly with incremental shuttle walk test (ISW) (r=-0.55), isometric quadriceps maximum voluntary contract (QMVC) (r=-0.45), Medical Research Council (MRC) score (r=0.40), Chronic Respiratory Questionnaire (CRQ)-Total (r=-0.21) and King's Brief Interstitial Lung Disease-Total (r=-0.21) but not forced vital capacity %predicted or quadriceps 1-repetition maximum (1RM). There was a significant but very weak correlation between change in 5STS and change in MRC (r=0.18), ISW (r=-0.21) and CRQ-Total (r=-0.26) but no significant correlation with change in 1RM (-0.12) or QMVC (r=-0.18). 5STS time improved with PR (median (25th, 75th centile) change: -1.97 (-3.47, -0.62) seconds; p<0.001). The effect size for 5STS was 0.66 and higher than quadriceps 1RM, QMVC and ISW. The mean (range) MID estimate was -1.93 (-1.85 to -2.10) seconds.

CONCLUSIONS: In people with IPF, the 5STS is a valid physical performance measure that is responsive to exercise-based interventions and suitable for use in most healthcare settings.

PMID:37847730 | DOI:10.1513/AnnalsATS.202306-561OC

Am J Respir Crit Care Med. 2023 Oct 17. doi: 10.1164/rccm.202301-0117OC. Online ahead of print.

ABSTRACT

RATIONALE: Idiopathic pulmonary fibrosis (IPF) causes progressive lung scarring and high mortality. Reliable and accurate prognostic biomarkers are urgently needed.

OBJECTIVE: To identify and validate circulating protein biomarkers of IPF survival.

METHODS: High-throughput proteomic data were generated using prospectively collected plasma samples from patients with IPF from the Pulmonary Fibrosis Foundation Patient Registry (discovery cohort) and the Universities of California-Davis, Chicago, and Virginia (validation cohort). Proteins associated with three-year transplant-free survival (TFS) were identified using multivariable Cox proportional hazards regression. Those associated with TFS after adjustment for false discovery in the discovery cohort were advanced for testing in the validation cohort, with proteins maintaining TFS association with consistent effect direction considered validated. After combining cohorts, functional analyses were performed, and machine learning used to derive a proteomic signature of TFS.

MAIN RESULTS: Of 2921 proteins tested in the discovery cohort (n=871), 231 were associated with differential TFS. Of these, 140 maintained TFS association with consistent effect direction in the validation cohort (n=355). After combining cohorts, validated proteins with strongest TFS association were latent-transforming growth factor beta-binding protein 2 (HR 2.43, 95% CI 2.09-2.82), collagen alpha-1(XXIV) chain (HR 2.21; 95% CI 1.86-2.39) and keratin 19 (HR 1.60; 95% CI 1.47-1.74). In decision curve analysis, a proteomic signature of TFS outperformed a similarly derived clinical prediction model.

CONCLUSIONS: In largest proteomic investigation of IPF outcomes performed to date, we identified and validated 140 protein biomarkers of TFS. These results shed important light on potential drivers of IPF progression.

PMID:37847691 | DOI:10.1164/rccm.202301-0117OC

Chest. 2023 Oct 14:S0012-3692(23)05569-1. doi: 10.1016/j.chest.2023.10.012. Online ahead of print.

ABSTRACT

BACKGROUND: As chest computed tomography (CT) has largely supplanted surgical lung biopsy for diagnosing most cases of interstitial lung disease (ILD), tools to standardize CT interpretation are urgently needed.

RESEARCH QUESTION: Does a deep learning based (DL) classifier for usual interstitial pneumonia (UIP) derived using CT features accurately discriminate radiologist-determined visual UIP?

STUDY DESIGN AND METHODS: A retrospective cohort study was performed. Chest CT acquired in individuals with and without ILD were drawn from a variety of public and private data sources. Using radiologist determined visual UIP as ground truth, a convolutional neural network was used to learn discrete CT features of UIP, with outputs used to predict the likelihood of UIP using a linear support vector machine. Test performance characteristics were assessed in an independent performance cohort and multi-center ILD clinical cohort. Transplant-free survival was compared between UIP classification approaches using the Kaplan-Meier estimator and Cox proportional hazards regression.

RESULTS: 2,907 chest CTs were included in the training (n=1934), validation (n=408), performance (n=565) datasets. The prevalence of radiologist determined visual UIP was 12.4% and 37.1% in the performance and ILD clinical cohorts, respectively. The DL UIP classifier predicted visual UIP in the performance cohort with sensitivity and specificity of 93% and 86%, respectively, and in the multi-center ILD clinical cohort with 81% and 77%, respectively. DL and visual UIP classification similarly discriminated survival, and outcomes were consistent among cases with positive DL UIP classification irrespective of visual classification.

INTERPRETATION: A DL classifier for UIP demonstrated good test performance across a wide range of UIP prevalence and similarly discriminated survival when compared to radiologist determined UIP. This automated tool could efficiently screen for UIP in patients undergoing chest CT and identify a high-risk phenotype among those with known ILD.

PMID:37844797 | DOI:10.1016/j.chest.2023.10.012

J Aerosol Med Pulm Drug Deliv. 2023 Oct 16. doi: 10.1089/jamp.2023.0002. Online ahead of print.

ABSTRACT

Background: A distinctive pathological feature of idiopathic pulmonary fibrosis (IPF) is the aberrant accumulation of extracellular matrix components in the alveoli in abnormal remodeling and reconstruction following scarring of the alveolar structure. The current antifibrotic agents used for IPF therapy frequently result in systemic side effects because these agents are distributed, through the blood, to many different tissues after oral administration. In contrast to oral administration, the intrapulmonary administration of aerosolized drugs is believed to be an efficient method for their direct delivery to the focus sites in the lungs. However, how fibrotic lesions alter the distribution of aerosolized drugs following intrapulmonary administration remains largely unknown. In this study, we evaluate the intrapulmonary distribution characteristics of aerosolized model compounds in mice with bleomycin-induced pulmonary fibrosis through imaging the organs and alveoli. Methods: Aerosolized model compounds were administered to mice with bleomycin-induced pulmonary fibrosis using a Liquid MicroSprayer®. The intrapulmonary distribution characteristics of aerosolized model compounds were evaluated through several imaging techniques, including noninvasive lung imaging using X-ray computed tomography, ex vivo imaging using zoom fluorescence microscopy, frozen tissue section observation, and three-dimensional imaging with tissue-clearing treatment using confocal laser microscopy. Results: In fibrotic lungs, the aerosolized model compounds were heterogeneously distributed. In observations of frozen tissue sections, model compounds were observed only in the fibrotic foci near airless spaces called honeycombs. In three-dimensional imaging of cleared tissue from fibrotic lungs, the area of the model compound in the alveolar space was smaller than in healthy lungs. Conclusion: The intrapulmonary deposition of extracellular matrix associated with pulmonary fibrosis limits the intrapulmonary distribution of aerosolized drugs. The development of delivery systems for antifibrotic agents to improve the distribution characteristics in fibrotic foci is necessary for effective IPF therapy.

PMID:37843890 | DOI:10.1089/jamp.2023.0002

Intern Med. 2023 Oct 13. doi: 10.2169/internalmedicine.2584-23. Online ahead of print.

ABSTRACT

Objective The daily step count is associated with mortality in idiopathic pulmonary fibrosis (IPF). However, the factors associated with this phenomenon are not yet fully understood. We therefore clarified its association with clinical parameters. Methods Fifty-nine patients with IPF with available data for daily step counts; 6-minute walk distance (6MWD); chest, abdominal, and pelvic computed tomography (CT); pulmonary function; psychological evaluations; and sarcopenia assessments were prospectively enrolled. The daily step count was measured continuously for seven consecutive days. The cross-sectional areas of the erector spinae muscles at the level of the 12th vertebra (ESMCSA) and psoas major muscle volume (PMV) obtained by CT were assessed. Results The average age of the patients was 73.3±8.1 years old, and the percent predicted forced vital capacity was 81.6% ±15.8%. The average daily step count was 4,258 (2,155-6,991) steps. The average 6MWD, ESMCSA, and PMV were 413±97 m, 25.5±6.7 cm2, and 270±75.6 cm3, respectively. A linear regression analysis for daily step count showed that the ESMCSA and 6MWD were independent factors for the daily step count, whereas the PMV and skeletal muscle index were not. The daily step count, ESMCSA, and 6MWD were lower in patients with sarcopenia than in those without sarcopenia. Conclusions A lower daily step count was associated with a smaller erector spinae muscle area and sarcopenia in patients with IPF. Further studies are warranted to confirm the importance of physical therapy for muscle strengthening in patients with IPF.

PMID:37839878 | DOI:10.2169/internalmedicine.2584-23

Respir Med. 2023 Oct 12:107428. doi: 10.1016/j.rmed.2023.107428. Online ahead of print.

ABSTRACT

RATIONALE: Non-invasive diagnosis of idiopathic pulmonary fibrosis (IPF) involves identification of usual interstitial pneumonia (UIP) pattern by computed tomography (CT) and exclusion of other known etiologies of interstitial lung disease (ILD). However, uncertainty in identification of radiologic UIP pattern leads to the continued need for invasive surgical biopsy. We thus developed and validated a machine learning algorithm using CT scans alone to augment non-invasive diagnosis of IPF.

METHODS: The primary algorithm was a deep learning convolutional neural network (CNN) with model inputs of CT images only. The algorithm was trained to predict IPF among cases of ILD, with reference standard of multidisciplinary discussion (MDD) consensus diagnosis. The algorithm was trained using a multi-center dataset of more than 2000 cases of ILD. A US-based multi-site cohort (n = 295) was used for algorithm tuning, and external validation was performed with a separate dataset (n = 295) from European and South American sources.

RESULTS: In the tuning set, the model achieved an area under the receiver operating characteristic curve (AUC) of 0.87 (CI: 0.83-0.92) in differentiating IPF from other ILDs. Sensitivity and specificity were 0.67 (0.57-0.76) and 0.90 (0.83-0.95), respectively. By contrast, pre-recorded assessment prior to MDD diagnosis had sensitivity of 0.31 (0.23-0.42) and specificity of 0.92 (0.87-0.95). In the external test set, c-statistic was also 0.87 (0.83-0.91). Model performance was consistent across a variety of CT scanner manufacturers and slice thickness.

CONCLUSION: The presented deep learning algorithm demonstrated consistent performance in identifying IPF among cases of ILD using CT images alone and suggests generalization across CT manufacturers.

PMID:37838076 | DOI:10.1016/j.rmed.2023.107428

Acta Histochem. 2023 Oct 12;125(8):152100. doi: 10.1016/j.acthis.2023.152100. Online ahead of print.

ABSTRACT

OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is considered as a chronic interstitial lung disease with underlying mechanism of IPF remaining unclear, while there are no definitive treatment options. In recent years, scientists have gradually paid attention to the influence of angiogenesis on IPF. Because IPF is a progressive with microvascular remodeling disorder, scientists have postulated that angiogenesis may also be one of the initiating and contributing factors of the disease. Bupleurum is a common natural Chinese herbal medicine with antibacterial, anti-inflammatory, anti-tumor and other pharmacological effects. As the most important active monomer of Bupleurum, Saikosaponin-d (SSd) is a new discovery with anti-pulmonary fibrosis (PF) activity. This study attempts to investigate the role of SSd in the interference of PF through regulation of angiogenesis in IPF through Angiopoietin (Angpt) /Tie receptor 2 (Tie2) pathway.

METHODS: Randomly, we allocated C57BL/6 mice into four groups (n = 20 in each group). Afterwards, establishment of IPF model was accomplished via intratracheal administration of bleomycin (BLM, 5 mg/kg), while corresponding drug intervention was given accordingly. On 3rd, 7th, 14th and 28th days after modeling, we performed histopathological examination through staining. Meanwhile, immunohistochemistry (IHC) of PF and the expression of related factors were observed, while Ang/Tie2 pathway was assessed by ELISA with the effect of SSd on angiogenesis related proteins in IPF being explored with IHC and Western Blot technique.

RESULTS: Our results showed that SSd could reduce inflammation and PF levels in lung tissue of experimental mice, while levels of angiogenesis-related factors, namely Tie-2, Ang-1 and ANGPT2 (Ang-2), fibrosis- associated factors like Alpha-smooth muscle actin (α-SMA), collagen-I and hydroxyproline in SSd and dexamethasone (DXM) mice were significantly reduced at each time point compared to BLM (p < 0.01). Additionally, we discovered substantial decreased expressions of Ang-1, Ang-2, Tie-2, α-SMA and collagen-I at protein level in SSd and DXM mice at each time point compared to BLM (p < 0.05). Besides, insignificant differences were observed between SSd and DXM groups (p > 0.05).

CONCLUSION: This study has demonstrated that SSd could down-regulate the expression of ANG-1, Ang-2 and Tie2 in the Ang/Tie2 pathway, and may reduce lung inflammation and PF in BLM-induced mice via inhibition of angiogenesis.

PMID:37837833 | DOI:10.1016/j.acthis.2023.152100

Adv Ther. 2023 Oct 14. doi: 10.1007/s12325-023-02701-z. Online ahead of print.

ABSTRACT

INTRODUCTION: Progression of fibrosis in interstitial lung diseases (ILD) has been associated with poor prognosis, lower quality of life for patients and caregivers, and higher healthcare costs. This study estimated the burden of disease and productivity loss of progressively fibrosing ILD, focusing on progressive pulmonary fibrosis other than idiopathic pulmonary fibrosis (non-IPF PPF) and systemic sclerosis-associated ILD (SSc-ILD) in the European Economic Area (EEA).

METHODS: An economic model was built to estimate the clinical burden of SSc-ILD and non-IPF PPF. The model was based on published data on disease prevalence and disease burden (in terms of comorbidities, exacerbations, and deaths) as well as on productivity loss (in terms of sick days, early retirement, permanent disability, and job loss). Aggregate income loss was obtained by multiplying productivity loss by the median daily income in each country/area of investigation. A sensitivity analysis was performed to test the impact of the variability of the model assumptions.

RESULTS: In the whole EEA, a total of 86,794 and 13,221 individuals were estimated to be affected by non-IPF PPF and SSc-ILD, respectively. Estimated annual sick days associated with the diseases were 3,952,604 and 672,172, early retirements were 23,174 and 5341, permanently disabled patients were 41,748 and 4037, and job losses were 19,789 and 2617 for non-IPF PPF and SSc-ILD, respectively. Annual exacerbations were estimated to be 22,401-31,181 and 1259-1753, while deaths were 5791-6171 and 572-638 in non-IPF PPF and SSc-ILD, respectively. The estimated annual aggregate income loss in EEA, accounting for losses due to annual sick days, early retirements, and permanently disabled patients, was €1433 million and €220 million in non-IPF PPF and SSc-ILD, respectively. The productivity loss due to job losses was €194 million and €26 million in non-IPF PPF and SSc-ILD, respectively. The main driver of aggregate income loss variability was the prevalence.

CONCLUSION: The impact of non-IPF PPF and SSc-ILD on society is definitely non-negligible. Actions to reduce the burden on our societies are highly needed.

PMID:37837527 | DOI:10.1007/s12325-023-02701-z

Diagnostics (Basel). 2023 Oct 9;13(19):3157. doi: 10.3390/diagnostics13193157.

ABSTRACT

(1) Introduction: Although historically, the lung has been considered a sterile organ, recent studies through 16S rRNA gene sequencing have identified a substantial number of microorganisms. The human microbiome has been considered an "essential organ," carrying about 150 times more information (genes) than are found in the entire human genome. The purpose of the present study is to characterize and compare the microbiome in three different interstitial lung diseases: idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis, and nondifferential interstitial lung disease. (2) Material and methods: This was a prospective cohort study where the DNA of 28 patients with ILD was extracted from the lavage and then processed using the standard technique of 16S RNA gene sequencing. In a tertiary teaching hospital in the northern, western part of Romania, samples were collected through bronchoscopy and then processed. (3) Results: The same four species were found in all the patients but in different quantities and compositions: Firmicutes, Actinobacteria, Proteobacteria and Bacteroides. Streptococcus was the most prevalent genus, followed by Staphylococcus and Prevotella. Statistically significant differences in the OUT count for the ten most abundant taxa were found for the genus: Gemella, Actinobacteria, Prevotella, Neisseria, Haemophilus, and Bifidobacterium. The comparative analysis showed a richer microbiota in patients with IPF, as shown by the alpha diversity index. (4) Conclusions: In interstitial lung diseases, the microorganisms normally found in the lung are reduced to a restricted flora dominated by the Firmicutes family. These changes significantly disrupt the continuity of the observed bacterial pattern from the oropharynx to the bronchial tree and lung, possibly impacting the evolution and severity of interstitial lung diseases.

PMID:37835899 | DOI:10.3390/diagnostics13193157

Eur J Med Chem. 2023 Oct 6;261:115856. doi: 10.1016/j.ejmech.2023.115856. Online ahead of print.

ABSTRACT

The immunoproteasome has emerged as a potential therapeutic target for idiopathic pulmonary fibrosis (IPF). We report herein our efforts to discover novel non-peptidic immunoproteasome inhibitors as potential treatment for IPF. A structure-based virtual screening was initially performed and the hit compound VS-7 with an IC50 of 9.437 μM against β5i was identified. Hit evolution based on the interaction mode of VS-7 proceeded, and a potent β5i inhibitor 54 (IC50 = 8.463 nM) with favorable subunit-selective profiles was obtained. Compound 54 also imposed significant effects on the release of TNF-α and IL-6, the transcriptional activity of NF-κB, as well as TGF-β1 induced fibroblast proliferation, activation and collagen synthesis. Notably, when administered at 30 mg/kg in a bleomycin-induced IPF mouse model, compound 54 showed anti-fibrotic effects comparable to the clinical drug nintedanib. The results suggest that selective inhibition of immunoproteasome could be an effective approach to treat IPF.

PMID:37826934 | DOI:10.1016/j.ejmech.2023.115856

Sci Rep. 2023 Oct 12;13(1):17289. doi: 10.1038/s41598-023-44138-y.

ABSTRACT

Pleuroparenchymal fibroelastosis (PPFE) progresses slowly but sometimes relatively quickly, leading to decreased activities of daily living (ADL) and muscle weakness. Skeletal muscle atrophy and muscle weakness in chronic obstructive pulmonary disease (COPD) patients may be caused by cachexia and are associated with reduced ADLs and increased risk of death. However, the association between skeletal muscle mass and the prognosis of PPFE patients remains unknown. We retrospectively analysed the clinical significance of the cross-sectional area of the erector spinae muscle (ESMCSA), a skeletal muscle index, and predictors of mortality within 3 years in PPFE 51 patients, idiopathic pulmonary fibrosis (IPF) 52 patients and COPD 62 patients. PPFE patients had significantly lower ESMCSA than IPF or COPD patients, and lower ESMCSA (< 22.57 cm2) was associated with prognosis within 3 years (log-rank test; p = 0.006), whereas lower body mass index (BMI) showed no association. Multivariate analysis showed that ESMCSA was an independent predictor of mortality within 3 years in PPFE patients (hazard ratio, 0.854; 95% confidence interval: 0.737-0.990, p = 0.036). These results suggest the importance of monitoring ESMCSA in PPFE patients and that assessing ESMCSA in PPFE patients could be a more useful prognostic indicator than BMI.

PMID:37828047 | DOI:10.1038/s41598-023-44138-y

Cytokine. 2023 Oct 10;172:156387. doi: 10.1016/j.cyto.2023.156387. Online ahead of print.

ABSTRACT

BACKGROUND: S100A12, S100A8, and S100A9 are inflammatory disease biomarkers whose functional significance in idiopathic pulmonary fibrosis (IPF) remains unclear. We evaluated the significance of S100A12, S100A8, and S100A9 levels in IPF development and prognosis.

METHODS: The dataset was collected from the Gene Expression Omnibus (GEO) database and differentially expressed genes were screened using GEO2R. We conducted a retrospective study of 106 patients with IPF to explore the relationships between different biomarkers and poor outcomes. Pearson's correlation coefficient, Kaplan-Meier, Cox regression, and functional enrichment analyses were used to evaluate relationships between these biomarkers' levels and clinical parameters or prognosis.

RESULTS: Serum levels of S100A12, S100A8, and S100A9 were significantly elevated in patients with IPF. The two most significant co-expression genes of S100A12 were S100A8 and S100A9. Patients with levels of S100A12 (median 231.21 ng/mL), S100A9 (median 57.09 ng/mL) or S100A8 (median 52.20 ng/mL), as well as combined elevated S100A12, S100A9, and S100A8 levels, exhibited shorter progression-free survival and overall survival. Serum S100A12 and S100A8, S100A12 and S100A9, S100A9 and S100A8 concentrations also displayed a strong positive correlation (rs2 = 0.4558, rs2 = 0.4558, rs2 = 0.6373; P < 0.001). S100A12 and S100A8/9 concentrations were independent of FVC%, DLCO%, and other clinical parameters (age, laboratory test data, and smoking habit). Finally, in multivariate analysis, the serum levels of S100A12, S100A8, and S100A9 were significant prognostic factors (hazard ratio 1.002, P = 0.032, hazard ratio 1.039, P = 0.001, and hazard ratio 1.048, P = 0.003).

CONCLUSIONS: S100A12, S100A8, and S100A9 are promising circulating biomarkers that may aid in determining IPF patient prognosis. Multicenter clinical trials are needed to confirm their clinical value.

PMID:37826869 | DOI:10.1016/j.cyto.2023.156387

JCI Insight. 2023 Oct 12:e164380. doi: 10.1172/jci.insight.164380. Online ahead of print.

ABSTRACT

Aberrant fibroblast function plays a key role in the pathogenesis of Idiopathic Pulmonary Fibrosis, a devastating disease of unrelenting extracellular matrix deposition in response to lung injury. Platelet-derived growth factor alpha-positive (PDGFRα+) lipofibroblasts (LipoFBs) are essential for lung injury response and maintenance of a functional alveolar stem cell niche. Little is known about the effects of lung injury on LipoFB function. Here, we used scRNA-Seq technology and PDGFRαGFP lineage tracing to generate a transcriptomic profile of PDGFRα+ fibroblasts in normal and injured mouse lungs 14 days after bleomycin exposure, generating eleven unique transcriptomic clusters that segregated according to treatment. While normal and injured LipoFBs shared a common gene signature, injured LipoFBs acquired fibrogenic pathway activity with an attenuation of lipogenic pathways. In a 3D organoid model, injured PDGFRα+ fibroblast- supported organoids were morphologically distinct from those cultured with normal FBs, and scRNA-Seq analysis suggested distinct transcriptomic changes in alveolar epithelia supported by injured PDGFRα+ fibroblasts. In summary, while LipoFBs in injured lung have not migrated from their niche and retain their lipogenic identity, they acquire a potentially reversible fibrogenic profile, which may alter the kinetics of epithelial regeneration and potentially contribute to dysregulated repair, leading to fibrosis.

PMID:37824216 | DOI:10.1172/jci.insight.164380

Tuberc Respir Dis (Seoul). 2023 Oct 12. doi: 10.4046/trd.2023.0087. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrosing interstitial pneumonia with a very poor prognosis. Accurate diagnosis of IPF is essential for good outcomes but remains a major medical challenge due to variability in clinical presentation and the shortcomings of existing diagnostic tests. Medical history collection is the first and most important step in the IPF diagnosis process; the clinical probability of IPF is high if the suspected patient is 60 years or older, male, and has a history of cigarette smoking. Systemic assessment for connective tissue disease is essential in the initial evaluation of patients with suspected IPF to identify potential causes of interstitial lung disease (ILD). Radiologic examination using high-resolution computed tomography (HRCT) plays a pivotal role in the evaluation of patients with ILD, and prone and expiratory CT images can be considered. If additional tests such as surgical lung biopsy or transbronchial lung cryobiopsy are needed, transbronchial lung cryobiopsy should be considered as an alternative to surgical lung biopsy in medical centers with experience performing this procedure. Diagnosis through multidisciplinary discussion (MDD) is strongly recommended as MDD has become the cornerstone for diagnosis of IPF, and the scope of MDD has expanded to monitoring of disease progression and suggestion of appropriate treatment options.

PMID:37822232 | DOI:10.4046/trd.2023.0087

J Intensive Care. 2023 Oct 11;11(1):45. doi: 10.1186/s40560-023-00693-0.

ABSTRACT

BACKGROUND: The prognosis for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is poor, and there is no established treatment. Hence, we aimed to investigate the effectiveness of a polymyxin B-immobilised fibre column (PMX) for the treatment of AE-IPF.

METHODS: Data were retrospectively collected from the Japanese Diagnosis Procedure Combination database from 1 July 2010 to 31 March 2018. We identified adult patients with idiopathic pulmonary fibrosis who received high-dose methylprednisolone (mPSL) therapy and mechanical ventilation upon admission. Eligible patients (n = 5616) were divided into those receiving PMX treatment combined with high-dose mPSL (PMX group, n = 199) and high-dose mPSL alone (mPSL alone group, n = 5417). To compare outcomes between the two groups, we applied a stabilised inverse probability of treatment weighting (IPTW) using propensity scores. The primary outcome was in-hospital mortality, and the secondary outcomes were 14- and 28-day mortality and length of hospital stay.

RESULTS: The in-hospital mortality rates of the PMX and mPSL alone groups were 79.9% and 76.4%, respectively. The results did not significantly differ between the two groups after performing a stabilised IPTW. The odds ratio of the PMX group compared with the mPSL alone group was 1.56 (95% confidence interval 0.80-3.06; p = 0.19). The 14- and 28-day mortality and length of hospital stay (secondary outcomes) also did not significantly differ between the two groups.

CONCLUSIONS: In AE-IPF patients using mechanical ventilation, the treatment outcome was not significantly better for PMX combined with high-dose mPSL than for high-dose mPSL alone.

PMID:37821999 | DOI:10.1186/s40560-023-00693-0