Thorax. 2024 Mar 6:thorax-2023-221148. doi: 10.1136/thorax-2023-221148. Online ahead of print.

ABSTRACT

BACKGROUND: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD).

METHODS: Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure.

RESULTS: The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results.

CONCLUSION: By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD.

PMID:38448221 | DOI:10.1136/thorax-2023-221148

Am J Respir Crit Care Med. 2024 Mar 6. doi: 10.1164/rccm.202402-0290VP. Online ahead of print.

NO ABSTRACT

PMID:38445949 | DOI:10.1164/rccm.202402-0290VP

Occup Ther Health Care. 2024 Mar 5:1-15. doi: 10.1080/07380577.2024.2324256. Online ahead of print.

ABSTRACT

This case-control study examined cognitive function in patients with mild idiopathic pulmonary fibrosis (IPF), in comparison with controls or moderate-to-severe IPF. Ten mild IPF, 10 moderate-to-severe IPF, and 16 controls were enrolled, and performance on seven different cognitive function tests was compared in each group. IPF showed decreased cognitive function compared to controls in verbal memory, cognitive flexibility and information processing speed. As the scores were lower even in mild IPF, this study suggests that cognitive function declines early in the disease process of IPF. Thus, occupational therapy for IPF should require an assessment of cognitive function and assistance appropriate to the client's function.

PMID:38440879 | DOI:10.1080/07380577.2024.2324256

Eur J Pharmacol. 2024 Mar 2:176459. doi: 10.1016/j.ejphar.2024.176459. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal and insidious interstitial lung disease. So far, there are no effective drugs for preventing the disease process. Cellular senescence plays a critical role in the development of IPF, with the senescence and insufficient mitophagy of alveolar epithelial cells being implicated in its pathogenesis. Tetrandrine is a natural alkaloid which is now produced synthetically. It was known that the tetrandrine has anti-fibrotic effects, but the efficacy and mechanisms are still not well evaluated. Here, we reveal the roles of tetrandrine on AECs senescence and the antifibrotic effects by using a bleomycin challenged mouse model of pulmonary fibrosis and a bleomycin-stimulated mouse alveolar epithelial cell line (MLE-12). We performed the β-galactosidase staining, immunohistochemistry and fluorescence to assess senescence in MLE-12 cells. The mitophagy levels were detected by co-localization of LC3 and COVIX. Our findings indicate that tetrandrine suppressed bleomycin-induced fibroblast activation and ultimately blocked the increase of collagen deposition in mouse model lung tissue. It has significantly inhibited the bleomycin-induced senescence and senescence-associated secretory phenotype (SASP) in alveolar epithelial cells (AECs). Mechanistically, tetrandrine suppressed the decrease of mitochondrial autophagy-related protein expression to rescue the bleomycin-stimulated impaired mitophagy in MLE-12 cells. We revealed that knockdown the putative kinase 1 (PINK1) gene by a short interfering RNA (siRNA) could abolish the ability of tetrandrine and reverse the MLE-12 cells senescence, which indicated the mitophagy of MLE-12 cells is PINK1 dependent. Our data suggest the tetrandrine could be a novel and effective drug candidate for lung fibrosis and senescence-related fibrotic diseases.

PMID:38438063 | DOI:10.1016/j.ejphar.2024.176459

Respirology. 2024 Mar 4. doi: 10.1111/resp.14695. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Establishing an accurate and timely diagnosis of idiopathic pulmonary fibrosis (IPF) is essential for appropriate management and prognostication. In some cases, surgical lung biopsy (SLB) is performed but carries non-negligible risk. The objective of this retrospective study was to determine if SLB is associated with accelerated lung function decline in patients with IPF using the Canadian Registry for Pulmonary Fibrosis.

METHODS: Linear mixed models and Cox proportional hazards regression models were used to compare decline in forced vital capacity (FVC)%, diffusion capacity of the lung (DLCO%) and risk of death or lung transplantation between SLB and non-SLB patients. Adjustments were made for baseline age, sex, smoking history, antifibrotic use, and lung function. A similar analysis compared lung function changes 12 months pre- and post-SLB.

RESULTS: A total of 81 SLB patients and 468 non-SLB patients were included. In the SLB group, the post-biopsy annual FVC% decline was 2.0% (±0.8) in unadjusted, and 2.1% (±0.8) in adjusted models. There was no difference in FVC% decline, DLCO% decline, or time to death or lung transplantation between the two groups, in adjusted or unadjusted models (all p-values >0.07). In the pre-post SLB group, no differences were identified in FVC% decline in unadjusted or adjusted models (p = 0.07 for both).

CONCLUSION: No association between SLB and lung function decline or risk of death or lung transplantation was identified in this multi-centre study of patients with IPF.

PMID:38436522 | DOI:10.1111/resp.14695

Cureus. 2024 Feb 1;16(2):e53383. doi: 10.7759/cureus.53383. eCollection 2024 Feb.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease that results in fibrotic lung tissue leading to symptoms of dyspnea, nonproductive cough, decreased mobility, and fatigue. This case report presents a well-documented case of a 73-year-old female presenting to a chiropractic and rehabilitation center seeking care after failing medication therapy. The patient presented hypoxic on room air with decreased mobility throughout her cervical, thoracic, and lumbar spine. Three manual therapy techniques were performed at the rehabilitation clinic aimed at improving the range of motion of the impacted joints and surrounding tissue. The patient was also given manual therapy exercises to perform at home. Pre- and post-intervention assessments showed an improvement in oxygenation saturation on room air, increased mobility, and stabilization of the patient's pulmonary function test (PFT) values. This case demonstrates the importance of considering manual therapy in patients who have failed the standard of care or are unable to tolerate the medications used to treat IPF.

PMID:38435171 | PMC:PMC10908445 | DOI:10.7759/cureus.53383

Heliyon. 2024 Feb 17;10(5):e26623. doi: 10.1016/j.heliyon.2024.e26623. eCollection 2024 Mar 15.

ABSTRACT

INTRODUCTION: The new diagnostic guidelines for idiopathic pulmonary fibrosis (IPF) did not rule out the possibility of combining the radiological patterns of usual interstitial pneumonia (UIP) and probable UIP, given the similar management and diagnostic capacity. However, the prognostic implications of these patterns have not been fully elucidated, with different studies showing heterogeneous results. We applied the new criteria to a retrospective series of patients with IPF, assessing survival based on radiological patterns, findings, and their extension.

METHODS: Two thoracic radiologists reviewed high-resolution computed tomography images taken at diagnosis in 146 patients with IPF, describing the radiological findings and patterns. The association of each radiological finding and radiological patterns with two-year mortality was analysed.

RESULTS: The two-year mortality rate was 40.2% in IPF patients with an UIP radiological pattern versus 7.1% in those with probable UIP. Compared to the UIP pattern, probable UIP was protective against mortality, even after adjusting for age, sex, pulmonary function, and extent of fibrosis (hazard ratio (HR) 0.23, 95% confidence interval (CI) 0.06-0.99). Receiving antifibrotic treatment was also a protective factor (HR 0.51, 95%CI 0.27-0.98). Honeycombing (HR 3.62, 95%CI 1.27-10.32), an acute exacerbation pattern (HR 4.07, 95%CI 1.84-8.96), and the overall extent of fibrosis (HR 1.04, 95%CI 1.02-1.06) were predictors of mortality.

CONCLUSIONS: In our series, two-year mortality was higher in patients with IPF who presented a radiological pattern of UIP versus probable UIP on the initial scan. Honeycombing, an acute exacerbation pattern, and a greater overall extent of fibrosis were also predictors of increased mortality. The prognostic differences between the radiological pattern of UIP and probable UIP in our series would support maintaining them as two differentiated patterns.

PMID:38434331 | PMC:PMC10906386 | DOI:10.1016/j.heliyon.2024.e26623

J Biomol Struct Dyn. 2024 Mar 3:1-13. doi: 10.1080/07391102.2024.2318655. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease with a survival rate of <5 years. The TGF-β plays a significant role in the progression and severity of IPF. The TGF-β receptor type1 TGFBR1 antagonists inhibit the process of fibrosis and may have a role in the treatment of IPF. The main objective of the study was to identify promising drug candidates against IPF using In-silico and In-vitro evaluation methods. An in-silico screening was carried out of the marketed Coxibs to find their TGFBR1 inhibitory potential considering their structural resemblance with the JZO-a co-crystalized ligand of the crystal structure of the TGFBR1. The virtual screening yielded rofecoxib as a TGFBR1 ligand with a significant docking score. To further validate the outcome of molecular docking studies, MD simulation of 200 ns was carried out followed by the determination of conformational stability, binding free energy calculation using MMPBSA/MMGBSA, and Free Energy Landscape (FEL). The therapeutic efficacy of rofecoxib was compared with that of nintedanib (a therapeutic agent used in the treatment of IPF) at equimolar concentrations (5 µM). The model of TGF-β1 (1 ng/ml)-induced EMT of A549 was used to determine the effect of rofecoxib on the EMT markers like cellular morphology, cytokine expressions, fibrosis associated protein, E-cadherin, and α-smooth muscle actin. In vitro results indicated that rofecoxib significantly suppresses the TGF-β1-induced EMT of A549 cells and validates the possible preventive/protective role of rofecoxib in pulmonary fibrosis. In conclusion, rofecoxib may be considered for repositioning as an anti-fibrotic agent.Communicated by Ramaswamy H. Sarma.

PMID:38433403 | DOI:10.1080/07391102.2024.2318655

Cell Mol Biol (Noisy-le-grand). 2024 Feb 29;70(2):128-136. doi: 10.14715/cmb/2024.70.2.18.

ABSTRACT

As the main active ingredient of Astragalus, Astragaloside IV (AS-IV) can ameliorate pulmonary fibrosis. In this experiment, we studied how AS-IV reduces idiopathic pulmonary fibrosis (IPF). Bleomycin (BLM) or TGF-β1 was treated in mice or alveolar epithelial cells to mimic IPF in vivo as well as in vitro. ASV-IV alleviated levels of inflammatory cytokines and fibrosis markers in IPF model. Through detection of autophagy-related genes, ASV-IV was observed to induce autophagy in IPF. Besides, ASV-IV inhibited miR-21 expression in IPF models, and overexpression of miR-21 could reverse the protective potential of ASV-IV on IPF. PTEN was targeted by miR-21 and was up-regulated by ASV-IV in IPF models. In addition, levels of inflammatory cytokines and fibrosis markers, autophagy, as well as the PI3K/AKT/mTOR pathway regulated by ASV-IV could be neutralized after treatment with autophagy inhibitors, miR-21 mimics, or si-PTEN. Our study demonstrates that ASV-IV inhibits IPF through activation of autophagy by miR-21-mediated PTEN/PI3K/AKT/mTOR pathway, suggesting that ASV-IV could be acted to be a promising therapeutic method for IPF.

PMID:38430031 | DOI:10.14715/cmb/2024.70.2.18

Ann Am Thorac Soc. 2024 Mar;21(3):377-380. doi: 10.1513/AnnalsATS.202311-959ED.

NO ABSTRACT

PMID:38426828 | DOI:10.1513/AnnalsATS.202311-959ED

Respir Med Case Rep. 2024 Feb 17;48:101996. doi: 10.1016/j.rmcr.2024.101996. eCollection 2024.

ABSTRACT

Idiopathic pulmonary hemosiderosis (IPH) is a rare and fatal lung disease. Mycoplasma pneumoniae pneumonia (MPP) is the main community-acquired pneumonia among children aged 5 and above in China. We report the following case of IPH complicated with severe mycoplasma pneumoniae pneumonia(SMPP). An 8-year-old boy with cough and fever was diagnosed with IPH for 3 years and his chest computed tomography showed bilateral bronchopneumonia, lobular consolidation and subpleural interstitial fibrosis. As far as we know, IPH related to SMPP is rarely reported. In the high incidence period of MPP, clinicians and radiologists should be alert to the co-occurrence of IPH and SMPP.

PMID:38426012 | PMC:PMC10904270 | DOI:10.1016/j.rmcr.2024.101996

Anticancer Res. 2024 Mar;44(3):1131-1142. doi: 10.21873/anticanres.16908.

ABSTRACT

BACKGROUND/AIM: Cancer stem cells (CSCs) contribute significantly to the poor prognosis of patients with epithelial ovarian cancer (EOC) due to their roles in drug resistance and tumor metastasis. Autotaxin (ATX) plays a pivotal role in the maintenance of the CSC-like properties of EOC tumors. BBT-877 is a novel ATX inhibitor used in clinical treatment of idiopathic pulmonary fibrosis. However, the effects of BBT-877 on drug resistance and metastasis in ovarian CSCs remain unknown. In this study, we aimed to investigate the effects of BBT-877 on drug resistance and intraperitoneal metastasis of EOC.

MATERIALS AND METHODS: Spheroid-forming CSCs, which were isolated from two EOC cell lines, A2780 and SKOV3, were investigated by cell viability, western blot, PCR, Spheroid-forming assay, and in vivo experiments.

RESULTS: Spheroid-forming CSCs exhibited increased CSC-like properties and paclitaxel (PTX) resistance. BBT-877 treatment inhibited the viability of spheroid-forming CSCs more potently than that of adherent ovarian cancer cell lines. Combinatorial treatment with BBT-877 and PTX significantly attenuated the viability of spheroid-forming CSCs. In a SKOV3 cells-derived intraperitoneal metastasis model, BBT-877 treatment reduced the number of metastatic tumor nodes, while combinatorial treatment with BBT-877 and PTX more potently attenuated the formation of metastatic nodes and accumulation of ascitic fluid.

CONCLUSION: These results suggest that BBT-877 can be combined with conventional anticancer drugs for the treatment of patients with recurrent or drug-resistant EOC.

PMID:38423649 | DOI:10.21873/anticanres.16908

J Allergy Clin Immunol Pract. 2024 Feb 27:S2213-2198(24)00196-X. doi: 10.1016/j.jaip.2024.02.022. Online ahead of print.

ABSTRACT

Organic dusts are complex bioaerosol mixtures comprised of dust and particulate matter of organic origin. These include components from bacteria, fungi, pollen, and viruses to fragments of animals and plants commonplace to several environmental/occupational settings encompassing agriculture/farming, grain processing, waste/recycling, textile, cotton, woodworking, bird breeding, and more. Organic dust exposures are linked to development of chronic bronchitis, chronic obstructive pulmonary disease (COPD), asthma, asthma-like syndrome, byssinosis, hypersensitivity pneumonitis (HP), and idiopathic pulmonary fibrosis (IPF). Risk factors of disease development include cumulative dust exposure, smoking, atopy, timing/duration, and nutritional factors. The immunopathogenesis predominately involves Toll-like receptor signaling cascade, Th1/Th17 lymphocyte responses, neutrophil influx, and potentiation of manifestations associated with allergy. The true prevalence of airway disease directly attributed to organic dust, especially in a workplace setting, remains challenging. Diagnostic confirmation can be difficult and complicated by hesitancy from workers to seek medical care, driven by fears of potential labor-related consequence. Clinical respiratory and systemic presentations coupled with allergy testing, lung function patterns of obstructive versus restrictive disease, and radiological characteristics are typically utilized to delineate these various organic dust-associated respiratory diseases. Prevention, risk reduction, and management primarily focus on reducing exposure to the offending dust, managing symptoms, and preventing disease progression.

PMID:38423290 | DOI:10.1016/j.jaip.2024.02.022

Chest. 2024 Feb 27:S0012-3692(24)00279-4. doi: 10.1016/j.chest.2024.02.043. Online ahead of print.

ABSTRACT

BACKGROUND: Previous studies have shown the importance of frailty in patients with fibrotic interstitial lung disease (ILD).

RESEARCH QUESTION: Is the Clinical Frailty Scale (CFS) a valid tool to improve risk stratification in patients with fibrotic ILD?

STUDY DESIGN AND METHODS: Patients with fibrotic ILD were included from the prospective multicenter Canadian Registry for Pulmonary Fibrosis. The CFS was assessed using available information from initial ILD clinic visits. Patients were stratified into fit (CFS 1-3), vulnerable (CFS 4), and frail (CFS 5-9) subgroups. Cox proportional hazards and logistic regression models with mixed effects were used to estimate time to death or lung transplantation. A derivation and validation cohort were used to establish prognostic performance. Trajectories of functional tests were compared using joint models.

RESULTS: Of the 1587 patients with fibrotic ILD, 858 (54%) were fit, 400 (25%) vulnerable and 329 (21%) frail. Frailty was a risk factor for early mortality (HR 5.58, 95%CI 3.64-5.76, p<0.001) in the entire cohort, in individual ILD diagnoses, and after adjustment for potential confounders. Adding frailty to established risk prediction parameters improved the prognostic performance in derivation and validation cohorts. Frail patients had larger annual declines in forced vital capacity (FVC) %-predicted compared to fit patients (-2.32 (95%CI -3.39 to -1.17) vs. -1.55 (95%CI -2.04 to -1.15); p=0.02, respectively).

INTERPRETATION: The simple and practical CFS is associated with pulmonary and physical function decline in patients with fibrotic ILD and provides additional prognostic accuracy in clinical practice.

PMID:38423280 | DOI:10.1016/j.chest.2024.02.043

Am J Respir Crit Care Med. 2024 Feb 29. doi: 10.1164/rccm.202309-1692OC. Online ahead of print.

ABSTRACT

RATIONALE: Distinguishing connective tissue disease associated interstitial lung disease (CTD-ILD) from idiopathic pulmonary fibrosis (IPF) can be clinically challenging.

OBJECTIVES: Identify proteins that separate and classify CTD-ILD from IPF patients.

METHODS: Four registries with 1247 IPF and 352 CTD-ILD patients were included in analyses. Plasma samples were subjected to high-throughput proteomics assays. Protein features were prioritized using Recursive Feature Elimination (RFE) to construct a proteomic classifier. Multiple machine learning models, including Support Vector Machine, LASSO regression, Random Forest (RF), and imbalanced-RF, were trained and tested in independent cohorts. The validated models were used to classify each case iteratively in external datasets.

MEASUREMENT AND MAIN RESULTS: A classifier with 37 proteins (PC37) was enriched in biological process of bronchiole development and smooth muscle proliferation, and immune responses. Four machine learning models used PC37 with sex and age score to generate continuous classification values. Receiver-operating-characteristic curve analyses of these scores demonstrated consistent Area-Under-Curve 0.85-0.90 in test cohort, and 0.94-0.96 in the single-sample dataset. Binary classification demonstrated 78.6%-80.4% sensitivity and 76%-84.4% specificity in test cohort, 93.5%-96.1% sensitivity and 69.5%-77.6% specificity in single-sample classification dataset. Composite analysis of all machine learning models confirmed 78.2% (194/248) accuracy in test cohort and 82.9% (208/251) in single-sample classification dataset.

CONCLUSIONS: Multiple machine learning models trained with large cohort proteomic datasets consistently distinguished CTD-ILD from IPF. Identified proteins involved in immune pathways. We further developed a novel approach for single sample classification, which could facilitate honing the differential diagnosis of ILD in challenging cases and improve clinical decision-making.

PMID:38422478 | DOI:10.1164/rccm.202309-1692OC

Respir Res. 2024 Feb 28;25(1):103. doi: 10.1186/s12931-024-02712-6.

ABSTRACT

BACKGROUND: The prognostic role of changes in body fat in patients with idiopathic pulmonary fibrosis (IPF) remains underexplored. We investigated the association between changes in body fat during the first year post-diagnosis and outcomes in patients with IPF.

METHODS: This single-center, retrospective study included IPF patients with chest CT scan and pulmonary function test (PFT) at diagnosis and a one-year follow-up between January 2010 and December 2020. The fat area (cm2, sum of subcutaneous and visceral fat) and muscle area (cm2) at the T12-L1 level were obtained from chest CT images using a fully automatic deep learning-based software. Changes in the body composition were dichotomized using thresholds dividing the lowest quartile and others, respectively (fat area: -52.3 cm2, muscle area: -7.4 cm2). Multivariable Cox regression analyses adjusted for PFT result and IPF extent on CT images and the log-rank test were performed to assess the association between the fat area change during the first year post-diagnosis and the composite outcome of death or lung transplantation.

RESULTS: In total, 307 IPF patients (69.3 ± 8.1 years; 238 men) were included. During the first year post-diagnosis, fat area, muscle area, and body mass index (BMI) changed by -15.4 cm2, -1 cm2, and - 0.4 kg/m2, respectively. During a median follow-up of 47 months, 146 patients had the composite outcome (47.6%). In Cox regression analyses, a change in the fat area < -52.3 cm2 was associated with composite outcome incidence in models adjusted with baseline clinical variables (hazard ratio [HR], 1.566, P = .022; HR, 1.503, P = .036 in a model including gender, age, and physiology [GAP] index). This prognostic value was consistent when adjusted with one-year changes in clinical variables (HR, 1.495; P = .030). However, the change in BMI during the first year was not a significant prognostic factor (P = .941). Patients with a change in fat area exceeding this threshold experienced the composite outcome more frequently than their counterparts (58.4% vs. 43.9%; P = .007).

CONCLUSION: A ≥ 52.3 cm2 decrease in fat area, automatically measured using deep learning technique, at T12-L1 in one year post-diagnosis was an independent poor prognostic factor in IPF patients.

PMID:38418966 | DOI:10.1186/s12931-024-02712-6

Am J Respir Crit Care Med. 2024 Feb 28. doi: 10.1164/rccm.202401-0203ED. Online ahead of print.

NO ABSTRACT

PMID:38417066 | DOI:10.1164/rccm.202401-0203ED

Front Pharmacol. 2024 Feb 13;15:1348708. doi: 10.3389/fphar.2024.1348708. eCollection 2024.

ABSTRACT

Background: The etiological underpinnings of gastroesophageal reflux disease (GERD) and idiopathic pulmonary fibrosis (IPF) remain elusive, coupled with a scarcity of effective therapeutic interventions for IPF. Angelicae sinensis radix (ASR, also named Danggui) is a Chinese herb with potential anti-fibrotic properties, that holds promise as a therapeutic agent for IPF. Objective: This study seeks to elucidate the causal interplay and potential mechanisms underlying the coexistence of GERD and IPF. Furthermore, it aims to investigate the regulatory effect of ASR on this complex relationship. Methods: A two-sample Mendelian randomization (TSMR) approach was employed to delineate the causal connection between gastroesophageal reflux disease and IPF, with Phennoscanner V2 employed to mitigate confounding factors. Utilizing single nucleotide polymorphism (SNPs) and publicly available microarray data, we analyzed potential targets and mechanisms related to IPF in GERD. Network pharmacology and molecular docking were employed to explore the targets and efficacy of ASR in treating GERD-related IPF. External datasets were subsequently utilized to identify potential diagnostic biomarkers for GERD-related IPF. Results: The IVW analysis demonstrated a positive causal relationship between GERD and IPF (IVW: OR = 1.002, 95%CI: 1.001, 1.003; p < 0.001). Twenty-five shared differentially expressed genes (DEGs) were identified. GO functional analysis revealed enrichment in neural, cellular, and brain development processes, concentrated in chromosomes and plasma membranes, with protein binding and activation involvement. KEGG analysis unveiled enrichment in proteoglycan, ERBB, and neuroactive ligand-receptor interaction pathways in cancer. Protein-protein interaction (PPI) analysis identified seven hub genes. Network pharmacology analysis demonstrated that 104 components of ASR targeted five hub genes (PDE4B, DRD2, ERBB4, ESR1, GRM8), with molecular docking confirming their excellent binding efficiency. GRM8 and ESR1 emerged as potential diagnostic biomarkers for GERD-related IPF (ESR1: AUCGERD = 0.762, AUCIPF = 0.725; GRM8: AUCGERD = 0.717, AUCIPF = 0.908). GRM8 and ESR1 emerged as potential diagnostic biomarkers for GERD-related IPF, validated in external datasets. Conclusion: This study establishes a causal link between GERD and IPF, identifying five key targets and two potential diagnostic biomarkers for GERD-related IPF. ASR exhibits intervention efficacy and favorable binding characteristics, positioning it as a promising candidate for treating GERD-related IPF. The potential regulatory mechanisms may involve cell responses to fibroblast growth factor stimulation and steroidal hormone-mediated signaling pathways.

PMID:38414734 | PMC:PMC10897002 | DOI:10.3389/fphar.2024.1348708

Int J Nanomedicine. 2024 Feb 23;19:1827-1842. doi: 10.2147/IJN.S444470. eCollection 2024.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a severe interstitial lung disease characterized by chronic lung injury leading to macrophage infiltration and fibroblast activation. However, there is no effective therapeutic strategy targeting the crucial crosstalk between macrophages and fibroblasts to halt IPF progression.

METHODS: Studies were conducted in IPF patients and fibrotic mice models to elucidate the role of Bcar3 in the pathogenesis of pulmonary fibrosis. The effect of Bcar3 on macrophage polarization, fibroblast activation, and related signaling pathways were next investigated to unravel the underlying mechanisms.

RESULTS: Our study elucidates a marked increase in Bcar3 expression in lung tissues from IPF patients and fibrotic mice, recording 1.7 and 7.8-fold increases compared to control subjects, respectively. Additionally, Bcar3 was found to significantly enhance macrophage activation and fibroblast differentiation, observable in both in vivo and in vitro settings. Mechanistically, the upregulation of Bcar3 in macrophages was reliant on Stat6, while in fibroblasts, it depended on TGFβR1/Smad3. Furthermore, Bcar3 augmented IL-4/Stat6 pathway in macrophages and TGF-β/Smad3 pathway in fibroblasts, supporting a synergistic activation loop that expedited lung fibrogenesis. Notably, intratracheal injection of liposomes containing Bcar3 siRNA precisely delivered gene therapeutics to lung macrophages and fibroblasts, effectively reducing Bcar3 expression to 59% of baseline levels. Importantly, this intervention protected mice from lung fibrosis induced by either FITC or bleomycin, as well as human precision-cut lung slices against TGF-β1 stimulation.

CONCLUSION: Our study underscores the pivotal role of Bcar3 in orchestrating the macrophage-fibroblast crosstalk during pulmonary fibrosis progression. Targeting Bcar3 emerges as a novel therapeutic avenue to halt IPF progression and enhance patient prognosis.

PMID:38414524 | PMC:PMC10898485 | DOI:10.2147/IJN.S444470

Ther Adv Respir Dis. 2024 Jan-Dec;18:17534666241232561. doi: 10.1177/17534666241232561.

ABSTRACT

BACKGROUND: Nintedanib and pirfenidone are preferred pharmacological therapies for patients with idiopathic pulmonary fibrosis (IPF). However, evidence favoring antifibrotic therapy in patients with non-IPF fibrosing interstitial lung diseases (ILD) is limited.

OBJECTIVE: To investigate the effects of antifibrotic therapy on disease progression, all-cause mortality, and acute exacerbation (AE) risk in patients with non-IPF fibrosing ILDs.

DESIGN: Meta-analysis.

DATA SOURCES AND METHODS: Electronic databases were searched for articles published before 28 February 2023. Studies that evaluated the efficacy of antifibrotic agents in patients with fibrosing ILDs were selected. The primary outcome was the disease progression risk, and the secondary outcomes included all-cause mortality and AE risk. The GRADE criteria were used for the certainty of evidence assessment.

RESULTS: Nine studies with 1990 participants were included. Antifibrotic therapy reduced the rate of patients with disease progression (five trials with 1741 subjects; relative risk (RR), 0.56; 95% CI, 0.42-0.75; p < 0.0001; I2 = 0; high-certainty evidence). Antifibrotic therapy did not significantly decrease all-cause mortality (nine trials with 1990 subjects; RR, 0.76; 95% CI, 0.55-1.03; p = 0.08; I2 = 0; low-certainty evidence). However, in patients with progressive fibrosing ILDs (PF-ILD), antifibrotic therapy decreased all-cause mortality (four trials with 1100 subjects; RR, 0.69; 95% CI, 0.48-0.98; p = 0.04; I2 = 0; low-certainty evidence).

CONCLUSION: Our study supports the use of antifibrotic agents in patients with PF-ILDs, which could slow disease progression and decrease all-cause mortality.

TRIAL REGISTRATION: This study protocol was registered with PROSPERO (registration number: CRD42023411272).

PMID:38414439 | DOI:10.1177/17534666241232561