Pharmaceuticals (Basel). 2024 Sep 26;17(10):1275. doi: 10.3390/ph17101275.

ABSTRACT

BACKGROUND/OBJECTIVES: Nintedanib (NTD), a triple tyrosine kinase receptor inhibitor, is the recommended first-line tackling option for idiopathic pulmonary fibrosis (IPF). Nevertheless, the adequacy of NTD is curtailed by issues associated with its low solubility, first-pass effect, poor bioavailability, and liver toxicity. The objective of our work was to develop a non-invasive intratracheal (i.t.) nanoparadigm based on NTD-loaded polymeric mixed micelles (NTD-PMMs) that can effectively treat IPF by sustaining the release of NTD, and snowballing its bioavailability, solubility, and efficacy.

METHODS: Design-Expert® software was used to optimize various NTD-PMMs formulations via Box-Behnken design adopting the thin-film hydration technique. The optimum formulation was chosen and in vivo tested in a rat model to explore its comparative bioavailability and toxicity.

RESULTS: The formulation composition with 309.217 mg of Soluplus, 150 mg of Tween 80, and 40 mg of sodium deoxycholate was found to fulfill the requisites of an optimum NTD-PMMs formulation. The optimum NTD-PMMs formulation divulged 90.26% entrapment efficiency with a surface charge of -14.72 mV and a nanoscale diameter of 61.36 nm. Also, it substantially sustained the release of NTD by 66.84% after 24 h and manifested a pronounced stability. In vivo histopathology investigations verified the safety of NTD-PMMs delivered intratracheally. Moreover, pharmacokinetic analyses disclosed accentuated relative bioavailability of the optimized NTD-PMMs by 2.4- and 3.82-fold as compared with both the i.t. and oral crude NTD suspensions, respectively.

CONCLUSIONS: Overall, the current results elicited the potential of PMMs to serve as a promising pulmonary nanovector for the targeted delivery of NTD.

PMID:39458916 | DOI:10.3390/ph17101275

J Clin Med. 2024 Oct 19;13(20):6247. doi: 10.3390/jcm13206247.

ABSTRACT

Background/Objectives: Pulmonary diseases are common in patients with thoracic aortic aneurysm (TAA) and abdominal aortic aneurysm (AAA). Although high prevalences of chronic obstructive pulmonary disease and lung cancer (LC) are known, the prevalence of these and other pulmonary diseases regarding their relation to the outcome of TAA and/or AAA are not determined. Methods: Pulmonary diseases present at aortic aneurysm (AA) diagnosis and follow-up periods and cause of death of 952 patients with TAA, AAA, or TAA + AAA (including thoracoabdominal AA) treated at our institution in Japan were retrospectively analyzed. Cox regression analysis was used to investigate potential risk factors of mortality. Results: The mean patient age was 72.4 years, and the median follow-up was 4.92 years. At diagnosis, 528 (55.5%) patients had pulmonary diseases, including emphysema without interstitial lung disease (ILD) or LC, LC, idiopathic pulmonary fibrosis (IPF) without LC, non-IPF ILD without LC, and interstitial lung abnormalities (ILAs) without LC in 250, 85, 65, 15, and 58 patients, respectively. During follow-up, LC and acute exacerbation (AE) of IPF developed in 50 and 12 patients, respectively. In 213 patients who died, there were 45 (21.1%) aortic disease-related deaths. Other causes of death included LC (27.7%), cardiovascular events (9.4%), pneumonia (5.6%), and interstitial lung disease (4.7%). In a multivariate Cox regression hazard model, age; larger maximum aneurysm diameter; and coexisting LC, IPF, or concomitant cancer were associated with poor prognosis. Conclusions: In patients with AA, not only age and aneurysm diameter but also coexisting LC and IPF were prognostic factors for mortality.

PMID:39458197 | DOI:10.3390/jcm13206247

J Clin Med. 2024 Oct 16;13(20):6159. doi: 10.3390/jcm13206159.

ABSTRACT

Background: The presence of the rs35705950 variant in the MUC5B gene promoter is a critical genetic risk factor in idiopathic pulmonary fibrosis (IPF). It has been associated with usual interstitial pneumonia (UIP) in several interstitial lung diseases (ILDs). In antisynthetase syndrome (ASSD), most high-resolution computed tomography (HRCT) patterns are inflammatory, but up to 13% have UIP, leading to a worse prognosis. Methods: This single-center study included 60 patients with ASSD-ILD. We investigated whether carrying the MUC5B rs35705950 promoter variant was associated with UIP. To estimate the strength of the association between the genotype of the MUC5B rs35705950 promoter variant and the fibrotic pattern we used the odds ratio (cOR), and to assess the effect of confounding variables (age, evolution time, and sex), we performed a logistic regression to obtained the adjusted odds ratio (aOR). Results: The GT genotype of the MUC5B rs35705950 promoter variant is associated with up to a 4-fold increased risk of UIP (cOR 5.0, 95% CI 1.13-22.10), and the effect was even maintained after adjusting for potentially confounding variables such as sex, age, and time to progression (aOR 5.2, 95% CI 1.04-25.89). Conclusions: our study supports the role of MUC5B rs35705950 in ASSD-ILD with UIP. It reinforces that this polymorphism in our population could have a similar genetic basis to that already described in other ILDs that present predominantly fibrotic patterns.

PMID:39458109 | DOI:10.3390/jcm13206159

Biomedicines. 2024 Oct 18;12(10):2382. doi: 10.3390/biomedicines12102382.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) leads to excessive fibrous tissue in the lungs, increasing the risk of lung cancer (LC) due to heightened fibroblast activity. Advances in nucleotide point mutation studies offer insights into fibrosis-to-cancer transitions. Methods: A two-sample Mendelian randomization (TSMR) approach was used to explore the causal relationship between IPF and LC. A weighted gene co-expression network analysis (WGCNA) identified shared gene modules related to immunogenic cell death (ICD) from transcriptomic datasets. Machine learning selected key genes, and a multi-layer perceptron (MLP) model was developed for IPF prediction and diagnosis. SMR and PheWAS were used to assess the expression of key genes concerning IPF risk. The impact of core genes on immune cells in the IPF microenvironment was explored, and in vivo experiments were conducted to examine the progression from IPF to LC. Results: The TSMR approach indicated a genetic predisposition for IPF progressing to LC. The predictive model, which includes eight ICD key genes, demonstrated a strong predictive capability (AUC = 0.839). The SMR analysis revealed that the elevated expression of MS4A4A was associated with an increased risk of IPF (OR = 1.275, 95% CI: 1.029-1.579; p = 0.026). The PheWAS did not identify any significant traits linked to MS4A4A expression. The rs9265808 locus in MS4A4A was identified as a susceptibility site for the progression of IPF to LC, with mutations potentially reprogramming lung neutrophils and increasing the LC risk. In vivo studies suggested MS4A4A as a promising therapeutic target. Conclusions: A causal link between IPF and LC was established, an effective prediction model was developed, and MS4A4A was highlighted as a therapeutic target to prevent IPF from progressing to LC.

PMID:39457694 | DOI:10.3390/biomedicines12102382

Biomedicines. 2024 Oct 15;12(10):2348. doi: 10.3390/biomedicines12102348.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a serious, progressive lung disease for which treatments are scarce. Pirfenidone has been approved for the treatment of IPF in Taiwan since 2016. This study aimed to gain a better insight into pirfenidone's real-world safety and effectiveness in adult IPF patients in Taiwan.

METHODS: We conducted a prospective, multicenter, post-marketing surveillance study, and analyzed data from a small sample of 50 IPF patients treated with pirfenidone.

RESULTS: Most patients were men, with a mean age of 72.8 years (±10.3). They were in physiology stage I or II with a baseline mean forced vital capacity (FVC) of 2.236 L (73.8% of predicted value). After treatment with pirfenidone, the mean FVC decreased by 0.088 L at week 24 and 0.127 L at week 52. The mean 6 min walk test was 325.5 m at baseline, increased by 8.1 m at week 24, but then decreased by 23.0 m at week 52. These changes from baseline did not reach statistical significance. Pirfenidone prevented worsening of cough but did not stabilize dyspnea. During 52 weeks of treatment, the incidence of total adverse drug reactions was 62.0%, with decreased appetite (32.0%) and pruritis (10.0%) being the most common. The adverse events leading to treatment discontinuation were decreased appetite (8.0%), nausea (4.0%), and respiratory failure (4.0%). No safety concern was raised by the study. Treatment with pirfenidone stabilized both FVC and the subjective symptom of cough in most patients.

CONCLUSIONS: This post-marketing surveillance study demonstrated that pirfenidone is an effective, safe, and well-tolerated treatment in patients with IPF in Taiwan.

PMID:39457660 | DOI:10.3390/biomedicines12102348

J Med Chem. 2024 Oct 24. doi: 10.1021/acs.jmedchem.4c01851. Online ahead of print.

ABSTRACT

Inhibition of integrin αvβ6 is a promising approach to the treatment of fibrotic disease such as idiopathic pulmonary fibrosis. Screening a small library combining head groups that stabilize the bent-closed conformation of integrin αIIbβ3 with αv integrin binding motifs resulted in the identification of hit compounds that bind the bent-closed conformation of αvβ6. Crystal structures of these compounds bound to αvβ6 and related integrins revealed opportunities to increase potency and selectivity, and these efforts were accelerated using accurate free energy perturbation (FEP+) calculations. Optimization of PK parameters including permeability, bioavailability, clearance, and half-life resulted in the discovery of development candidate MORF-627, a highly selective inhibitor of αvβ6 that stabilizes the bent-closed conformation and has good oral PK. Unfortunately, the compound showed toxicity in a 28-day NHP safety study, precluding further development. Nevertheless, MORF-627 is a useful tool compound for studying the biology of integrin αvβ6.

PMID:39446989 | DOI:10.1021/acs.jmedchem.4c01851

Respir Res. 2024 Oct 23;25(1):383. doi: 10.1186/s12931-024-03015-6.

ABSTRACT

BACKGROUND: Blood biomarkers predictive of the progression of idiopathic pulmonary fibrosis (IPF) would be of value for research and clinical practice. We used data from the IPF-PRO Registry to investigate whether the addition of "omics" data to risk prediction models based on demographic and clinical characteristics improved prediction of the progression of IPF.

METHODS: The IPF-PRO Registry enrolled patients with IPF at 46 sites across the US. Patients were followed prospectively. Median follow-up was 27.2 months. Prediction models for disease progression included omics data (proteins and microRNAs [miRNAs]), demographic factors and clinical factors, all assessed at enrollment. Data on proteins and miRNAs were included in the models either as raw values or based on clusters in various combinations. Least absolute shrinkage and selection operator (Lasso) Cox regression was applied for time-to-event composite outcomes and logistic regression with L1 penalty was applied for binary outcomes assessed at 1 year. Model performance was assessed using Harrell's C-index (for time-to-event outcomes) or area under the curve (for binary outcomes).

RESULTS: Data were analyzed from 231 patients. The models based on demographic and clinical factors, with or without omics data, were the top-performing models for prediction of all the time-to-event outcomes. Relative changes in average C-index after incorporating omics data into models based on demographic and clinical factors ranged from 1.7 to 3.2%. Of the blood biomarkers, surfactant protein-D, serine protease inhibitor A7 and matrix metalloproteinase-9 (MMP-9) were among the top predictors of the outcomes. For the binary outcomes, models based on demographics alone and models based on demographics plus omics data had similar performances. Of the blood biomarkers, CC motif chemokine 11, vascular cell adhesion protein-1, adiponectin, carcinoembryonic antigen and MMP-9 were the most important predictors of the binary outcomes.

CONCLUSIONS: We identified circulating protein and miRNA biomarkers associated with the progression of IPF. However, the integration of omics data into prediction models that included demographic and clinical factors did not materially improve the performance of the models.

TRIAL REGISTRATION: ClinicalTrials.gov; No: NCT01915511; registered August 5, 2013; URL: www.

CLINICALTRIALS: gov .

PMID:39443991 | DOI:10.1186/s12931-024-03015-6

Gen Thorac Cardiovasc Surg. 2024 Oct 23. doi: 10.1007/s11748-024-02096-w. Online ahead of print.

ABSTRACT

OBJECTIVE: Post-surgical survival outcomes in patients with non-small-cell lung cancer (NSCLC) and idiopathic pulmonary fibrosis (IPF) are expected to be worse than those in patients with other idiopathic interstitial pneumonias (IIPs). However, these remain unclear regarding patients with NSCLC and IPF histologically diagnosed as usual interstitial pneumonia [IPF(UIP)]. We aimed to assess the surgical and survival outcomes and identify prognostic factors in patients with NSCLC and IPF(UIP).

METHODS: This retrospective cohort study included patients with pathological stage I-III NSCLC and UIP. Prognostic factors and their association with lung cancer deaths (LCDs) and non-LCDs (NLCDs) were investigated.

RESULTS: The overall survival of patients with UIP was significantly poorer than that of others with IIPs. The main causes of death were lung cancer (36%) and respiratory disease (44%). Multivariate analyses revealed the pathological stage of NSCLC ≥ II (hazard ratio [HR], 2.196; p = 0.009) and GAP stage ≥ II (HR, 2.821; p = 0.016) to be significant prognostic factors. NLCD incidence was significantly high in patients with GAP stage ≥ II. Recurrence occurred in 26 patients (36.1%); the period from recurrence to death was shorter in patients with IPF(UIP) than in patients without IPF(UIP).

CONCLUSIONS: Patients with NSCLC and IPF(UIP) had poor prognosis after surgery. However, the prognosis varied greatly depending on the GAP stage. Considering the difficulty in managing post-surgical recurrence and high incidence of LCDs in patients with IPF(UIP), pursuing a radical resection is recommended in patients with GAP stage I. For patients with GAP stage ≥ II, comprehensive management of UIP is also necessary.

PMID:39441471 | DOI:10.1007/s11748-024-02096-w

Chron Respir Dis. 2024 Jan-Dec;21:14799731241255138. doi: 10.1177/14799731241255138.

ABSTRACT

BACKGROUND: Individuals with interstitial lung disease (ILD) often experience worsening symptoms and activity avoidance. Limited data exists on outcome measures for assessing functional status (capacity and performance), as well as on the effectiveness of pulmonary rehabilitation (PR) in improving these outcomes in ILD.

AIM: This review aimed to systematically assess the effects of PR on both functional capacity and performance in individuals with ILD.

METHODS: Randomised controlled trials involving pulmonary rehabilitation (PR) in adults with ILD, which included at least an exercise training component and education and/or psychosocial support, were included. Risk of bias and quality of evidence were assessed. Mean changes from baseline and standard deviations were retrieved for each group, and a random-effects model was applied.

RESULTS: Eight studies were included, mostly involving individuals with idiopathic pulmonary fibrosis (n = 5). PR duration ranged from 3 to 26 weeks. Seven studies used the 6MWT to evaluate functional capacity and one also used the 30-s STS. Two studies assessed functional performance, measuring time spent in moderate physical activity with the SenseWear Armband, number of steps per day with the same device, and energy expenditure in MET-min using the international physical activity questionnaire. PR improved functional capacity (6MWT-MD 45.82 m, 95%CI [26.14; 65.50], I2 = 71.54%, p < .001; 30-s STS- PR: 3.7 ± 2.6 reps; control group: -0.4 ± 2.5 reps, p < .001) compared to usual care. Only self-reported physical activity levels increased after PR (PR: 51.4 ± 57.7MET-min; control group: 20.9 ± 37.2MET-min, p = .03).

CONCLUSION: PR is effective at improving functional capacity; however, functional performance is often overlooked, resulting in limited and inconclusive findings.

PMID:39440394 | DOI:10.1177/14799731241255138

Respirology. 2024 Oct 22. doi: 10.1111/resp.14849. Online ahead of print.

NO ABSTRACT

PMID:39438408 | DOI:10.1111/resp.14849

Inflammation. 2024 Oct 23. doi: 10.1007/s10753-024-02153-9. Online ahead of print.

ABSTRACT

Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common complication of SSc and a major contributor to SSc-related deaths. Besides nintedanib and tocilizumab, there are currently no clinically approved drugs for SSc-ILD, highlighting the urgent need for new treatment strategies. Previous studies have shown that cyclic adenosine monophosphate (cAMP) plays a crucial role in the pathogenesis of SSc and lung fibrosis. Phosphodiesterases (PDEs) are enzymes that specifically hydrolyze cAMP, making PDE inhibitors promising candidates for SSc-ILD treatment. Nerandomilast, a preferential phosphodiesterase 4B (PDE4B) inhibitor currently undergoing phase III clinical trials for idiopathic pulmonary fibrosis and progressive fibrosing interstitial lung diseases (PF-ILD), has good preference for PDE4B but lacks studies for SSc-ILD. Our research demonstrates that nerandomilast effectively inhibits skin and lung fibrosis in a bleomycin-induced mouse model of SSc-ILD. For lung fibrosis, we found that nerandomilast could improve bleomycin-induced SSc-ILD through inhibiting PDE4B and the TGF-β1-Smads/non-Smads signaling pathways, which provides a theoretical basis for potential therapeutic drug development for SSc-ILD.

PMID:39438343 | DOI:10.1007/s10753-024-02153-9

Respirology. 2024 Oct 22. doi: 10.1111/resp.14848. Online ahead of print.

ABSTRACT

In this review, we have discussed several important developments in 2023 in Interstitial Lung Disease (ILD). The association of pollution with genetic predispositions increased the risk of Idiopathic Pulmonary Fibrosis (IPF). An interesting comorbidity of malnutrition was not adequately recognized in ILD. Novel genes have been identified in IPF involving predominantly short telomere length and surfactant protein production leading to alveolar epithelial cell dysfunction. Genetics also predicted progression in IPF. Crosstalk between vascular endothelial cells and fibroblasts in IPF mediated by bone morphogenic protein signalling may be important for remodelling of the lung. A novel modality for monitoring of disease included the 4-min gait speed. New treatment modalities include inhaled pirfenidone, efzofitimod, for sarcoidosis, and earlier use of immunosuppression in connective tissue disease-ILD.

PMID:39438044 | DOI:10.1111/resp.14848

Am J Physiol Lung Cell Mol Physiol. 2024 Oct 22. doi: 10.1152/ajplung.00280.2023. Online ahead of print.

ABSTRACT

OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease which is usually diagnosed late in advanced stages. Little is known about the subclinical development of IPF. We previously generated a mouse model with conditional Nedd4-2 deficiency (Nedd4-2-/-) that develops IPF-like lung disease. The aim of this study was to characterize the onset and progression of IPF-like lung disease in conditional Nedd4-2-/- mice by longitudinal micro-computed tomography (CT).

METHODS: In vivo micro-CT was performed longitudinally in control and conditional Nedd4-2-/- mice at 1, 2, 3, 4 and 5 months after doxycycline induction. Further, terminal in vivo micro-CT followed by pulmonary function testing and post mortem micro-CT was performed in age-matched mice. Micro-CT images were evaluated for pulmonary fibrosis using an adapted fibrosis scoring system. Histological assessment of lung collagen content was conducted as well.

RESULTS: Micro-CT is sensitive to detect onset and progression of pulmonary fibrosis in vivo and to quantify distinct radiological IPF-like features along disease development in conditional Nedd4-2-/- mice. Nonspecific interstitial alterations were detected from 3 months, whereas key features such as honeycombing-like lesions were detected from 4 months onwards. Pulmonary function correlated well with in vivo (r=-0.738) and post mortem (r=-0.633) micro-CT fibrosis scores and collagen content.

CONCLUSION: Longitudinal micro-CT enables in vivo monitoring of onset and progression and detects radiologic key features of IPF-like lung disease in conditional Nedd4-2-/- mice. Our data support micro-CT as sensitive quantitative endpoint for preclinical evaluation of novel antifibrotic strategies.

PMID:39437758 | DOI:10.1152/ajplung.00280.2023

Cell Death Discov. 2024 Oct 21;10(1):443. doi: 10.1038/s41420-024-02170-5.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, fibrotic lung disease with limited treatment options and efficacy. Evidence suggests that IPF arises from genetic, environmental, and aging-related factors. The pathogenic mechanisms of IPF primarily involve dysregulated repeated microinjuries to epithelial cells, abnormal fibroblast/myofibroblast activation, and extracellular matrix (ECM) deposition, but thus far, the exact etiology remains unclear. Noncoding RNAs (ncRNAs) play regulatory roles in various biological processes and have been implicated in the pathophysiology of multiple fibrotic diseases, including IPF. This review summarizes the roles of ncRNAs in the pathogenesis of IPF and their potential as diagnostic and therapeutic targets.

PMID:39433746 | DOI:10.1038/s41420-024-02170-5

J Med Virol. 2024 Oct;96(10):e70019. doi: 10.1002/jmv.70019.

ABSTRACT

Cytomegalovirus (CMV) pneumonia, often presented as pneumonitis, is characterized by respiratory failure and large interstitial infiltrates visible on chest radiographs. This retrospective cohort study investigates the predictive significance of plasma CMV DNA load on the short- and long-term mortality among immunocompetent patients diagnosed with CMV pneumonia. The study included 61 immunocompetent patients suspected of having CMV pneumonia, treated with intravenous ganciclovir after positive CMV DNA results from bronchoalveolar lavage or plasma. Our multivariate Cox regression analysis identified several independent predictors of mortality. Having idiopathic pulmonary fibrosis (IPF) significantly increased the risk of in-hospital mortality (HR: 7.27, 95% CI: 1.62-32.52, p = 0.009), as did shorter durations of antiviral therapy (HR: 0.90, 95% CI: 0.84-0.97, p = 0.005) and higher CMV DNA levels (>3870 IU/mL; HR: 9.63, 95% CI: 2.32-39.98, p = 0.002). High CMV DNA levels (>5154 IU/mL) were also predictors of 30-day mortality (HR: 9.39, 95% CI: 2.20-40.01, p = 0.002). For 1-year mortality, the presence of IPF (HR: 2.96, 95% CI: 1.08-8.06, p = 0.034), hypersensitivity pneumonia (HP) (HR: 4.30, 95% CI: 1.57-11.78, p = 0.005), shorter duration of total antiviral therapy (HR: 0.95, 95% CI: 0.93-0.99, p = 0.010), and higher CMV DNA levels (>327 IU/mL) (HR: 3.36, 95% CI: 1.33-8.47, p = 0.010) were identified as independent determinants. The study reveals that IPF increases short and long-term mortality risks, while HP increases long-term mortality. Extended antiviral treatment duration results in a 10% reduction in in-hospital mortality for each additional day of treatment. Furthermore, elevated viral loads are associated with higher mortality rates, highlighting the necessity for careful monitoring.

PMID:39428968 | DOI:10.1002/jmv.70019

Respir Res. 2024 Oct 18;25(1):379. doi: 10.1186/s12931-024-03008-5.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a complex lung disease with a very poor prognosis. Existing drugs for the treatment of IPF are still insufficient. Therefore, there is still a need to explore new drug targets for preventing and treating IPF.

METHODS: We included quantitative trait loci (QTL) for genes, DNA methylation, and proteins in plasma, as well as the summary statistics for IPF. Genetic variants located within 500 kb of the gene and strongly associated with plasma exposure were used as instrumental variables. The causal association between plasma exposures and IPF was primarily estimated using summary-data-based Mendelian randomization (SMR) analysis. Five other MR methods and sensitivity analyses were employed to validate the SMR results. Bayesian tests for colocalization between QTL and IPF risk loci further strengthen the MR results.

RESULTS: We identified three genes and five DNA methylation sites causally associated with IPF by SMR analysis, validation of MR analysis, sensitivity analysis, and colocalization analysis. BTRC and LINC01252 were negatively associated with IPF risk (OR: 0.30, 95% CI: 0.17-0.54, FDRSMR = 0.029; OR: 0.85, 95% CI: 0.78-0.92, FDRSMR = 0.043), and RIPK4 was positively associated with IPF risk (OR: 2.60, 95% CI: 1.64-4.12, FDRSMR = 0.031). cg00045227 (OR8U8, OR: 1.16, 95% CI: 1.08-1.24, FDRSMR = 0.010), cg00577578 (GBAP1, OR: 1.23, 95% CI: 1.12-1.36, FDRSMR = 0.014), cg14222479 (ARPM1, OR: 3.17, 95% CI: 1.98-5.08, FDRSMR = 0.001), and cg19263494 (PMF1, OR: 1.20, 95% CI: 1.10-1.30, FDRSMR = 0.012) were positively associated with the risk of IPF, whereas cg07163735 (MAPT, OR: 0.22, 95% CI: 0.11-0.45, FDRSMR = 0.013) was negatively correlated with the risk of IPF.

CONCLUSIONS: This study demonstrated that genetically determined plasma levels of the BTRC, RIPK4, and LINC01252 genes, as well as methylation levels of cg00045227 (OR8U8), cg00577578 (GBAP1), cg07163735 (MAPT), cg14222479 (ARPM1), and cg19263494 (PMF1), have causal influences on the risk of IPF.

PMID:39425105 | DOI:10.1186/s12931-024-03008-5

Inflammation. 2024 Oct 19. doi: 10.1007/s10753-024-02167-3. Online ahead of print.

ABSTRACT

Acute lung injury (ALI) is primarily driven by an intense inflammation in the alveolar epithelium. Key to this is the pro-inflammatory cytokine, Interleukin 17 (IL-17), which influences pulmonary immunity and modifies p53 function. The direct role of IL-17A in p53-fibrinolytic system is still unclear, it is important to evaluate this mechanism to regulate the ALI progression to idiopathic pulmonary fibrosis (IPF). C57BL/6 mice, exposed to recombinant IL-17A protein and treated with curcumin, provided insight into IL-17A mechanisms and curcumin's potential for modulating early pulmonary fibrosis stages. A diverse methodology, including proteomics, single-cell RNA sequencing (scRNA-seq) integration, molecular, and Schroedinger approach were utilized. In silico approaches facilitated the potential interactions between curcumin, IL-17A, and apoptosis-related proteins. A notable surge in the expression levels of IL-17A, p53, and fibrinolytic components such as Plasminogen Activator Inhibitor-1 (PAI-I) was discerned upon the IL17A exposure in mouse lungs. Furthermore, the enrichment of pathways and differential expression of proteins underscored the significance of IL-17A in governing downstream regulatory pathways such as inflammation, NF-kappaB signaling, Mitogen-Activated Protein Kinases (MAPK), p53, oxidative phosphorylation, JAK-STAT, and apoptosis. The integration of scRNA-seq data from 20 IPF and 10 control lung specimens emphasized the importance of IL-17A mediated downstream regulation in PF patients. A potent immuno-pharmacotherapeutic agent, curcumin, demonstrated a substantial capacity to modulate the lung pathology and molecular changes induced by IL-17A in mouse lungs. Human IPF single cell data integration confirmed the effects of IL-17A mediated fibrinolytic components in ALI to IPF progression.

PMID:39424752 | DOI:10.1007/s10753-024-02167-3

Physiol Rep. 2024 Oct;12(20):e70093. doi: 10.14814/phy2.70093.

ABSTRACT

Interstitial lung diseases (ILDs) include a variety of inflammatory and fibrotic pulmonary conditions. This study employs high-resolution metabolomics (HRM) to explore plasma metabolites and pathways across ILD phenotypes, including non-fibrotic ILD, idiopathic pulmonary fibrosis (IPF), and non-IPF fibrotic ILD. The study used 80 plasma samples for HRM, and involved linear trend and group-wise analyses of metabolites altered in ILD phenotypes. We utilized limma one-way ANOVA and mummichog algorithms to identify differences in metabolites and pathways across ILD groups. Then, we focused on metabolites within critical pathways, indicated by high pathway overlap sizes and low p-values, for further analysis. Targeted HRM identified putrescine, hydroxyproline, prolyl-hydroxyproline, aspartate, and glutamate with significant linear increases in more fibrotic ILD phenotypes, suggesting their role in ILD fibrogenesis. Untargeted HRM highlighted pathway alterations in lysine, vitamin D3, tyrosine, and urea cycle metabolism, all associated with pulmonary fibrosis. In addition, methylparaben level had a significantly increasing linear trend and was higher in the IPF than fibrotic and non-ILD groups. This study highlights the importance of specific amino acids, metabolic pathways, and xenobiotics in the progression of pulmonary fibrosis.

PMID:39424430 | DOI:10.14814/phy2.70093

Pneumologie. 2024 Oct;78(10):693-784. doi: 10.1055/a-2194-6914. Epub 2024 Feb 9.

ABSTRACT

This article is an abridged version of the updated AWMF mould guideline "Medical clinical diagnostics in case of indoor mould exposure - Update 2023", presented in July 2023 by the German Society of Hygiene, Environmental Medicine and Preventive Medicine (Gesellschaft für Hygiene, Umweltmedizin und Präventivmedizin, GHUP), in collaboration with German and Austrian scientific medical societies, and experts. Indoor mould growth is a potential health risk, even if a quantitative and/or causal relationship between the occurrence of individual mould species and health problems has yet to be established. There is no evidence for a causal relationship between moisture/mould damage and human diseases, mainly because of the ubiquitous presence of fungi and hitherto inadequate diagnostic methods. Sufficient evidence for an association between moisture/mould damage and the following health effects has been established for: allergic respiratory diseases, allergic rhinitis, allergic rhino-conjunctivitis, allergic bronchopulmonary aspergillosis (ABPA), other allergic bronchopulmonary mycosis (ABPM), aspergilloma, Aspergillus bronchitis, asthma (manifestation, progression, exacerbation), bronchitis (acute, chronic), community-acquired Aspergillus pneumonia, hypersensitivity pneumonitis (HP; extrinsic allergic alveolitis (EEA)), invasive Aspergillosis, mycoses, organic dust toxic syndrome (ODTS) [workplace exposure], promotion of respiratory infections, pulmonary aspergillosis (subacute, chronic), and rhinosinusitis (acute, chronically invasive, or granulomatous, allergic). In this context the sensitizing potential of moulds is obviously low compared to other environmental allergens. Recent studies show a comparatively low sensitization prevalence of 3-22,5 % in the general population across Europe. Limited or suspected evidence for an association exist with respect to atopic eczema (atopic dermatitis, neurodermatitis; manifestation), chronic obstructive pulmonary disease (COPD), mood disorders, mucous membrane irritation (MMI), odor effects, and sarcoidosis. (iv) Inadequate or insufficient evidence for an association exist for acute idiopathic pulmonary hemorrhage in infants, airborne transmitted mycotoxicosis, arthritis, autoimmune diseases, cancer, chronic fatigue syndrome (CFS), endocrinopathies, gastrointestinal effects, multiple chemical sensitivity (MCS), multiple sclerosis, neuropsychological effects, neurotoxic effects, renal effects, reproductive disorders, rheumatism, sick building syndrome (SBS), sudden infant death syndrome, teratogenicity, thyroid diseases, and urticaria.The risk of infection posed by moulds regularly occurring indoors is low for healthy persons; most species are in risk group 1 and a few in risk group 2 (Aspergillus fumigatus, A. flavus) of the German Biological Agents Act (Biostoffverordnung). Only moulds that are potentially able to form toxins can be triggers of toxic reactions. Whether or not toxin formation occurs in individual cases is determined by environmental and growth conditions, water activity, temperature and above all the growth substrates.In case of indoor moisture/mould damage, everyone can be affected by odor effects and/or mood disorders.However, this is not an acute health hazard. Predisposing factors for odor effects can include genetic and hormonal influences, imprinting, context and adaptation effects. Predisposing factors for mood disorders may include environmental concerns, anxiety, condition, and attribution, as well as various diseases. Risk groups to be protected particularly regarding infection risk are immunocompromised persons according to the classification of the German Commission for Hospital Hygiene and Infection Prevention (Kommission für Krankenhaushygiene und Infektionsprävention, KRINKO) at the Robert Koch-Institute (RKI), persons suffering from severe influenza, persons suffering from severe COVID-19, and persons with cystic fibrosis (mucoviscidosis); with regard to allergic risk, persons with cystic fibrosis (mucoviscidosis) and patients with bronchial asthma must be protected. The rational diagnostics include the medical history, physical examination, and conventional allergy diagnostics including provocation tests if necessary; sometimes cellular test systems are indicated. In the case of mould infections, the reader is referred to the specific guidelines. Regarding mycotoxins, there are currently no useful and validated test procedures for clinical diagnostics. From a preventive medical point of view, it is important that indoor mould infestation in relevant magnitudes cannot be tolerated for precautionary reasons.For evaluation of mould damage in the indoor environment and appropriate remedial procedures, the reader is referred to the mould guideline issued by the German Federal Environment Agency (Umweltbundesamt, UBA).

PMID:39424320 | DOI:10.1055/a-2194-6914

Chron Respir Dis. 2024 Jan-Dec;21:14799731241291538. doi: 10.1177/14799731241291538.

ABSTRACT

Although smoking-related interstitial lung diseases (SR-ILD) are a relatively rare group of entities, they are a relevant public health problem of growing importance, both because they affect young adults and because of their increasing prevalence in recent years due to increased tobacco consumption. In patients who smoke and have non-specific respiratory symptoms, SR-ILD should be ruled out, a term that encompasses a group of different entities in which the basis for diagnosis is the smoking history together with compatible respiratory functional findings, radiology and/or histology. An association has been established between tobacco smoke and a group of diseases that include respiratory bronchiolitis-associated interstitial lung disease (2%-3% of all ILD), desquamative interstitial pneumonia (<1%), Langerhans cell histiocytosis (3%-5%) and acute eosinophilic pneumonia. Smoking is considered a risk factor for idiopathic pulmonary fibrosis which has also been called combined fibroemphysema (5%-10% of all ILD); however, the role and impact of smoking in its development, remains to be determined. The likely interconnection between the mechanisms involved in inflammation and pulmonary fibrosis in all these processes often results in an overlapping of clinical, radiological, and histological features. In the absence of robust scientific evidence on its management, smoking cessation is the first measure to be taken into account. Although most diseases have a benign clinical course after smoking cessation, some cases may progress to chronic respiratory failure.

PMID:39423337 | DOI:10.1177/14799731241291538