J Med Chem. 2024 Oct 18. doi: 10.1021/acs.jmedchem.4c01580. Online ahead of print.

ABSTRACT

Traf2- and Nck-interacting kinase (TNIK) has been identified as a promising therapeutic target for the treatment of fibrosis-driven diseases. Utilizing a structure-based drug design workflow, we developed a series of potent TNIK inhibitors that modulate the conformation of the gatekeeper Met105 side chain and access the TNIK back pocket. The lead optimization efforts culminated in the discovery of the recently reported compound 4 (INS018_055), a novel TNIK inhibitor. This molecule demonstrated excellent activity in both enzymatic and cell-based assays, along with high selectivity in a kinome panel. Further, in vitro and in vivo preclinical studies revealed favorable in vitro and in vivo DMPK properties. Results from multiple cell-based and animal models proved that compound 4 exhibits considerable antifibrotic and anti-inflammatory efficacy. Currently, phase II clinical trials of compound 4 are underway for the treatment of idiopathic pulmonary fibrosis (IPF).

PMID:39422731 | DOI:10.1021/acs.jmedchem.4c01580

Eur J Med Res. 2024 Oct 18;29(1):501. doi: 10.1186/s40001-024-02107-9.

ABSTRACT

BACKGROUND: It is known severe influenza infections and idiopathic pulmonary fibrosis (IPF) disease might stimulate each other. Till now, no associated mechanism has been reported.

METHOD: We collected the genetic pattern of expression of severe influenza (GSE111368) and IPF (GSE70866) from the Gene Expression Omnibus (GEO) database. Common differentially expressed genes (C-DEGs) were identified from the two datasets, and using this data, we conducted three forms of analyses, functional annotation, protein-protein interaction (PPI) network and module construction, and hub gene identification and co-expression analysis.

RESULTS: In all, 174 C-DEGs were selected for additional analyses. Based on our functional analysis, these C-DEGs mediated inflammatory response and cell differentiation. Furthermore, using cytoHubba, we identified 15 genes, namely, MELK, HJURP, BIRC5, TPX2, TK1, CDT1, UBE2C, UHRF1, CCNA2, TYMS, CDCA5, CDCA8, RAD54L, CCNB2, and ITGAM, which served as hub genes to possibly contribute to severe influenza patients with IPF disease as comorbidity. The hub gene expressions were further confirmed using two stand-alone datasets (GSE101702 for severe influenza and GSE10667 for IPF).

CONCLUSION: Herein, we demonstrated the significance of common pathways and critical genes in severe influenza and IPF etiologies. The identified pathways and genes may be employed as possible therapeutic targets for future therapy against severe influenza patients with IPF.

PMID:39420432 | DOI:10.1186/s40001-024-02107-9

PLoS One. 2024 Oct 17;19(10):e0312044. doi: 10.1371/journal.pone.0312044. eCollection 2024.

ABSTRACT

INTRODUCTION: We assessed the prognostic utility of circulating levels of matrix metalloproteinases (MMPs) and tissue inhibitors of matrix metalloproteinases (TIMPs) in patients with idiopathic pulmonary fibrosis (IPF) in the IPF-PRO Registry.

METHODS: MMP and TIMP concentrations were quantified by ELISA in plasma from 300 patients. A Cox proportional hazard regression model was used to assess associations between select MMPs and TIMPs and death and disease progression (absolute decline in forced vital capacity ≥10% predicted, death, or lung transplant).

RESULTS: Over a median follow-up of 30.4 months, 98 patients died and 182 patients had disease progression. In unadjusted analyses, higher concentrations of MMPs 2, 3, 8 and 9 and TIMPs 1, 2 and 4 were associated with an increased risk of death. MMPs 2 and 8 and TIMP1 remained associated with death after adjustment for clinical factors. In unadjusted analyses, higher concentrations of MMPs 8 and 9 and TIMPs 1 and 4 were associated with an increased risk of disease progression. MMPs 8 and 9 and TIMP1 remained associated with progression after adjustment for clinical factors.

CONCLUSION: Circulating levels of MMP8 and TIMP1 may provide information on the risk of outcomes in patients with IPF not captured by clinical measures.

PMID:39418259 | DOI:10.1371/journal.pone.0312044

Rheumatology (Oxford). 2024 Oct 17:keae573. doi: 10.1093/rheumatology/keae573. Online ahead of print.

ABSTRACT

OBJECTIVES: The MUC5B promoter single nucleotide polymorphism (SNP) rs35705950 has been associated with idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis (RA)-related interstitial lung disease (ILD), but not with systemic sclerosis (SSc)-ILD. We hypothesized that the MUC5B promoter polymorphism or other IPF susceptibility loci are associated with an increased risk for the uncommon SSc-usual interstitial pneumonia (UIP) endophenotype, rather than SSc-ILD in general.

METHODS: We performed a cross-sectional study of SSc-ILD patients from 4 US Scleroderma Programs to investigate the frequency of MUC5B rs35705950 and 12 additional IPF susceptibility loci. SSc-ILD patients were stratified by high resolution chest CT (HRCT) imaging findings into UIP and non-UIP groups. Analysis of HRCTs performed by a thoracic radiologist blinded to participants' characteristics classified each scan as definite UIP, probable UIP, indeterminate, or alternative diagnosis, according to American Thoracic Society criteria.

RESULTS: Four-hundred eighty-nine SSc-ILD patients were included; 80% were female and 75% were White. Twenty-three (4.7%) patients had a definite UIP pattern. The MUC5B SNP rs35705950 was not associated with a definite UIP pattern in SSc-ILD. In contrast, patients carrying 2 copies of the IPF risk gene FAM13A minor allele rs2609255 had significantly higher odds of a definite UIP pattern compared with the other patterns (OR 3.40, 95% CI 1.19-9.70), and compared with an alternative diagnosis (OR 3.65, 95% CI 1.25-10.65).

CONCLUSION: We demonstrated a novel association between FAM13A and SSc-UIP. Contrary to IPF and RA-ILD, the MUC5B promoter polymorphism was not associated with a definite UIP pattern in SSc-ILD.

PMID:39418199 | DOI:10.1093/rheumatology/keae573

Ther Adv Respir Dis. 2024 Jan-Dec;18:17534666241280704. doi: 10.1177/17534666241280704.

ABSTRACT

BACKGROUND: Real-world data on the use, healthcare resource utilization (HCRU), and associated costs of antifibrotic therapies in patients with idiopathic pulmonary fibrosis (IPF) are limited.

OBJECTIVES: To assess the prevalence of antifibrotic treatment, characteristics of patients receiving treatment, discontinuation rates, and HCRU and costs associated with treatment.

DESIGN: This retrospective study analyzed de-identified longitudinal and cross-sectional data, respectively, from two US claims databases: Optum's de-identified Clinformatics® Data Mart Database (CDM; commercial claims, Medicare Advantage) and the Veterans Health Administration (VHA) database. The study periods were October 1, 2013-March 31, 2019 and October 1, 2014-September 30, 2019, respectively. Eligible individuals were adults with ⩾1 diagnosis claim for IPF.

METHODS: Antifibrotic prevalence, patient demographics, treatment discontinuation rates, and HCRU and costs were determined separately for each cohort and described using summary statistics. Bivariate comparisons were analyzed using Chi-square and Student's t-tests for categorical and continuous variables, respectively.

RESULTS: Overall, 4223 and 4459 eligible patients were identified in the CDM and VHA databases, respectively. Prevalence of antifibrotic uptake was 9.2% and 29.1% and the rate of index treatment discontinuation was 47% and 66% during follow-up in the CDM and VHA cohorts, respectively. Antifibrotic-treated patients were significantly younger (p < 0.0001) with lower mean Charlson Comorbidity Index scores at baseline versus untreated patients in both cohorts. In the CDM cohort, the number of outpatient and pharmacy visits was significantly higher in treated versus untreated patients during follow-up (both p < 0.0001). A similar trend was observed for the VHA cohort. Total follow-up costs in both cohorts were significantly higher in treated versus untreated patients due to higher pharmacy costs (CDM; p < 0.0001) or higher outpatient and pharmacy costs (VHA; p < 0.0001).

CONCLUSION: The low prevalence of antifibrotic usage in both cohorts, together with the high rate of antifibrotic discontinuation, and increased HCRU and costs in treated versus untreated patients, support the need for novel treatment options for IPF.

TRIAL REGISTRATION: Not applicable.

PMID:39418137 | DOI:10.1177/17534666241280704

J Cell Mol Med. 2024 Oct;28(20):e70157. doi: 10.1111/jcmm.70157.

ABSTRACT

Lung cancer is the leading cause of cancer-related deaths worldwide. Patients with lung cancer usually exhibit poor prognoses and low 5-year survival rates. Idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) are both chronic lung dysfunctions resulting in lung fibrosis and increased risk of lung cancer. Myofibroblasts contribute to the progression of asthma, COPD and IPF, leading to fibrosis in the airway and lungs. A growing body of evidence demonstrates that metabolic reprogramming is a major hallmark of fibrosis, being important in the progression of fibrosis. Using gene expression microarray, we identified and validated that the lipid metabolic pathway was upregulated in lung fibroblasts upon interleukin (IL)-4, IL-13 and tumour necrosis factor (TNF)-α treatment. In this study, we described that prostaglandin E synthase (PTGES) was upregulated in lung fibroblasts after IL-4, IL-13 and TNF-α treatments. PTGES increased α-SMA levels and promoted lung fibroblast cell migration and invasion abilities. Furthermore, PTGES was upregulated in a lung fibrosis rat model in vivo. PTGES increased AKT phosphorylation, leading to activation of the HIF-1α-glycolysis pathway in lung fibroblast cells. HIF-1α inhibitor or 2-DG treatments reduced α-SMA expression in recombinant PTGES (rPTGES)-treated lung fibroblast cells. Targeting PGE2 signalling in PTGES-overexpressing cells by a PTGES inhibitor reduced α-SMA expression. In conclusion, the results of this study demonstrate that PTGES increases the expression of myofibroblast marker via HIF-1α-dependent glycolysis and contributes to myofibroblast differentiation.

PMID:39417702 | DOI:10.1111/jcmm.70157

Postgrad Med J. 2024 Oct 17:qgae144. doi: 10.1093/postmj/qgae144. Online ahead of print.

ABSTRACT

BACKGROUND: To determine the conditions that prevented transplant in patients referred to our center due to end-stage lung disease.

STUDY DESIGN: Descriptive study.

PLACE AND DURATION OF THE STUDY: Department of lung transplant clinic, Koşuyolu High Specialization Education and Research Hospital, Istanbul, Turkey, from December 2017 to January 2022.

METHODS: Patients with end-stage lung disease referred to our clinic were retrospectively evaluated with regard to reasons for exclusion, diagnosis, and demographic data. The Karnofsky Performance Status scoring scale was used to measure the functional status of the patients.

RESULTS: A total of 311 patients were evaluated during the study period. The mean age was 44.2 (range 4-73) years. There were 207 (66.6%) male patients. The most common indications were idiopathic interstitial pneumonia in 104 (33.4%) patients, chronic obstructive pulmonary disease in 53 (17%) patients, bronchiectasis in 49 (15.7%) patients, and cystic fibrosis in 28 (9%) patients. Of the patients, 106 (34%) were not appropriate candidates for a lung transplant. The most common reasons for refusal were preventable situations such as activity limitation and poor performance in 53 (50%) patients, weight in 49 (46.2%) patients, and smoking in 10 (9.4%) patients.

CONCLUSION: Impaired performance status was the most common cause of lung transplant exclusion. Weight and smoking were preventable causes of exclusion. Implementing pulmonary rehabilitation in very few patients was the most important handicap. It is believed that providing optimal treatment with a multidisciplinary approach and timely referral to transplant centers will significantly reduce the reasons for exclusion. Key message What is already known on this topic? Referring lung transplant candidates to clinics at the earliest stage is essential for assessing their condition and exploring treatment options. What this study adds? Factors like smoking, obesity, and muscle loss can hinder the transplantation process; thus, timely interventions are crucial. The primary reason for excluding candidates from lung transplantation is the decline in performance status. How this study might affect research, practice or policy? Programs focused on smoking cessation, weight management, and muscle strengthening can play a vital role in enhancing patients' health before transplantation. It is imperative to expand and enhance the accessibility of pulmonary rehabilitation programs.

PMID:39417288 | DOI:10.1093/postmj/qgae144

Heliyon. 2024 Sep 20;10(19):e38122. doi: 10.1016/j.heliyon.2024.e38122. eCollection 2024 Oct 15.

ABSTRACT

OBJECTIVE: We used evidence-based medicine, bioinformatics and experimental verification to comprehensively analyze the efficacy and pharmacological mechanism of Xuefu Zhuyu decoction (XFZYD) in the treatment of idiopathic pulmonary fibrosis (IPF).

METHODS: Major databases were retrieved for randomized controlled trials (RCTs) of XFZYD treating IPF to perform meta-analysis. Active ingredients and target genes of XFZYD were identified from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). IPF-related differentially expressed genes (DEGs) were identified from the Gene Expression Omnibus (GEO) database. The RGUI software was utilized for Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. The ingredient-target and protein-protein interaction (PPI) networks were achieved through Cytoscape software and the STRING database to identify the key compounds and target proteins. Molecular docking was performed using AutoDockTool and AutoDock Vina software. The effect between key compounds and target proteins was verified in animal experiments.

RESULTS: Six RCTs were included for meta-analysis, which uncovered that the total effective rate of clinical efficacy was higher in the experimental group than control group. Then, 156 active ingredients and 254 target genes of XFZYD, and 1,566 IPF-related DEGs were identified. The intersection analysis identified 48 target genes correlating with 130 active ingredients of XFZYD treating IPF. GO functional enrichment, KEGG pathway enrichment, ingredient-target network and PPI network were achieved. Following the identification of key compounds and target proteins, we performed molecular docking. Ultimately, our research focused on the key compound quercetin for experimental validation to assess its interactions with two key target proteins, JUN and PTGS2.

CONCLUSION: The effectiveness of XFZYD on IPF has been substantiated through evidence-based medicine. The pharmacological mechanism of XFZYD for IPF treatment involves a complex interplay of various compounds and targets, with quercetin exerting pronounced impacts on JUN and PTGS2 proteins.

PMID:39416822 | PMC:PMC11481653 | DOI:10.1016/j.heliyon.2024.e38122

Ther Adv Respir Dis. 2024 Jan-Dec;18:17534666241288417. doi: 10.1177/17534666241288417.

ABSTRACT

Fibrosing interstitial lung diseases (FILDs) other than idiopathic pulmonary fibrosis (IPF) can develop into progressive pulmonary fibrosis (PPF) despite initial management. A substantial proportion of patients with non-IPF interstitial lung diseases (ILDs) progress to PPF, including connective tissue disease-associated ILD (such as rheumatoid arthritis-associated ILD, systemic sclerosis-associated ILD, and idiopathic inflammatory myositis-associated ILD), fibrosing hypersensitivity pneumonitis, and fibrosing occupational ILD. The concept of PPF emerged only recently and several studies have confirmed the impact of PPF on mortality. In addition to poor prognosis among patients with PPF, there remains a lack of consensus in the diagnosis and treatment of PPF across different types of ILDs. There is a need to raise awareness of PPF in FILDs and to explore measures to improve PPF diagnosis and treatment, which in turn could potentially reduce the progression from FILD to PPF. This review discusses the disease burden of PPF and recent advances in the management of PPF among patients with ILDs, including antifibrotic medications that have emerged as promising treatment options. Additionally, this review highlights the perspectives of expert Chinese physicians with regard to their experience in managing PPF in clinical practice.

PMID:39415340 | DOI:10.1177/17534666241288417

Sci Total Environ. 2024 Oct 14:176938. doi: 10.1016/j.scitotenv.2024.176938. Online ahead of print.

ABSTRACT

As revealed by culture-independent methodologies, disruption of the normal lung microbiota (LM) configuration (LM dysbiosis) is a potential mediator of adverse effects from inhaled chemicals. LM, which consists of microbiota in the upper and lower respiratory tract, is influenced by various factors, including inter alia environmental exposures. LM dysbiosis has been associated with multiple respiratory pathologies such as asthma, lung cancer, idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). Chemically-induced LM dysbiosis appears to play significant roles in human respiratory diseases, as has been shown for some air pollutants, cigarette smoke and some inhalable chemical antibiotics. Lung microbiota are also linked with the central nervous system (CNS) in the so-called lung-brain axis. Inhaled chemicals that undergo mucociliary clearance may be linked to respiratory conditions through gut microbiota (GM) dysbiosis in the so-called Gut-Lung axis. However, current linkages of various disease states to LM appears to be associative, with causal linkages requiring further studies using more robust approaches, methods and techniques that are different from those applied in studies involving (GM). Most importantly, the sampling techniques determine the level of risk of cross contamination. Furthermore, the development of continuous or semi-continuous systems designed to replicate the lung microbiome will go a long way to further LM dysbiosis studies. These challenges notwithstanding, the preponderance of evidence points to the significant role of LM-mediated chemical toxicity in human disease and conditions.

PMID:39414049 | DOI:10.1016/j.scitotenv.2024.176938

Respir Med Res. 2024 Oct 5;86:101141. doi: 10.1016/j.resmer.2024.101141. Online ahead of print.

ABSTRACT

INTRODUCTION: The impact of physical activity on the incidence of idiopathic pulmonary fibrosis (IPF) remains less well studied. This study aimed to investigate the relationship between moderate-to-vigorous physical activity (MVPA) and the risk of developing IPF.

METHODS: We analyzed data from a prospective cohort study within the UK Biobank involving 502,476 participants. Participants were categorized as meeting or not meeting the 2017 UK Physical Activity Guidelines (150 min of moderate activity or 75 min of vigorous activity per week). The cumulative incidence and hazard ratios (HRs) for IPF were analyzed using the Kaplan-Meier method, log-rank test, and Cox regression. Two-sample Mendelian randomization (MR) analyses were performed to identify potential causal links between physical activity and IPF risk.

RESULTS: Over a median of 12.2 y follow-up, we identified 1,639 incident IPF cases and 395,172 controls. Individuals who met the physical activity guidelines had a significantly lower risk of IPF than those who did not meet the guidelines (adjusted HR = 0.843, 95 % confidence interval [CI] = 0.765-0.930).The cumulative incidence of IPF was lower in the meeting guideline group than in the nonmeeting guideline group (Log-rank P = 0.0019). Two-sample MR analysis revealed that a 1-standard deviation increase in moderate-to-vigorous physical activity was linked to a reduced IPF risk (odds ratio [OR] = 0.17, 95 % CIs = 0.04 to 0.81, P = 0.026). Moreover, an increase in the number of days per week of moderate physical activity was genetically correlated with decreased IPF risk (OR = 0.32, 95 % CIs = 0.15-0.70, P = 0.003).

CONCLUSION: Higher levels of moderate-to-vigorous physical activity are causally associated with a significant reduction in the risk of developing IPF.

PMID:39413579 | DOI:10.1016/j.resmer.2024.101141

Rheumatology (Oxford). 2024 Oct 16:keae572. doi: 10.1093/rheumatology/keae572. Online ahead of print.

ABSTRACT

OBJECTIVES: Though interstitial lung disease (ILD) contributes to excess morbidity and mortality in rheumatoid arthritis (RA), RA-ILD pathogenesis remains incompletely defined. As intermediate, non-classical and suppressed CD14+ monocytes are expanded in RA-ILD, this study sought to characterize gene expression profiles of circulating monocytes in RA-ILD.

METHODS: Peripheral blood mononuclear cells were collected from patients with RA without lung disease (N = 5), RA-ILD (N = 5), idiopathic pulmonary fibrosis (IPF; N = 5), and controls without lung and autoimmune disease (N = 4). RNA was extracted from CD14+ isolated monocytes and subjected to transcriptional analysis of 1365 genes. Gene enrichment and pathway analyses were performed.

RESULTS: Unsupervised clustering grouped patients with RA-ILD together with IPF for myeloid innate genes. For fibrosis genes, patients with RA-ILD clustered independent of comparator groups. There were 103, 66, and 64 upregulated and 66, 14, and 25 downregulated genes for RA-ILD, RA, and IPF, vs controls, respectively. For RA-ILD, there was increased expression of genes involved in regulating inflammation and fibrosis (SOCS3, CECAM1, LTB4R2, CLEC7A, IRF7, PHYKPL, GBP5, RAPGEF), epigenetic modification (KDM5D, KMT2D, OGT), and macrophage activation. Top canonical pathways included macrophage differentiation-activation, IL-12, neuroinflammatory, glucocorticoid receptor, and IL-27 signalling.

CONCLUSIONS: Circulating monocytes in RA-ILD patients demonstrate unique gene expression profiles with innate immune gene features more aligned with IPF as opposed to RA in the absence of clinical lung disease with fibrosis gene expression that was distinct from RA and IPF. These studies are important for understanding disease pathogenesis and may provide information for future therapeutic targets in RA-ILD.

PMID:39412518 | DOI:10.1093/rheumatology/keae572

Monaldi Arch Chest Dis. 2024 Oct 15. doi: 10.4081/monaldi.2024.3070. Online ahead of print.

ABSTRACT

COVID-19 has a negative impact on the survival of respiratory patients, especially those with interstitial lung disease. This review aims to better understand the effect of COVID-19 on patients with idiopathic pulmonary fibrosis (IPF). A systematic search of MEDLINE, PubMed, Embase, and Scopus performed from December 2019 up to July 2024 identified relevant studies. Eligibility criteria included English language, sample size ≥10 patients, COVID-19 infection and outcome measures. Two independent reviewers assessed studies using the Newcastle-Ottawa Scale for bias and extracted data. Meta-analysis employed a random-effects model, and the Grading of Recommendations Assessment, Development and Evaluation assessed evidence quality. Outcomes considered were hospitalization, intensive care unit admission, and mortality. Of the 1541 initially identified articles, 6 high-quality studies were included. Meta-analysis revealed a 34% mortality rate [95% confidence interval (CI): 21-48%], 36% hospitalization rate (95% CI: 10-75%), and 31% ICU admission rate (95% CI: 7-71%) among IPF patients with COVID-19. The certainty of evidence was low or very low due to publication bias and heterogeneity. This study underscores the elevated risk of hospitalization and death in IPF patients with COVID-19, emphasizing the vulnerability of this population. Prompt and tailored care is crucial to mitigate the impact of COVID-19 on IPF patients, necessitating proactive measures, vaccination, and comprehensive management.

PMID:39410827 | DOI:10.4081/monaldi.2024.3070

J Clin Med. 2024 Oct 2;13(19):5874. doi: 10.3390/jcm13195874.

ABSTRACT

Background: The advanced lung cancer inflammation index (ALI) is an innovative and thorough measure designed to assess both inflammation and nutritional status. It includes parameters such as albumin, body mass index (BMI), and the neutrophil-to-lymphocyte ratio (NLR). This research seeks to evaluate the prognosis of idiopathic pulmonary fibrosis (IPF) patients by integrating both inflammation and nutritional status, distinguishing it from conventional inflammation biomarkers. Methods: This study included 102 patients with IPF. Clinical data were extracted from the patients' medical records. NLR and ALI scores were calculated based on data collected at the initiation of antifibrotic treatment using the following formulas: Neut/Lym for NLR and albumin × BMI/NLR for ALI. Results: ALI values were assessed across various IPF patient subgroups based on gender-age-physiology (GAP) stages (1, 2, and 3), forced vital capacity (FVC) (median split: <70% vs. ≥70%), diffusing capacity for carbon monoxide (DLCO) (<51% vs. ≥51%), 6-Minute Walk Test (6MWT) (<350 vs. ≥350), and the Charlson comorbidity index (CCI) (≤1 vs. >1). Significant differences in ALI were observed with respect to GAP stages, FVC, DLCO, and 6MWT categories (p = 0.000 for all), but not for CCI categories (p = 0.233). Receiver operating characteristic (ROC) curve analysis revealed that ALI had a sensitivity of 63.6% and a specificity of 98.9% at a threshold of 11.2 (AUC = 0.945, 95% CI 0.892-0.998, p < 0.000). Conclusions: Our findings indicate that ALI levels are significantly associated with disease severity and mortality in IPF patients.

PMID:39407934 | DOI:10.3390/jcm13195874

J Clin Med. 2024 Sep 26;13(19):5733. doi: 10.3390/jcm13195733.

ABSTRACT

Background/Objectives: Acute exacerbation (AE) of interstitial lung disease (ILD) is a major challenge. This study aimed to retrospectively investigate occurrences of AEs in patients with ILDs, including idiopathic pulmonary fibrosis (IPF), non-IPF (iNSIP: idiopathic nonspecific interstitial pneumonia), and connective tissue disease (CTD)-associated ILDs (CTD-ILDs), at a single tertiary center before and after the coronavirus disease 2019 (COVID-19) pandemic. The study aimed to clarify the seasonal and regional trends of AEs of ILDs, assess the roles of viral and bacterial infections, and identify key prognostic factors for patient outcomes. Methods: We conducted a retrospective review of hospitalized adult patients with AEs of ILDs from January 2019 to February 2024. Results: A total of 93 patients were enrolled: IPF (n = 42), iNSIP (n = 37), and CTD-ILDs (n = 14). The median age was 80 years (interquartile range: 74.0-86.0 years), with males comprising 64.5% (n = 60). AEs of ILDs predominantly occurred in winter and were particularly notable after summer 2023, coinciding with the lifting of COVID-19-related travel restrictions in Japan. Patient referrals from different areas (Northern Tama, East and/or Southern Tama, and other Tokyo metropolitan areas) were evenly distributed throughout the study period. Viral infections were detected in only two patients (SARS-CoV-2), and bacterial infections included methicillin-resistant Staphylococcus aureus and Pseudomonas aeruginosa. The Cox regression analysis identified serum lactate dehydrogenase levels ≥350 IU/L and tachypnea (respiratory rate ≥ 30 breaths per min) on admission as prognostic factors for mortality, with a hazard ratio [HR] of 2.783 (95% confidence interval [CI]: 1.480-5.235, p = 0.001) and an HR of 3.332 (95% CI: 1.710-6.492, p < 0.001), respectively. Conclusions: AEs of ILDs predominantly occur in winter, and viral and bacterial infections are infrequently detected. Elevated serum LDH levels and tachypnea are crucial prognostic markers for mortality. This study highlights the seasonal trend in the AE of ILD and emphasizes the importance of specific prognostic indicators in clinical practice.

PMID:39407792 | DOI:10.3390/jcm13195733

Results Probl Cell Differ. 2024;74:257-290. doi: 10.1007/978-3-031-65944-7_10.

ABSTRACT

Macrophages are key regulators of tissue repair and fibrosis. Following injury, macrophages undergo marked phenotypic and functional changes to play crucial roles throughout the phases of tissue repair. Idiopathic Pulmonary Fibrosis, which is the most common fibrosing lung disease, has been described as an aberrant reparative response to repetitive alveolar epithelial injury in a genetically susceptible aging individual. The marked destruction of the lung architecture results from the excessive secretion of extracellular matrix by activated fibroblasts and myofibroblasts. Accumulating evidence suggests that macrophages have a pivotal regulatory role in pulmonary fibrosis. The origins and characteristics of macrophages in the lung and their role in regulating lung homeostasis, repair, and fibrosis are reviewed herein. We discuss recent studies that have employed single-cell RNA-sequencing to improve the identification and characterization of macrophage populations in the context of homeostatic and fibrotic conditions. We also discuss the current understanding of the macrophage-mediated mechanisms underlying the initiation and progression of pulmonary fibrosis, with a focus on the phenotypic and functional changes that aging macrophages acquire and how these changes ultimately contribute to age-related chronic lung diseases.

PMID:39406909 | DOI:10.1007/978-3-031-65944-7_10

Results Probl Cell Differ. 2024;74:239-256. doi: 10.1007/978-3-031-65944-7_9.

ABSTRACT

Our understanding of the origin, phenotype, and function of pulmonary macrophages has evolved over recent years. The use of lineage tracing and single-cell RNA sequencing has led to a greater understanding of how these cells regulate homeostasis in the lung. The primary function of alveolar macrophages is to clear any inhaled particles or pathogens and they as well as tissue-resident cells also play a role in the clearance of apoptotic cells and the resolution of inflammation. Lung diseases affect over half a billion people globally and are attributable to 7% of all deaths each year. The common diseases are chronic obstructive pulmonary disease (COPD) and asthma but others that contribute to this statistic include cystic fibrosis and idiopathic pulmonary fibrosis (IPF). Macrophages are aberrant in all these diseases with a reduced phagocytic capacity and a high proinflammatory phenotype with changes to their capacity to resolve inflammation. The pathways leading to these macrophage dysfunctions differ with disease and may relate to the specific lung environment in each condition. However, there are clear changes in metabolic profiles and mitochondrial activity in many of these conditions that contribute to a change in macrophage phenotype towards a more proinflammatory, less homeostatic cell. Understanding the mechanisms that drive these changes will allow for more targeted therapies for the treatment of these long-term and debilitating conditions.

PMID:39406908 | DOI:10.1007/978-3-031-65944-7_9

Am J Physiol Lung Cell Mol Physiol. 2024 Oct 15. doi: 10.1152/ajplung.00182.2024. Online ahead of print.

ABSTRACT

The IPF lung contains mesenchymal progenitor cells (MPCs) that display durable activation of oncogenic signaling and cell-autonomous fibrogenicity in vivo. Prior work identified a CD44/Brg1/PRMT5 nuclear regulatory module in IPF MPCs that increased expression of genes positively regulating pluripotency and self-renewal. Left unanswered is how IPF MPCs evade negative regulation of self-renewal. Here we sought to identify mechanisms disabling negative regulation of self-renewal in IPF MPCs. We demonstrate that expression of the tumor suppressor genes rbl1 and pten is decreased in IPF MPCs. The mechanism involves CD44-facilitated association of the chromatin remodeler Brg1 with the histone modifying methyltransferase PRMT5. Brg1 enhances chromatin accessibility leading to PRMT5-mediated methylation of H3R8 and H4R3 on the rbl1 and pten genes, repressing their expression. Genetic knock-down or pharmacological inhibition of either Brg1 or PRMT5 restored RBL1 and PTEN expression, reduced IPF MPC self-renewal in vitro and inhibited IPF MPC-mediated pulmonary fibrosis in vivo. Our studies indicate that the CD44/Brg1/PRMT5 regulatory module not only functions to activate positive regulators of pluripotency and self-renewal, but also functions to repress tumor suppressor genes rbl1 and pten. This confers IPF MPCs with the cancer-like property of cell-autonomous self-renewal providing a molecular mechanism for relentless fibrosis progression in IPF.

PMID:39406384 | DOI:10.1152/ajplung.00182.2024

JCI Insight. 2024 Oct 15:e178381. doi: 10.1172/jci.insight.178381. Online ahead of print.

ABSTRACT

Hermansky-Pudlak syndrome (HPS), particularly in types 1 and 4, is characterized by progressive pulmonary fibrosis, a major cause of morbidity and mortality. However, the precise mechanisms driving pulmonary fibrosis in HPS are not fully elucidated. Our previous studies suggested that CHI3L1-driven fibroproliferation may be a notable factor in HPS-associated fibrosis. This study aimed to explore the role of CHI3L1-CRTH2 interaction on ILC2s and explored the potential contribution of ILC2-fibroblast crosstalk in the development of pulmonary fibrosis in HPS. We identified ILC2s in lung tissues from idiopathic pulmonary fibrosis (IPF) and HPS patients. Using bleomycin-challenged wild type (WT) and Hps1-/- mice we observed that ILC2s were recruited and appeared to contribute to fibrosis development in the Hps1-/- mice, with CRTH2 playing a notable role in ILC2 accumulation. We sorted ILC2s, profiled fibrosis-related genes and mediators, and conducted co-culture experiments with primary lung ILC2s and fibroblasts. Our findings suggest that ILC2s may directly stimulate the proliferation and differentiation of primary lung fibroblasts partially through Amphiregulin-EGFR-dependent mechanisms. Additionally, specific overexpression of CHI3L1 in the ILC2 population using the IL-7Rcre driver, which was associated with increased fibroproliferation, indicates that ILC2-mediated, CRTH2-dependent mechanisms might contribute to optimal CHI3L1-induced fibroproliferative repair in HPS-associated pulmonary fibrosis.

PMID:39405112 | DOI:10.1172/jci.insight.178381

Ann Am Thorac Soc. 2024 Oct 15. doi: 10.1513/AnnalsATS.202404-430RL. Online ahead of print.

NO ABSTRACT

PMID:39404835 | DOI:10.1513/AnnalsATS.202404-430RL