Res Sq. 2024 Jan 29:rs.3.rs-3879423. doi: 10.21203/rs.3.rs-3879423/v1. Preprint.

ABSTRACT

Aging is the main risk factor for chronic lung diseases (CLDs) including idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD). Accordingly, hallmarks of aging such as cellular senescence are present in different lung cell types such as fibroblasts in these patients. However, whether the senescent phenotype of fibroblasts derived from IPF or COPD patients differs is still unknown. Therefore, we characterized senescence at baseline and after exposure to disease-relevant insults (H 2 O 2 , bleomycin, and TGF-β1) in cultured primary human lung fibroblasts (phLF) from control donors, IPF, or COPD patients. We found that phLF from different disease-origins have a low baseline senescence. H 2 O 2 and bleomycin treatment induced a senescent phenotype in phLF, whereas TGF-β1 had primarily a pro-fibrotic effect. Notably, we did not observe any differences in susceptibility to senescence induction in phLF based on disease origin, while exposure to different stimuli resulted in distinct senescence programs in phLF. Moreover, senescent phLF reduced colony formation efficiency of distal alveolar epithelial progenitor cells in a stimuli-dependent manner. In conclusion, the senescent phenotype of phLF is mainly determined by the senescence inducer and impairs alveolar epithelial progenitor capacity in vitro .

PMID:38352619 | PMC:PMC10862971 | DOI:10.21203/rs.3.rs-3879423/v1

Acta Biomater. 2024 Feb 11:S1742-7061(24)00066-7. doi: 10.1016/j.actbio.2024.02.008. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), for which effective treatments are limited, results in excessive and disorganized deposition of aberrant extracellular matrix (ECM). An altered ECM microenvironment is postulated to contribute to disease progression through inducing profibrotic behavior of lung fibroblasts, the main producers and regulators of ECM. Here, we examined this hypothesis in a 3D in vitro model system by growing primary human lung fibroblasts in ECM-derived hydrogels from non-fibrotic (control) or IPF lung tissue. Using this model, we compared how control and IPF lung-derived fibroblasts responded in control and fibrotic microenvironments in a combinatorial manner. Culture of fibroblasts in fibrotic hydrogels did not alter in the overall amount of collagen or glycosaminoglycans but did cause a drastic change in fiber organization compared to culture in control hydrogels. High-density collagen percentage was increased by control fibroblasts in IPF hydrogels at day 7, but decreased at day 14. In contrast, IPF fibroblasts only decreased the high-density collagen percentage at day 14, which was accompanied by enhanced fiber alignment in IPF hydrogels. Similarly, stiffness of fibrotic hydrogels was increased only by control fibroblasts by day 14 while those of control hydrogels were not altered by fibroblasts. These data highlight how the ECM-remodeling responses of fibroblasts are influenced by the origin of both the cells and the ECM. Moreover, by showing how the 3D microenvironment plays a crucial role in directing cells, our study paves the way in guiding future investigations examining fibrotic processes with respect to ECM remodeling responses of fibroblasts. STATEMENT OF SIGNIFICANCE: In this study, we investigated the influence of the altered extracellular matrix (ECM) in Idiopathic Pulmonary Fibrosis (IPF), using a 3D in vitro model system composed of ECM-derived hydrogels from both IPF and control lungs, seeded with human IPF and control lung fibroblasts. While our results indicated that fibrotic microenvironment did not change the overall collagen or glycosaminoglycan content, it resulted in a dramatically alteration of fiber organization and mechanical properties. Control fibroblasts responded differently from IPF fibroblasts, highlighting the unique instructive role of the fibrotic ECM and the interplay with fibroblast origin. These results underscore the importance of 3D microenvironments in guiding pro-fibrotic responses, offering potential insights for future IPF therapies as well as other fibrotic diseases and cancer.

PMID:38350556 | DOI:10.1016/j.actbio.2024.02.008

Aging (Albany NY). 2024 Feb 12;16. doi: 10.18632/aging.205530. Online ahead of print.

ABSTRACT

BACKGROUND: Interstitial lung disease (ILD) encompasses a diverse group of disorders characterized by chronic inflammation and fibrosis of the pulmonary interstitium. Three ILDs, namely idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis (fHP), and connective tissue disease-associated ILD (CTD-ILD), exhibit similar progressive fibrosis phenotypes, yet possess distinct etiologies, encouraging us to explore their different underlying mechanisms.

METHODS: Transcriptome data of fibrotic lung tissues from patients with IPF, fHP, and CTD-ILD were subjected to functional annotation, network, and pathway analyses. Additionally, we employed the xCell deconvolution algorithm to predict immune cell infiltration in patients with fibrotic ILDs and healthy controls.

RESULTS: We identified a shared progressive fibrosis-related module in these diseases which was related to extracellular matrix (ECM) degradation and production and potentially regulated by the p53 family transcription factors. In IPF, neuron-related processes emerged as a critical specific mechanism in functional enrichment. In fHP, we observed that B cell signaling and immunoglobulin A (IgA) production may act as predominant processes, which was further verified by B cell infiltration and the central role of CD19 gene. In CTD-ILD, active chemokine processes were enriched, and active dendritic cells (aDCs) were predicted to infiltrate the lung tissues.

CONCLUSIONS: This study revealed shared and specific molecular and cellular pathways among IPF, fHP, and CTD-ILD, providing a basis for understanding their pathogenesis and identifying potential therapeutic targets.

PMID:38349858 | DOI:10.18632/aging.205530

Brief Bioinform. 2024 Jan 22;25(2):bbae035. doi: 10.1093/bib/bbae035.

ABSTRACT

Standigm ASK™ revolutionizes healthcare by addressing the critical challenge of identifying pivotal target genes in disease mechanisms-a fundamental aspect of drug development success. Standigm ASK™ integrates a unique combination of a heterogeneous knowledge graph (KG) database and an attention-based neural network model, providing interpretable subgraph evidence. Empowering users through an interactive interface, Standigm ASK™ facilitates the exploration of predicted results. Applying Standigm ASK™ to idiopathic pulmonary fibrosis (IPF), a complex lung disease, we focused on genes (AMFR, MDFIC and NR5A2) identified through KG evidence. In vitro experiments demonstrated their relevance, as TGFβ treatment induced gene expression changes associated with epithelial-mesenchymal transition characteristics. Gene knockdown reversed these changes, identifying AMFR, MDFIC and NR5A2 as potential therapeutic targets for IPF. In summary, Standigm ASK™ emerges as an innovative KG and artificial intelligence platform driving insights in drug target discovery, exemplified by the identification and validation of therapeutic targets for IPF.

PMID:38349059 | PMC:PMC10862655 | DOI:10.1093/bib/bbae035

Oncol Lett. 2024 Jan 25;27(3):123. doi: 10.3892/ol.2024.14254. eCollection 2024 Mar.

ABSTRACT

New therapeutic approaches are needed for osteosarcoma, which is the most common malignancy of the bone, especially for metastatic cases. Nintedanib is a potent, oral tyrosine kinase inhibitor approved for treating idiopathic pulmonary fibrosis, which blocks a variety of receptor signals, including fibroblast growth factor receptors, vascular endothelial growth factor receptors and platelet-derived growth factor receptors. The present study assessed the effect of nintedanib on previously developed mouse AXT osteosarcoma cells, and on AXT-derived osteosarcoma developed in C57BL/6 mice, which displays lethal tumors with osteoid formation and lung metastatic lesions that mimics human disease. In vitro analysis, including flow cytometry and immunoblotting, revealed that nintedanib inhibited AXT cell proliferation and cell cycle progression, induced apoptosis, and inactivated AKT and ERK1/2. Immunoblot analysis using tumor lysates demonstrated that nintedanib inhibited its target molecules in vivo. As a single agent, nintedanib decreased the size of primary AXT-derived osteosarcoma, and reduced circulating tumor cells and lung metastasis. Immunohistochemical findings indicated that nintedanib exerted antitumor activity mainly by inhibiting the formation of CD31-positive tumor vasculature, while αSMA-positive cells were still enriched in tumors after nintedanib treatment. In addition, nintedanib exhibited an anti-osteosarcoma effect on C57BL/6 severe combined immunodeficient mice in which T- and B-cell function is obsolete, suggesting that the antitumor effect of nintedanib was not attributable to antitumor immunity. Collectively, these findings indicated that nintedanib holds potential for treating osteosarcoma.

PMID:38348384 | PMC:PMC10859826 | DOI:10.3892/ol.2024.14254

ERJ Open Res. 2024 Feb 12;10(1):00740-2023. doi: 10.1183/23120541.00740-2023. eCollection 2024 Jan.

ABSTRACT

BACKGROUND: Overnight desaturation predicts poor prognosis across interstitial lung diseases (ILDs). The aim of the present study was to investigate whether nocturnal desaturation is associated with pulmonary vasculopathy and mortality.

METHODS: A retrospective single centre study of 397 new ILD patients was carried out including patients with idiopathic pulmonary fibrosis (IPF) (n=107) and patients with non-IPF fibrotic ILD (n=290). This is the largest study to date of the effect of significant nocturnal desaturation (SND) (≥10% of total sleep time with oxygen saturation ≤90% measured by pulse oximetry).

RESULTS: The prevalence of SND was 28/107 (26.2%) in IPF and 80/290 (27.6%) in non-IPF ILD. The prevalence of SND was higher in non-IPF ILDs than in IPF (p=0.025) in multivariate analysis. SND was associated with noninvasive markers of pulmonary hypertension (PH): tricuspid regurgitation velocity (TRV) (p<0.0001), brain natriuretic peptide (p<0.007), carbon monoxide transfer coefficient (p<0.0001), A-a gradient (p<0.0001), desaturation >4% in 6-min walking test (p<0.03) and pulmonary artery diameter (p<0.005). SND was independently associated with high echocardiographic PH probability in the entire cohort (OR 2.865, 95% CI 1.486-5.522, p<0.002) and in non-IPF fibrotic ILD (OR 3.492, 95% CI 1.597-7.636, p<0.002) in multivariate analysis. In multivariate analysis, SND was associated with mortality in the entire cohort (OR 1.734, 95% CI 1.202-2.499, p=0.003) and in IPF (OR 1.908, 95% CI 1.120-3.251, p=0.017) and non-IPF fibrotic ILD (OR 1.663, 95% CI 1.000-2.819, p=0.041). Separate models with exclusion of each one of the diagnostic subgroups showed that no subgroup was responsible for this finding in non-IPF ILDs. SND was a stronger marker of 5-year mortality than markers of PH.

CONCLUSION: SND was associated with high echocardiographic probability and mortality and was a stronger predictor of mortality in IPF and non-IPF ILDs grouped together to power the study.

PMID:38348245 | PMC:PMC10860199 | DOI:10.1183/23120541.00740-2023

ERJ Open Res. 2024 Feb 12;10(1):00722-2023. doi: 10.1183/23120541.00722-2023. eCollection 2024 Jan.

ABSTRACT

BACKGROUND: Our objective was to evaluate the short-, medium- and long-term benefits of home-based pulmonary rehabilitation (PR) on the physical and affective components of dyspnoea in people with fibrotic idiopathic interstitial pneumonias (f-IIPs). Anxiety and depressive symptoms, fatigue, health-related quality of life and exercise tolerance were also assessed.

METHODS: Data on 166 individuals with f-IIPs who enrolled in an 8-week home-based PR programme (weekly supervised 90-min session) were retrospectively analysed. Assessments included the Dyspnoea-12 (D-12) questionnaire, Hospital Anxiety and Depression Scale, Fatigue Assessment Scale, Visual Simplified Respiratory Questionnaire and 6-min stepper test, and were performed at home at short, medium (6 months) and long (12 months) term.

RESULTS: Among the 166 individuals with f-IIPs who enrolled in PR, 75 (45%) and 91 (55%) participants had a diagnosis of idiopathic pulmonary fibrosis and fibrosing non-specific interstitial pneumonia, respectively, and 87 (52%) participants concluded a full year of follow-up. In the total group, both physical and affective components of dyspnoea were improved, at short, medium and long term, after PR. Overall, half of the participants reached the minimally important difference of 3 points of the D-12 questionnaire at the end of PR, and at the 6- and 12-month follow-ups. Anxiety and depressive symptoms, fatigue and health-related quality of life were also improved, while the short-term benefits in exercise tolerance were not maintained 1 year after PR.

CONCLUSION: An individualised home-based PR programme resulted in short-, medium- and long-term improvements in both physical and affective components of dyspnoea assessed by the D-12 questionnaire.

PMID:38348242 | PMC:PMC10860206 | DOI:10.1183/23120541.00722-2023

Front Immunol. 2024 Jan 25;15:1326922. doi: 10.3389/fimmu.2024.1326922. eCollection 2024.

ABSTRACT

Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma-associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging- and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissues from 38 SSc-ILD and 18 healthy controls and found that markers (GDF15, COMP, and CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found that epithelial and fibroblast senescence signatures had a 3.6- and 3.7-fold enrichment, respectively, in the lung tissue of SSc-ILD and that lung aging genes (CDKN2A, FRZB, PDE1A, and NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in the lung tissue and found that, independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.

PMID:38348044 | PMC:PMC10859856 | DOI:10.3389/fimmu.2024.1326922

J Clin Pharmacol. 2024 Feb 12. doi: 10.1002/jcph.2408. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a continuous, progressive, and lethal age-related respiratory disease. It is characterized by condensed and rigid lung tissue, which leads to a decline in the normal functioning of the lungs. The pathophysiology of IPF has still not been completely elucidated, so current strategies are lagging behind with respect to improving the condition of patients with IPF and increasing their survival rate. The desire for a better understanding of the pathobiology of IPF and its early detection has led to the identification of various biomarkers associated with IPF. The use of drugs such as pirfenidone and nintedanib as a safe and effective treatment alternative have marked a new chapter in the treatment of IPF. However, nonpharmacological therapies, involving long-term oxygen therapy, transplantation of the lungs, pulmonary rehabilitation, ventilation, and palliative care for cough and dyspnea, are still considered to be beneficial as supplementary methods for IPF therapy. A major risk factor for IPF is aging, with associated hallmarks such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis, and mitochondrial dysfunction. These are promising earmarks for the development of potential therapy for the disease. In this review, we have discussed current and emerging novel therapeutic strategies for IPF, especially for targets associated with age-related mechanisms.

PMID:38346921 | DOI:10.1002/jcph.2408

Chin Med J Pulm Crit Care Med. 2023 Jun;1(2):67-76. doi: 10.1016/j.pccm.2023.05.002. Epub 2023 Jun 19.

ABSTRACT

Tissue inhibitors of metalloproteases (TIMPs) have caught the attention of many scientists due to their role in various physiological and pathological processes. TIMP-1, 2, 3, and 4 are known members of the TIMPs family. TIMPs exert their biological effects by, but are not limited to, inhibiting the activity of metalloproteases (MMPs). The balance between MMPs and TIMPs is critical for maintaining homeostasis of the extracellular matrix (ECM), while the imbalance between MMPs and TIMPs can lead to pathological changes, such as cancer. In this review, we summarized the current knowledge of TIMP-1 in several pulmonary diseases namely, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), pneumonia, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and pulmonary fibrosis. Considering the potential of TIMP-1 serving as a non-invasive diagnostic and/or prognostic biomarker, we also reviewed the circulating TIMP-1 levels in translational and clinical studies.

PMID:38343891 | PMC:PMC10857872 | DOI:10.1016/j.pccm.2023.05.002

medRxiv. 2024 Jan 25:2024.01.24.24301742. doi: 10.1101/2024.01.24.24301742. Preprint.

ABSTRACT

RATIONALE: Neutrophil counts in bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis are associated with worse outcomes; however, the underlying mechanisms are unknown. Neutrophil extracellular trap formation is associated with worse outcomes in several chronic lung diseases however, there is an unknown role in idiopathic pulmonary fibrosis.

OBJECTIVES: To determine the relationship between neutrophil extracellular trap formation in the lungs of idiopathic pulmonary fibrosis patients and clinical outcomes.

METHODS: In a discovery cohort of 156 patients with idiopathic pulmonary fibrosis, we measured neutrophil extracellular trap markers in bronchoalveolar lavage fluid, including extracellular DNA, DNA-myeloperoxidase complexes, calprotectin, and neutrophil elastase. We assessed the correlation of these markers with baseline pulmonary function and survival. In a subset of 50 patients, label-free quantitative proteomics was performed to identify the source of extracellular DNA. A validation cohort of 52 patients was similarly assessed.

MEASUREMENTS AND MAIN RESULTS: Neutrophil extracellular trap markers in the discovery cohort were significantly correlated with worse pulmonary function (p<0.03). Higher levels of these markers predicted worse survival after adjusting for gender, age, and baseline physiologic severity (hazard ratio range: 1.79-2.19). Proteomics revealed a significant correlation between extracellular DNA levels and proteins related to neutrophil extracellular trap formation. The validation cohort showed that extracellular DNA levels were associated with reduced pulmonary function (p=0.04) and trend towards worse survival (hazard ratio=2.16).

CONCLUSIONS: Neutrophil extracellular trap formation markers were associated with disease severity and worse survival in idiopathic pulmonary fibrosis. These findings suggest neutrophil extracellular trap formation contributes to lung injury and decreased survival and may represent a potential therapeutic target.

PMID:38343853 | PMC:PMC10854325 | DOI:10.1101/2024.01.24.24301742

J Imaging Inform Med. 2024 Jan 11. doi: 10.1007/s10278-023-00914-w. Online ahead of print.

ABSTRACT

We previously validated Fibresolve, a machine learning classifier system that non-invasively predicts idiopathic pulmonary fibrosis (IPF) diagnosis. The system incorporates an automated deep learning algorithm that analyzes chest computed tomography (CT) imaging to assess for features associated with idiopathic pulmonary fibrosis. Here, we assess performance in assessment of patterns beyond those that are characteristic features of usual interstitial pneumonia (UIP) pattern. The machine learning classifier was previously developed and validated using standard training, validation, and test sets, with clinical plus pathologically determined ground truth. The multi-site 295-patient validation dataset was used for focused subgroup analysis in this investigation to evaluate the classifier's performance range in cases with and without radiologic UIP and probable UIP designations. Radiologic assessment of specific features for UIP including the presence and distribution of reticulation, ground glass, bronchiectasis, and honeycombing was used for assignment of radiologic pattern. Output from the classifier was assessed within various UIP subgroups. The machine learning classifier was able to classify cases not meeting the criteria for UIP or probable UIP as IPF with estimated sensitivity of 56-65% and estimated specificity of 92-94%. Example cases demonstrated non-basilar-predominant as well as ground glass patterns that were indeterminate for UIP by subjective imaging criteria but for which the classifier system was able to correctly identify the case as IPF as confirmed by multidisciplinary discussion generally inclusive of histopathology. The machine learning classifier Fibresolve may be helpful in the diagnosis of IPF in cases without radiological UIP and probable UIP patterns.

PMID:38343230 | DOI:10.1007/s10278-023-00914-w

Cancers (Basel). 2024 Jan 26;16(3):538. doi: 10.3390/cancers16030538.

ABSTRACT

The accurate selection of the recipient is a crucial aspect in the field of lung transplantation (LTX), especially if patients were previously affected by oncological disease. The aim of this bicentric retrospective study was to evaluate short- and long-term outcomes in patients with previous oncological disease or unknown neoplasia found on native lungs submitted to LTX, compared to a control group. A total of 433 patients were included in the analysis, 31 with malignancies (Group 1) and 402 without neoplastic disease (Group 2). The two groups were compared in terms of short- and long-term outcomes. Patients in Group 1 were older (median age 58 years vs. 50 years, p = 0.039) and mostly affected by idiopathic pulmonary fibrosis (55% vs. 40% p = 0.002). Even though in Group 1 a lower rate of late post-operative complications was found (23% vs. 45%, p = 0.018), the median overall survival (OS) was lower compared to the control group (10 months vs. 29 months, p = 0.015). LTX represents a viable therapeutic option for patients with end-stage lung disease and a history of neoplastic disease. However, every case should be carefully debated in a multidisciplinary setting, considering oncological (histology, stage, and proper disease free-interval) and clinical factors (patient's age and comorbidities). A scrupulous post-transplant follow-up is especially mandatory in those cases.

PMID:38339288 | PMC:PMC10854809 | DOI:10.3390/cancers16030538

Int J Mol Sci. 2024 Jan 26;25(3):1562. doi: 10.3390/ijms25031562.

ABSTRACT

The COVID-19 pandemic has had a significant impact on the health and economy of the global population. Even after recovery from the disease, post-COVID-19 symptoms, such as pulmonary fibrosis, continue to be a concern. This narrative review aims to address pulmonary fibrosis (PF) from various perspectives, including the fibrotic mechanisms involved in idiopathic and COVID-19-induced pulmonary fibrosis. On the other hand, we also discuss the current therapeutic drugs in use, as well as those undergoing clinical or preclinical evaluation. Additionally, this article will address various biomarkers with usefulness for PF prediction, diagnosis, treatment, prognosis, and severity assessment in order to provide better treatment strategies for patients with this disease.

PMID:38338840 | PMC:PMC10855955 | DOI:10.3390/ijms25031562

J Clin Med. 2024 Jan 30;13(3):797. doi: 10.3390/jcm13030797.

ABSTRACT

Hypersensitivity pneumonitis (HP) is a diffuse parenchymal lung disease (DLPD) characterized by complex interstitial lung damage with polymorphic and protean inflammatory aspects affecting lung tissue targets including small airways, the interstitium, alveolar compartments and vascular structures. HP shares clinical and often radiological features with other lung diseases in acute or chronic forms. In its natural temporal evolution, if specific therapy is not initiated promptly, HP leads to progressive fibrotic damage with reduced lung volumes and impaired gas exchange. The prevalence of HP varies considerably worldwide, influenced by factors like imprecise disease classification, diagnostic method limitations for obtaining a confident diagnosis, diagnostic limitations in the correct processing of high-resolution computed tomography (HRCT) radiological parameters, unreliable medical history, diverse geographical conditions, heterogeneous agricultural and industrial practices and occasionally ineffective individual protections regarding occupational exposures and host risk factors. The aim of this review is to present an accurate and detailed 360-degree analysis of HP considering HRCT patterns and the role of the broncho-alveolar lavage (BAL), without neglecting biopsy and anatomopathological aspects and future technological developments that could make the diagnosis of this disease less challenging.

PMID:38337490 | PMC:PMC10856167 | DOI:10.3390/jcm13030797

ACS Biomater Sci Eng. 2024 Feb 9. doi: 10.1021/acsbiomaterials.3c01499. Online ahead of print.

ABSTRACT

Fibrosis has been characterized as a global health problem and ranks as one of the primary causes of organ dysfunction. Currently, there is no cure for pulmonary fibrosis, and limited therapeutic options are available due to an inadequate understanding of the disease pathogenesis. The absence of advanced in vitro models replicating dynamic temporal changes observed in the tissue with the progression of the disease is a significant impediment in the development of novel antifibrotic treatments, which has motivated research on tissue-mimetic three-dimensional (3D) models. In this review, we summarize emerging trends in preparing advanced lung models to recapitulate biochemical and biomechanical processes associated with lung fibrogenesis. We begin by describing the importance of in vivo studies and highlighting the often poor correlation between preclinical research and clinical outcomes and the limitations of conventional cell culture in accurately simulating the 3D tissue microenvironment. Rapid advancement in biomaterials, biofabrication, biomicrofluidics, and related bioengineering techniques are enabling the preparation of in vitro models to reproduce the epithelium structure and operate as reliable drug screening strategies for precise prediction. Improving and understanding these model systems is necessary to find the cross-talks between growing cells and the stage at which myofibroblasts differentiate. These advanced models allow us to utilize the knowledge and identify, characterize, and hand pick medicines beneficial to the human community. The challenges of the current approaches, along with the opportunities for further research with potential for translation in this field, are presented toward developing novel treatments for pulmonary fibrosis.

PMID:38335198 | DOI:10.1021/acsbiomaterials.3c01499

Biochem Genet. 2024 Feb 9. doi: 10.1007/s10528-023-10650-z. Online ahead of print.

ABSTRACT

There is a potential link between rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF). The aim of this study is to investigate the molecular processes that underlie the development of these two conditions by bioinformatics methods. The gene expression samples for RA (GSE77298) and IPF (GSE24206) were retrieved from the Gene Expression Omnibus (GEO) database. After identifying the overlapping differentially expressed genes (DEGs) for RA and IPF, we conducted functional annotation, protein-protein interaction (PPI) network analysis, and hub gene identification. Finally, we used the hub genes to predict potential medications for the treatment of both disorders. We identified 74 common DEGs for further analysis. Functional analysis demonstrated that cellular components, biological processes, and molecular functions all played a role in the emergence and progression of RA and IPF. Using the cytoHubba plugin, we identified 7 important hub genes, namely COL3A1, SDC1, CCL5, CXCL13, MMP1, THY1, and BDNF. As diagnostic indicators for RA, SDC1, CCL5, CXCL13, MMP1, and THY1 showed favorable values. For IPF, COL3A1, SDC1, CCL5, CXCL13, THY1, and BDNF were favorable diagnostic markers. Furthermore, we predicted 61 Chinese and 69 Western medications using the hub genes. Our research findings demonstrate a shared pathophysiology between RA and IPF, which may provide new insights for more mechanistic research and more effective treatments. These common pathways and hub genes identified in our study offer potential opportunities for developing more targeted therapies that can address both disorders.

PMID:38334875 | DOI:10.1007/s10528-023-10650-z

Cells. 2024 Jan 26;13(3):238. doi: 10.3390/cells13030238.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown origin, with a median patient survival time of ~3 years after diagnosis without anti-fibrotic therapy. It is characterized by progressive fibrosis indicated by increased collagen deposition and high numbers of fibroblasts in the lung. It has been demonstrated that CCL18 induces collagen and αSMA synthesis in fibroblasts. We aimed to identify the CCL18 receptor responsible for its pro-fibrotic activities.

METHODS: We used a random phage display library to screen for potential CCL18-binding peptides, demonstrated its expression in human lungs and fibroblast lines by PCR and immunostaining and verified its function in cell lines.

RESULTS: We identified CCR6 (CD196) as a CCL18 receptor and found its expression in fibrotic lung tissue and lung fibroblast lines derived from fibrotic lungs, but it was almost absent in control lines and tissue. CCL18 induced receptor internalization in a CCR6-overexpressing cell line. CCR6 blockade in primary human lung fibroblasts reduced CCL18-induced FGF2 release as well as collagen-1 and αSMA expression. Knockdown of CCR6 in a mouse fibroblast cell line abolished the induction of collagen and α-smooth muscle actin expression.

CONCLUSION: Our data indicate that CCL18 triggers pro-fibrotic processes via CCR6, highlighting its role in fibrogenesis.

PMID:38334630 | PMC:PMC10854834 | DOI:10.3390/cells13030238

ACG Case Rep J. 2024 Feb 8;11(2):e01282. doi: 10.14309/crj.0000000000001282. eCollection 2024 Feb.

ABSTRACT

Nintedanib is a medication that has been increasingly used for treatment of idiopathic and progressive pulmonary fibrosis. In this case series, we describe 3 patients with colitis symptoms associated with nintedanib use. Nintedanib discontinuation resulted in symptomatic resolution in all patients. Budesonide decreased symptoms in 1 patient. Clinicians should be vigilant in taking a thorough medication history and include nintedanib as a cause for gastrointestinal symptoms including colitis.

PMID:38333722 | PMC:PMC10852397 | DOI:10.14309/crj.0000000000001282

J Pathol. 2024 Feb 9. doi: 10.1002/path.6253. Online ahead of print.

ABSTRACT

Pulmonary fibrosis, especially idiopathic pulmonary fibrosis (IPF), portends significant morbidity and mortality, and current therapeutic options are suboptimal. We have previously shown that type I collagen signaling through discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase expressed by fibroblasts, is critical for the regulation of fibroblast apoptosis and progressive fibrosis. However, the downstream signaling pathways for DDR2 remain poorly defined and could also be attractive potential targets for therapy. A recent phosphoproteomic approach indicated that PIK3C2α, a poorly studied member of the PI3 kinase family, could be a downstream mediator of DDR2 signaling. We hypothesized that collagen I/DDR2 signaling through PIK3C2α regulates fibroblast activity during progressive fibrosis. To test this hypothesis, we found that primary murine fibroblasts and IPF-derived fibroblasts stimulated with endogenous or exogenous type I collagen led to the formation of a DDR2/PIK3C2α complex, resulting in phosphorylation of PIK3C2α. Fibroblasts treated with an inhibitor of PIK3C2α or with deletion of PIK3C2α had fewer markers of activation after stimulation with TGFβ and more apoptosis after stimulation with a Fas-activating antibody. Finally, mice with fibroblast-specific deletion of PIK3C2α had less fibrosis after bleomycin treatment than did littermate control mice with intact expression of PIK3Cα. Collectively, these data support the notion that collagen/DDR2/PIK3C2α signaling is critical for fibroblast function during progressive fibrosis, making this pathway a potential target for antifibrotic therapy. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

PMID:38332727 | DOI:10.1002/path.6253