Biofabrication. 2024 Dec 17. doi: 10.1088/1758-5090/ada092. Online ahead of print.

ABSTRACT

Recent studies have shown promising results using decellularized extracellular matrix (dECM) matrikines-based hydrogel as attractive strategies for preventing and alleviating fibrosis.
Methods & Results: Porcine lung decellularization and pepsin digestion were used to prepare the lung dECM hydrogel. Proteomic analysis revealed that the lung dECM hydrogel was enriched in glycoproteins, collagens, laminins, fibrinogen, held receptors, and bound growth factors. With porous structures and good mechanical properties and stability, the lung dECM hydrogel showed low cytotoxicity and good biocompatibility both in vitro and in vivo. The lung dECM hydrogel was further administered to verify the safety and effectiveness of reversing pulmonary fibrosis in a bleomycin induced rat model. The results revealed a relatively complete alveolar structure with less inflammatory infiltration and a reduced amount of collagen fiber deposition. TMT quantification proteomic analyses revealed significant downregulation of proteins, pathways, and interactions involved in the regulation of ECM components, tissue remodeling, inflammation, and the cytoskeleton and indicated that fibrosis-related proteins were obviously downregulated and inflammation-related proteins were significantly changed, particularly in macrophages, after administration of the lung dECM hydrogel. Multiplex immunohistochemical (mIHC) staining of lung tissue revealed that the inflammatory response was regulated by the lung dECM hydrogel, as indicated by a decrease in the number of CD3+ T cells and macrophages and the suppression of M2 macrophage polarization. Gene set enrichment analysis revealed that downregulated ficolin signaling was enriched in macrophages after lung dECM hydrogel administration, and the findings were verified in lung tissue by mIHC. Additionally, the effects of ficolin B proteins on macrophage polarization were proved in vitro.
Conclusion: This study suggested that the lung dECM hydrogel can reverse pulmonary fibrosis by suppressing M2 macrophage polarization through downregulation of the ficolin signaling pathway. Thus, the dECM hydrogel represent a promising class of biological materials for use in regenerative medicine.

PMID:39689433 | DOI:10.1088/1758-5090/ada092

ERJ Open Res. 2024 Dec 16;10(6):00558-2023. doi: 10.1183/23120541.00558-2023. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Biomarkers that change in response to nintedanib in subjects with idiopathic pulmonary fibrosis (IPF) would be valuable. We investigated the effects of nintedanib on circulating biomarkers in subjects with IPF in the INMARK trial.

METHODS: Subjects with IPF were randomised 1:2 to receive nintedanib 150 mg twice daily or placebo for 12 weeks, after which all patients received open-label nintedanib for 40 weeks. Fold changes in adjusted mean levels of circulating biomarkers were analysed using a linear mixed model for repeated measures.

RESULTS: 346 subjects were treated (116 randomised to nintedanib, 230 to placebo). Surfactant protein D (SP-D) and cancer antigen 125 (CA-125), markers of epithelial injury, decreased in subjects treated with nintedanib versus placebo. Fold changes from baseline in SP-D at week 12 corresponded to a 4% decrease and 3% increase in the nintedanib and placebo groups, respectively (ratio 0.94, 95% CI 0.89-0.99; p=0.024). Fold changes in CA-125 at week 12 corresponded to a 22% decrease and 4% increase in the nintedanib and placebo groups, respectively (ratio 0.75, 95% CI 0.71-0.81; p<0.0001). A mediation analysis suggested that 42.1% of the effect of nintedanib on change in forced vital capacity over 12 weeks was attributable to the change in CA-125. A small increase in C3A (collagen 3 degraded by ADAMTS-1/4/8) and a small decrease in C3M (collagen 3 degraded by matrix metalloproteinase-9), markers of extracellular matrix turnover, were observed in subjects treated with nintedanib versus placebo.

CONCLUSIONS: Effects of nintedanib on circulating markers of epithelial dysfunction and collagen degradation, most notably CA-125, were observed in patients with IPF.

PMID:39687396 | PMC:PMC11647937 | DOI:10.1183/23120541.00558-2023

ERJ Open Res. 2024 Dec 16;10(6):00192-2024. doi: 10.1183/23120541.00192-2024. eCollection 2024 Nov.

ABSTRACT

BACKGROUND: Idiopathic interstitial pneumonias (IIPs), such as idiopathic pulmonary fibrosis and interstitial pneumonia with autoimmune features, present diagnostic and therapeutic challenges due to their heterogeneous nature. This study aimed to identify intrinsic molecular signatures within the lung microenvironment of these IIPs through proteomic analysis of bronchoalveolar lavage fluid (BALF).

METHODS: Patients with IIP (n=23) underwent comprehensive clinical evaluation including pre-treatment bronchoscopy and were compared with controls without lung disease (n=5). Proteomic profiling of BALF was conducted using label-free quantitative methods. Unsupervised cluster analyses identified protein expression profiles that were then analysed to predict survival outcomes and investigate associated pathways.

RESULTS: Proteomic profiling successfully differentiated IIP from controls. k-means clustering based on protein expression revealed three distinct IIP clusters, which were not associated with age, smoking history, or baseline pulmonary function. These clusters had unique survival trajectories and provided more accurate survival predictions than the Gender Age Physiology index (concordance index 0.794 versus 0.709). The cluster with the worst prognosis featured decreased inflammatory signalling and complement activation, with pathway analysis highlighting altered immune response pathways related to immunoglobulin production and B-cell-mediated immunity.

CONCLUSIONS: The unsupervised clustering of BALF proteomics provided a novel stratification of IIP patients, with potential implications for prognostic and therapeutic targeting. The identified molecular phenotypes underscore the diversity within the IIP classification and the potential importance of personalised treatments for these conditions. Future validation in larger, multi-ethnic cohorts is essential to confirm these findings and to explore their utility in clinical decision-making for patients with IIP.

PMID:39687393 | PMC:PMC11647942 | DOI:10.1183/23120541.00192-2024

J Clin Med. 2024 Nov 26;13(23):7170. doi: 10.3390/jcm13237170.

ABSTRACT

Background: Both a probable usual interstitial pneumonia (UIP) pattern (p-UIP) and a definite UIP pattern (d-UIP) on high-resolution computed tomography (HRCT) are sufficient to establish a diagnosis of idiopathic pulmonary fibrosis (IPF) without the need for a surgical lung biopsy, according to the 2022 IPF guidelines. However, it remains unknown whether patients with p-UIP and d-UIP have similar disease behaviors and clinical courses. Material and Methods: We retrospectively collected clinical data of patients with IPF and divided the patients into two groups according to their HRCT patterns: a p-UIP group and a d-UIP group. The baseline characteristics, survival rates, and pulmonary function tests were compared between the two groups. The risk factors for mortality were determined by Cox regression in p-UIP and d-UIP separately. Results: There were 304 patients in the p-UIP group and 480 patients in the d-UIP group. Patients in the d-UIP group were more likely to have smoking histories (p < 0.001) and had lower baseline FVC% (74% vs. 77%, p = 0.021) and DLCO% (50% vs. 58%, p < 0.001). Survival rates were higher in p-UIP compared with d-UIP (p = 0.004). There were no differences in changes in FVC% or DLCO% between the two groups. Baseline DLCO% was the only independent risk factor for mortality in p-UIP. Baseline FVC% was independently associated with mortality in d-UIP. Symptom of cough was a risk factor for disease progression (OR = 1.2, p = 0.002) in p-UIP, while symptom of dyspnea might be associated with disease progression in d-UIP (OR = 2.7, p = 0.065). Male patients (OR = 1.88, p = 0.002) with a smoking history (OR = 1.16, p = 0.002) were at higher risk of developing d-UIP. Conclusions: We observed the different disease trajectories between p-UIP and d-UIP. P-UIP on HRCT might identify a subgroup of IPF patients who are in the early stage with a better prognosis.

PMID:39685629 | DOI:10.3390/jcm13237170

Int J Mol Sci. 2024 Dec 4;25(23):13026. doi: 10.3390/ijms252313026.

ABSTRACT

Alterations to post-translational crosslinking modifications in the extracellular matrix (ECM) are known to drive the pathogenesis of fibrotic diseases, including idiopathic pulmonary fibrosis (IPF). Thus, the methodology for measuring crosslinking dynamics is valuable for understanding disease progression. The existing crosslinking analysis sample preparation and liquid chromatography tandem mass spectrometry (LC-MS/MS) methods are typically labor-intensive and time-consuming which limits throughput. We, therefore, developed a rapid approach minimizing specialized equipment and hands-on time. The LC-MS/MS sample analysis time was reduced to two minutes per sample. We then improved the analytical integrity of the method by developing a novel surrogate matrix approach for the dihydroxylysinonorleucine (DHLNL) crosslink. By modifying sample preparation, we prepared a tissue-based surrogate matrix with undetectable levels of endogenous DHLNL, providing a strategy for quantifying this crosslink with a more relevant standard matrix. We then applied this rapid methodology to evaluating crosslinking in lung fibrosis. We showed an increase in DHLNL in human IPF lung relative to healthy donors, as well as in a fibrotic mouse model. Finally, we demonstrated that this increase in DHLNL could be mitigated with an anti-fibrotic compound, suggesting that this assay has potential for evaluating pharmaceutical compound efficacy.

PMID:39684739 | DOI:10.3390/ijms252313026

Int J Mol Sci. 2024 Nov 28;25(23):12783. doi: 10.3390/ijms252312783.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a pulmonary disease characterized by excessive extracellular matrix protein deposition in the lung interstitium, subsequently causing respiratory failure. IPF still has a high medical unmet requirement due to the lack of effective treatments to inhibit disease progression. The etiology of IPF remains unclear, but mitochondrial dysfunction is considered to be associated with IPF development. Therefore, targeting mitochondrial abnormalities would be a promising strategy for treating IPF. Recently, exogenous mitochondrial transplantation has been beneficial for treating mitochondrial dysfunction. The current study aimed to examine the therapeutic effect of mitochondrial transplantation on IPF in vitro and in vivo. Mitochondria were isolated from human umbilical cord mesenchymal stem cells, referred to as PN-101. Human lung fibroblasts and human bronchial epithelial cells were exposed to transforming growth factor-β, followed by PN-101 treatment to determine the in vitro efficacy of mitochondrial transplantation. An IPF mouse model established by a single intratracheal instillation of bleomycin was utilized to determine the in vivo efficacy of the intravenously treated mitochondria. PN-101 attenuated mitochondrial damage, inhibited EMC production, and suppressed epithelial-to-mesenchymal transition in vitro. Additionally, intravenous PN-101 administration alleviated bleomycin-induced fibrotic processes in the IPF mouse model with a therapeutic context. Our data indicate that PN-101 is a novel and potential therapeutic agent for IPF.

PMID:39684495 | DOI:10.3390/ijms252312783

Cells. 2024 Dec 5;13(23):2005. doi: 10.3390/cells13232005.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is the most common interstitial lung disease with unknown etiology, characterized by chronic inflammation and tissue scarring. Although, Pirfenidone and Nintedanib slow the disease progression, no currently available drugs or therapeutic interventions address the underlying cause, highlighting the unmet medical need. A matricellular protein, Wnt-1-induced secreted protein 1 (WISP1), also referred to as CCN4 (cellular communication network factor 4), is a secreted multi-modular protein implicated in multi-organ fibrosis. Although the precise mechanism of WISP1-mediated fibrosis remains unclear, emerging evidence indicates that WISP1 is profibrotic in nature. While WISP1-targeting therapy is applied in the clinic for fibrosis, detailed interrogation of WISP1-mediated fibrogenic molecular and biological pathways is lacking. Here, for the first time, using NanoString® technology, we identified a novel WISP1-associated profibrotic gene signature and molecular pathways potentially involved in the initiation and progression of fibrosis in primary human dermal and lung fibroblasts from both healthy individuals and IPF patients. Our data demonstrate that WISP1 is upregulated in IPF-lung fibroblasts as compared to healthy control. Furthermore, our results confirm that WISP1 is downstream of the transforming growth factor-β (TGFβ), and it induces fibroblast cell proliferation. Additionally, WISP1 induced IL6 and CCL2 in fibroblasts. We also developed a novel, combined TGFβ and WISP1 in vitro system to demonstrate a role for WISP1 in the progression of fibrosis. Overall, our findings uncover not only similarities but also striking differences in the molecular profile of WISP1 in human fibroblasts, both during the initiation and progression phases, as well as in disease-specific context.

PMID:39682753 | DOI:10.3390/cells13232005

Respirology. 2024 Dec 16. doi: 10.1111/resp.14866. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Acute exacerbation (AE) is often the fatal complication of idiopathic pulmonary fibrosis (IPF). Emerging evidence indicates that metabolic reprogramming and dysregulation of lipid metabolism are distinctive characteristics of IPF. However, the lipid metabolic mechanisms that underlie the pathophysiology of AE-IPF remain elusive.

METHODS: Serum samples for pilot study were collected from 34 Controls, 37 stable IPF (S-IPF) cases and 41 AE-IPF patients. UHPLC-MS/MS was utilized to investigate metabolic variations and identify lipid biomarkers in serum. ELISA, quantitative PCR and western blot were employed to validate the identified biomarkers.

RESULTS: There were 32 lipid metabolites and 5 lipid metabolism pathways enriched in all IPF patients compared to Controls. In AE-IPF versus S-IPF, 19 lipid metabolites and 12 pathways were identified, with 5-hydroxyeicosatetraenoic Acid (5-HETE) significantly elevated in AE-IPF. Both in internal and external validation cohorts, the serum levels of 5-HETE were significantly elevated in AE-IPF patients compared to S-IPF subjects. Consequently, the indicators related to 5-HETE in lipid metabolic pathway were significantly changed in AE-IPF patients compared with S-IPF cases in the lung tissues. The serum level of 5-HETE was significantly correlated with the disease severity (CT score and PaO2/FiO2 ratio) and survival time. Importantly, the receiver operating characteristic (ROC) curve, Kaplan-Meier analysis and Multivariate Cox regression analysis demonstrated that 5-HETE represents a promising lipid biomarker for the diagnosis and prognosis of AE-IPF.

CONCLUSION: Our study highlights lipid reprogramming as a novel therapeutic approach for IPF, and 5-HETE may be a potential biomarker of AE-IPF patients.

PMID:39681341 | DOI:10.1111/resp.14866

Curr Opin Allergy Clin Immunol. 2024 Dec 17. doi: 10.1097/ACI.0000000000001055. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: To critically discuss the rationale for the use of drugs approved for idiopathic pulmonary fibrosis (IPF) to treat occupational interstitial lung diseases (OILDs).

RECENT FINDINGS: Although IPF and OILDs share several clinical, radiological and probably pathogenetic features, currently, OILDs do not have a standard of care. In recent years, our knowledge and understanding of ILDs has improved substantially. Recently, the progressive pulmonary fibrosis (PPF) phenotype, which refers to non-IPF fibrotic ILDs that progress despite appropriate treatment, has been defined. OILDs may also be progressive. Nintedanib, initially approved for treatment of IPF, is also approved in patients with PPF. On the other hand, pirfenidone is approved in IPF but not in PPF, due to the lack of robust evidence of efficacy in this patient subset.

SUMMARY: OILDs are a large and highly heterogeneous group of conditions without a proper standard of care. Nintedanib may slow functional decline and disease progression in progressive OILDs, and new clinical trials are ongoing.

PMID:39680372 | DOI:10.1097/ACI.0000000000001055

J Thorac Dis. 2024 Nov 30;16(11):7427-7445. doi: 10.21037/jtd-24-760. Epub 2024 Nov 14.

ABSTRACT

BACKGROUND: The prognosis for patients diagnosed with idiopathic pulmonary fibrosis (IPF) is exceedingly grim, and there are currently no pharmacological interventions available that effectively reduce mortality rates. Emerging evidence underscores the intimate connection between mitochondrial dysfunction and the onset and advancement of IPF. However, there remains a scarcity of prognostic models for assessing the risk associated with mitochondrial-related genes in IPF. This study aims to develop a comprehensive prognostic model for IPF that incorporates mitochondrial-related genes to enhance risk assessment and guide clinical decision-making.

METHODS: Two IPF-related microarray expression profiling datasets (GSE28042 and GSE70866) accompanied with survival data were acquired from the Gene Expression Omnibus (GEO) database. The "limma" R package was used to identify differentially expressed mitochondrial-related genes between normal samples and IPF samples. The prognostic model was constructed using univariate Cox regression, the least absolute shrinkage and selection operator (LASSO) Cox regression analyses, and multivariate Cox regression analysis. Multivariate independent prognostic analysis was conducted to ascertain whether the risk score could serve as an independent prognostic factor for predicting clinicopathological outcomes. A nomogram was employed to forecast the survival probability of IPF patients, providing valuable support for clinical decision-making processes. The CIBERSORT algorithm was utilized to examine discrepancies in immune cell infiltration within the model. The expression of genes screened from the prognostic model was validated in external data sets and western blot assays.

RESULTS: We developed a prognostic model for mitochondrial-related risks, incorporating ARMCX2 and ACOT11, and subsequently validated its predictive efficacy in the validation set. The IPF samples were stratified into high-risk and low-risk groups based on the median of the risk score. According to Kaplan-Meier curve analysis, the high-risk group exhibited inferior outcomes compared to the low-risk group. The time-dependent receiver operating characteristic (ROC) analysis demonstrated the accurate prognostic capability of the risk model for IPF. A nomogram, accompanied by calibration curves, was presented to predict 1-, 2-, and 3-year survival in IPF patients. The risk model we employed not only unveiled significant disparities in functional enrichment between the high-risk and low-risk groups, but also demonstrated a robust correlation with the infiltration of specific immune cells.

CONCLUSIONS: In this study, the mitochondrial-related prognostic model incorporating ARMCX2 and ACOT11 demonstrates potential clinical utility for informing decision-making in IPF patients and offers valuable insights for future therapeutic interventions.

PMID:39678889 | PMC:PMC11635208 | DOI:10.21037/jtd-24-760

Adv Sci (Weinh). 2024 Dec 15:e2406751. doi: 10.1002/advs.202406751. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lethal disease with substantial unmet medical needs. While aberrant epithelial remodeling is a key factor in IPF progression, the molecular mechanisms behind this process remain elusive. Harnessing a 3D patient-derived organoid model and multi-omics approach, the first inventory of the connection between metabolic alteration, chromatin accessibility, and transcriptional regulation in IPF aberrant epithelial remodeling is provided. This remodeling is characterized by an increase in chromatin accessibility, particularly at JUNB motif-enriched promoter regions proximal to transcription start sites of metabolic and pro-fibrotic genes. Mechanistically, JUNB undergoes O-linked β-N-acetylglucosamine modification (O-GlcNAcylation), a critical step in modulating pro-fibrotic responses to chronic injury. This modification is pivotal in fostering the emergence of aberrant epithelial basal cells in the alveolar niche, a proposed driver of IPF pathology. Specific deletion of O-GlcNAcylation sites on JUNB attenuates the metaplastic differentiation of basal cells, thereby aiding in the restoration of the alveolar lineage. Together, the findings reveal a novel link between metabolic dysregulation and cell fate regulation at the chromatin level in fibrosis, mediated by the O-GlcNAc-JUNB axis, suggesting avenues for the development of new therapeutic strategies in IPF.

PMID:39676507 | DOI:10.1002/advs.202406751

Lab Invest. 2024 Dec 13:102210. doi: 10.1016/j.labinv.2024.102210. Online ahead of print.

ABSTRACT

Interstitial lung disease (ILD), characterized by inflammation and fibrosis, often suffers from low diagnostic accuracy and consistency. Traditional H&E staining primarily reveals cellular inflammation with limited detail on fibrosis. To address these issues, we introduce a pioneering label-free quantitative multiphoton fiber histology (MPFH) technique that delineates the intricate characteristics of collagen and elastin fibers for ILDs diagnosis. We acquired co-located multiphoton and H&E-stained images from a single tissue slice. Multiphoton imaging was performed on the deparaffinized section to obtain fibrotic tissue information, followed by H&E staining to capture cellular information. This approach was tested in a blinded diagnostic trial among 7 pathologists involving 14 relatively normal lung patients and 31 ILD patients (11 idiopathic pulmonary fibrosis (IPF) / usual interstitial pneumonia (UIP), 14 nonspecific interstitial pneumonia (NSIP), and 6 pleuroparenchymal fibroelastosis (PPFE)). A customized algorithm extracted quantitative fiber indicators from multiphoton images. These indicators, combined with clinical and radiological features, were used to develop an automatic multi-class ILDs classifier. Using MPFH, we can acquire high-quality, co-localized images of collagen fibers, elastin fibers, and cells. We found that the type, distribution, and degree of fibrotic proliferation can effectively distinguish between different subtypes. The blind study showed MPFH enhanced diagnostic consistency (kappa values from 0.56 to 0.72) and accuracy (from 73.0% to 82.5%, p=0.0090). The combination of quantitative fiber indicators effectively distinguished between different tissues, with areas under the receiver operating characteristic curves exceeding 0.92. The automatic classifier achieved 93.8% accuracy, closely paralleling the 92.2% accuracy of expert pathologists. The outcomes of our research underscore the transformative potential of MPFH in the field of f-ILD diagnostics. By integrating quantitative analysis of fiber characteristics with advanced machine learning algorithms, MPFH facilitates the automatic and accurate identification of various fibrotic disease subtypes, showcasing a significant leap forward in precision diagnostics.

PMID:39675724 | DOI:10.1016/j.labinv.2024.102210

Adv Med Sci. 2024 Dec 13:S1896-1126(24)00064-6. doi: 10.1016/j.advms.2024.12.001. Online ahead of print.

ABSTRACT

PURPOSE: Interstitial lung disease (ILD) damages the lungs and can be caused by environmental exposures and collagen-vascular diseases. The systemic immune-inflammation index (SII) is investigated to diagnose and manage ILDs in different etiological diseases. The study aims to examine the usefulness of SII in diagnosing specific ILDs like Sjogren's syndrome (SjS)-ILD, interstitial pneumonia with autoimmune features (IPAF), and idiopathic pulmonary fibrosis (IPF).

MATERIALS AND METHODS: In this cross-sectional study, we included 109 patients with IPAF, IPF, and SjS-ILD. Demographic characteristics, symptoms, lung patterns, autoantibodies, and SII were assessed. Morphologic, serologic, and clinical factors determined the classification of IPAF. Student's t-test, Mann-Whitney U test, Pearson-Spearman's method, and receiver operating characteristic (ROC) curves were used to analyze data.

RESULTS: Male patients were more common in IPF and IPAF, while SjS-ILD had mostly female patients. Raynaud's phenomenon and dry mouth/eyes were more common in SjS-ILD compared to IPF and IPAF. The groups had significant differences in patterns, antinuclear antibody positivity, and SII levels. SII levels differed significantly between IPAF, SjS-ILD, and IPF patients, and were correlated with CRP in IPAF and SjS-ILD. The cut-off value of the SII between IPAF and IPF in patients with ILD was 576.1 with 76.0% sensitivity and 76.0% specificity.

CONCLUSIONS: Evaluation of SII provides valuable information for understanding and identifying different disease groups with ILDs.

PMID:39675699 | DOI:10.1016/j.advms.2024.12.001

Int J Pharm. 2024 Dec 12:125074. doi: 10.1016/j.ijpharm.2024.125074. Online ahead of print.

ABSTRACT

Pirfenidone (PFD) is one of the first-line drugs for treating idiopathic pulmonary fibrosis, while directly delivering PFD to lung showed better efficiency. However, PFD is a non-glass former and easily precipitates into larger-sized crystals that are undesirable for pulmonary delivery. Hence, the fabrication of PFD particles with pulmonary delivery efficiency remains challenging. Herein, a series of particles were prepared by spray freeze drying a PFD and leucine mixed solution. The sub-ambient behavior of the mixed solution was evaluated via a differential scanning calorimeter. The effects of the PFD/leucine mass ratio and freezing temperature on the particle morphology, size, crystal polymorphism, molecular structure and in vitro aerosol performance were investigated. Shortening the lifetime of the droplet and adding proper amounts of leucine are the keys to decreasing the PFD crystal size and improving its dispersity. The optimal sample is SF-80D-P95L5-2, with high FPF and eFPF values of ∼ 65.97 % and ∼ 27.86 %, and owing to its high drug loading (95 %), the FPD and eFPD are extremely high at ∼ 6.27 mg and ∼ 2.65 mg, respectively, equivalent to ∼ 6.27 mg and ∼ 2.65 mg PFD deposited in the lungs and alveoli, respectively, when 10 mg dry powder is inhaled. This work provides a potential strategy for tuning the precipitation behavior of PFD microcrystals with high pulmonary drug delivery efficiency.

PMID:39674382 | DOI:10.1016/j.ijpharm.2024.125074

Int J Biochem Cell Biol. 2024 Dec 11:106728. doi: 10.1016/j.biocel.2024.106728. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe lung disease affecting around 5 million people globally, with a median survival of 3-4 years. Characterized by excessive scarring of lung tissue, IPF results from the accumulation of myofibroblasts that deposit extracellular matrix (ECM), causing fibrosis. Current treatments, pirfenidone and nintedanib, slow the disease but do not stop its progression. IPF pathogenesis involves repeated alveolar injury, leading to pro-fibrotic mediators like TGFβ1, which trigger fibroblast-to-myofibroblast transitions and ECM deposition. Recent research suggests that transient receptor potential (TRP) channels, such as TRPV4, TRPC6, and TRPA1, play a key role in regulating calcium signalling and mechanical stress, crucial in myofibroblast activation. Targeting TRP channels may disrupt fibrosis and offer new therapeutic strategies. Preclinical studies indicate that inhibiting TRP channels could reduce fibrosis, warranting further trials to explore their efficacy and safety in treating IPF and related fibrotic conditions.

PMID:39672503 | DOI:10.1016/j.biocel.2024.106728

Respir Investig. 2024 Dec 12;63(1):102-108. doi: 10.1016/j.resinv.2024.11.017. Online ahead of print.

ABSTRACT

BACKGROUND: The prognosis of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is extremely poor. However, recent clinical reports suggest that direct hemoperfusion with polymyxin B-immobilized fiber column (PMX) treatment may have beneficial effects in patients with AE-IPF. The aim of this multicenter prospective study was to investigate the effectiveness and safety of PMX treatment in AE-IPF.

METHODS: We conducted a prospective study of patients with AE-IPF treated by PMX at two institutions in Japan. Each patient received 2-3 sessions of PMX treatment with a target duration of 6-24 h. The primary endpoint was the survival rate at day 28 after the PMX treatment.

RESULTS: The survival rate of the patients on day 28 after PMX treatment was 65% [95% confidence interval (CI): 40.3-81.5%]. The lower limit of 95% CI in the study was higher than the survival rate of 40%, which was the upper limit of the survival rate in AE-IPF receiving conventional treatments, as reported previously. The survival rate of the patients 12 weeks after PMX was 50% (95% CI: 27.1-69.2%). The changes in the difference between alveolar and arterial oxygen tension and the partial pressure of arterial oxygen/fraction of inspired oxygen improved as the number of PMX sessions increased, and significant improvements were observed at the end of the second PMX session. The safety of PMX was clinically acceptable.

CONCLUSIONS: This prospective multicenter study suggests that PMX treatment is safe for patients with AE-IPF and may improve their oxygenation and prognosis.

PMID:39672072 | DOI:10.1016/j.resinv.2024.11.017

Medicina (B Aires). 2024;84(6):1286.

NO ABSTRACT

PMID:39666430

Oncogene. 2024 Dec 11. doi: 10.1038/s41388-024-03236-5. Online ahead of print.

ABSTRACT

Lung cancer is a fatal complication of idiopathic pulmonary fibrosis (IPF) with a poor prognosis. Current treatments are insufficient in improving the prognosis of lung cancer patients with comorbid idiopathic pulmonary fibrosis (IPF-LC). Senescent fibroblasts, as stromal cells in the tumor microenvironment, influence tumor progression via exosomes. With evidence that fibroblast senescence is an important mechanism of IPF, we investigated the impact of senescent IPF lung fibroblast (diseased human lung fibroblasts, DHLF)-derived exosomes on non-small cell lung cancer (NSCLC). We found DHLF expressed significant senescence markers, and promoted NSCLC proliferation, invasion, and epithelial-mesenchymal transition. Specifically, senescent DHLF showed strong secretion of exosomes, and these exosomes enhanced the proliferation and colony-forming ability of cancer cells. Proteomic analysis showed DHLF-derived exosomes exhibited upregulated senescence-associated secretory phenotype (SASP) factors, notably MMP1, which activates the surface receptor PAR1. Knocking down MMP1 or using PAR1 inhibitors reduced the tumor-promoting effects of DHLF-derived exosomes in vivo and in vitro. Mechanistically, MMP1 acted by activating the PI3K-AKT-mTOR pathway. In conclusion, our results suggest that exosomal MMP1 derived from senescent IPF fibroblasts promotes NSCLC proliferation and colony formation by targeting PAR1 and activating the PI3K-AKT-mTOR pathway. These findings provide a novel therapeutic approach for patients with IPF-LC.

PMID:39663393 | DOI:10.1038/s41388-024-03236-5

Life Sci. 2024 Dec 9:123302. doi: 10.1016/j.lfs.2024.123302. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease characterized by irreversible lung scarring with a poor prognosis. Emerging evidence has revealed that IPF is an aging-related disease, and the development of cellular senescence plays a pivotal role in persistent remodeling and fibrotic scarring, acting as a key mechanism in the pathophysiology of IPF. Exploring therapeutic strategies for modulating cellular senescence can provide crucial insights into unraveling IPF processes. Here, we have identified Nitazoxanide (NTZ), an FDA-approved antiprotozoal agent, has specific effects on inhibiting cellular senescence development. In the bleomycin and D-galactose-induced senescence model, NTZ effectively inhibits senescence associated-β-gal staining and preserves cell proliferation ability. We also found that NTZ effectively impedes senescence progression in the bleomycin-induced pulmonary fibrosis model, while mitigating the release of senescence-associated secretory phenotype and alleviating pulmonary fibrosis. The anti-senescence effect of NTZ is mechanistically dependent on the preservation of nuclear SIRT1 expression. We observed that PI3K induces a WIPI1-mediated nucleophagic degradation of SIRT1, while NTZ effectively inhibits PI3K and suppresses WIPI1 expression, thereby maintaining SIRT1 expression in the nucleus and exerting its anti-senescence function. Collectively, our research has shown that NTZ can inhibit PI3K in senescence progression, leading to the inhibition of WIPI1-mediated SIRT1 nucleophagic degradation. As a result, NTZ alleviates fibrosis by inhibiting senescence development.

PMID:39662775 | DOI:10.1016/j.lfs.2024.123302

Semin Thorac Cardiovasc Surg. 2024 Dec 9:S1043-0679(24)00103-5. doi: 10.1053/j.semtcvs.2024.10.003. Online ahead of print.

ABSTRACT

OBJECTIVE: The American Association for Thoracic Surgery (AATS) Clinical Practice Standards Committee (CPSC) previously published important considerations in determining who is at high risk for complications or mortality after lobectomy. Sublobar resection, stereotactic ablative radiotherapy, or image-guided thermal ablation is typically considered when the risks associated with lobectomy are high. The current objective was to evaluate important lung-nodule-related factors to consider during treatment selection for high-risk patients with stage I non-small cell lung cancer (NSCLC).

METHODS: The AATS CPSC assembled an expert panel. The expert panel generated an a priori list of lung-nodule-related factors to consider in treatment selection and graded the relative importance of each factor on a scale of 1-10 in an anonymous survey after systematic review of the literature.

RESULTS: The expert panel survey identified several lung-nodule-related factors to consider in treatment selection. The panel ranked tumor location (peripheral vs central, mean score 8.4), tumor size (mean score 8.1), proximity to bronchovascular and critical structures (mean score 7.8), and the presence of interstitial lung disease/idiopathic pulmonary fibrosis (mean score 7.8) as the most important factors to consider.

CONCLUSIONS: This article summarizes the lung-nodule-related factors to consider when deciding between sublobar resection, stereotactic ablative radiotherapy, and image-guided thermal ablation during treatment selection for high-risk patients with stage I NSCLC. When possible, obtaining a biopsy is very important prior to non-surgical treatments. The choice of which modality is optimal in high-risk patients with stage I NSCLC is complex. A multi-disciplinary review of patient and tumor characteristics is essential for achieving an optimal decision.

PMID:39662535 | DOI:10.1053/j.semtcvs.2024.10.003