Ann Am Thorac Soc. 2023 Nov 14. doi: 10.1513/AnnalsATS.202304-323OC. Online ahead of print.

ABSTRACT

RATIONALE: Living in a disadvantaged neighborhood has been associated with worse survival in idiopathic pulmonary fibrosis (IPF), however prior studies have only examined the impact of neighborhood health on outcomes in IPF as a composite measure.

OBJECTIVES: Investigate the association between neighborhood health and disease severity, measured by pulmonary function at presentation, and death in follow-up, with an additional focus on the contributions of the neighborhood's underlying physical and social factors to these outcomes.

METHODS: In a retrospective study of participants from the University of California, San Francisco IPF Cohort (2001-2020), geocoded home addresses were matched to the California Healthy Places Index (HPI), a census-tract measure of neighborhood health. The HPI is comprised of 25 indicators of neighborhood health that are organized into eight physical and social domains, each of which is weighted and summed to provide a composite HPI score. Regression models were used to examine associations between the HPI as a continuous variable, in quartiles, and across each physical and social domain of the HPI (higher values indicate greater advantage) and forced vital capacity (FVC) %predicted, diffusion capacity for carbon monoxide (DLCO) %predicted, and death, adjusting for demographic and clinical covariates. We also studied the interaction between disease severity at presentation and neighborhood health in our time-to-event models.

RESULTS: In 783 participants with IPF, each 10% increase in HPI was associated with a 1% increase in FVC %predicted and DLCO %predicted (95%CI 0.55%, 1.72% and 95%CI 0.49%, 1.49%, respectively). This association appeared primarily driven by the economic, education, access, and social HPI domains. We also observed differences in the associations of HPI with mortality depending on disease severity at presentation. In participants with normal/mildly impaired FVC %predicted (≥70%) and DLCO %predicted (≥60%), decreased HPI was associated with higher mortality (HR=2.91 Q1 vs. Q4; 95%CI 1.20, 7.05). No association was observed between the HPI and death for participants with moderate/severely impaired FVC %predicted and DLCO %predicted.

CONCLUSIONS: Living in disadvantaged neighborhoods was associated with worse pulmonary function in participants with IPF and was independently associated with increased mortality in participants with normal to mild physiological impairment at presentation.

PMID:37962494 | DOI:10.1513/AnnalsATS.202304-323OC

medRxiv. 2023 Nov 5:2023.11.03.23297727. doi: 10.1101/2023.11.03.23297727. Preprint.

ABSTRACT

BACKGROUND: Anti-MDA5 (Melanoma differentiation-associated protein-5) positive dermatomyositis (MDA5 + -DM) is characterised by rapidly progressive interstitial lung disease (ILD) and high mortality. MDA5 senses single-stranded RNA and is a key pattern recognition receptor for the SARS-CoV-2 virus.

METHODS: This is a retrospective observational study of a surge in MDA5 autoimmunity, as determined using a 15 muscle-specific autoantibodies (MSAs) panel, between Janurary 2018-December 2022 in Yorkshire, UK. MDA5-positivity was correlated with clinical features and outcome, and regional SARS-CoV-2 positivity and vaccination rates. Gene expression patterns in COVID-19 were compared with autoimmune lung disease and idiopathic pulmonary fibrosis (IPF) to gain clues into the genesis of the observed MDA5 + -DM outbreak.

RESULTS: Sixty new anti-MDA5+, but not other MSAs surged between 2020-2022, increasing from 0.4% in 2019 to 2.1% (2020), 4.8% (2021) and 1.7% (2022). Few (8/60) had a prior history of confirmed COVID-19, peak rates overlapped with regional SARS-COV-2 community positivity rates in 2021, and 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. Few (8/60) had a prior history of COVID-19, whereas 58% (35/60) had received anti-SARS-CoV-2 RNA vaccines. 25/60 cases developed ILD which rapidly progression with death in 8 cases. Among the 35/60 non-ILD cases, 14 had myositis, 17 Raynaud phenomena and 10 had dermatomyositis spectrum rashes. Transcriptomic studies showed strong IFIH1 (gene encoding for MDA5) induction in COVID-19 and autoimmune-ILD, but not IPF, and IFIH1 strongly correlated with an IL-15-centric type-1 interferon response and an activated CD8+ T cell signature that is an immunologic hallmark of progressive ILD in the setting of systemic autoimmune rheumatic diseases. The IFIH1 rs1990760TT variant blunted such response.

CONCLUSIONS: A distinct pattern of MDA5-autoimmunity cases surged contemporaneously with circulation of the SARS-COV-2 virus during COVID-19. Bioinformatic insights suggest a shared immunopathology with known autoimmune lung disease mechanisms.

PMID:37961408 | PMC:PMC10635254 | DOI:10.1101/2023.11.03.23297727

Aging Cell. 2023 Nov 13:e14024. doi: 10.1111/acel.14024. Online ahead of print.

ABSTRACT

The study of aging and its mechanisms, such as cellular senescence, has provided valuable insights into age-related pathologies, thus contributing to their prevention and treatment. The current abundance of high-throughput data combined with the surge of robust analysis algorithms has facilitated novel ways of identifying underlying pathways that may drive these pathologies. For the purpose of identifying key regulators of lung aging, we performed comparative analyses of transcriptional profiles of aged versus young human subjects and mice, focusing on the common age-related changes in the transcriptional regulation in lung macrophages, T cells, and B immune cells. Importantly, we validated our findings in cell culture assays and human lung samples. Our analysis identified lymphoid enhancer binding factor 1 (LEF1) as an important age-associated regulator of gene expression in all three cell types across different tissues and species. Follow-up experiments showed that the differential expression of long and short LEF1 isoforms is a key regulatory mechanism of cellular senescence. Further examination of lung tissue from patients with idiopathic pulmonary fibrosis, an age-related disease with strong ties to cellular senescence, revealed a stark dysregulation of LEF1. Collectively, our results suggest that LEF1 is a key factor of aging, and its differential regulation is associated with human and murine cellular senescence.

PMID:37961030 | DOI:10.1111/acel.14024

J Clin Med. 2023 Oct 29;12(21):6832. doi: 10.3390/jcm12216832.

ABSTRACT

Although the level of physical activity in daily life (PADL) plays a vital role concerning the health of subjects with chronic lung diseases, it remains uncertain how PADL patterns compare among different conditions. This study's objective was to compare the PADL levels of subjects with COPD, asthma and idiopathic pulmonary fibrosis (IPF); and to investigate PADL behaviour in different diseases' severity. Stable subjects who had not undergone pulmonary rehabilitation in the previous year were included. Subjects were divided into two subgroups according to disease severity: mild/moderate and severe/very severe. The primary outcome was time spent in moderate-to-vigorous physical activities (MVPA) (Actigraph GT3x) measured during one week over 12 h/day; other assessments included pulmonary function, peripheral muscle strength and exercise capacity. Comparisons among subgroups were corrected for age, BMI and sex. The analysis involved 119 subjects (47 asthma, 48 COPD and 24 IPF). Subjects with asthma had higher PADL levels than those with COPD and IPF (MVPA 18(14-22) vs. 8(4-12) vs. 7(1-12) min/day, respectively; p ancova = 0.002). Subjects with severe/very severe IPF had the lowest PADL level among all subgroups. Adult subjects with asthma have higher PADL levels than those with COPD and IPF, whereas patients with severe and very severe IPF are the most physically inactive subjects.

PMID:37959297 | DOI:10.3390/jcm12216832

Int J Mol Sci. 2023 Oct 31;24(21):15813. doi: 10.3390/ijms242115813.

ABSTRACT

Idiopathic pulmonary fibrosis has poor clinical outcomes despite antifibrotic treatment. The nucleotide-binding domain leucine-rich repeat-containing receptor, pyrin domain-containing-3 (NLRP3) inflammasome and endothelial-to-mesenchymal transition (EndoMT) were shown to be involved in the pathogenesis of pulmonary fibrosis. However, the detailed mechanism is unknown. Our study aimed to investigate the role of the NLRP3 inflammasome in the regulation of EndoMT in pulmonary fibrosis. The inhibition of the NLRP3 inflammasome via a caspase-1 inhibitor, Ac-YVAD-cmk (YVAD), was intraperitoneally administered to male C57BL/6 mice (8-12 weeks old) one hour before bleomycin intratracheal injection (1.5 U/kg). Immunohistochemical staining, Masson's trichrome staining, enzyme-linked immunosorbent assay, immunofluorescence, and Western blotting were used to assess the activity of the NLRP3 inflammasome and EndoMT in lung samples from mice. Human pulmonary microvascular endothelial cells (HPMECs) were used as a model of EndoMT in vitro with YVAD and bleomycin stimulation. We observed the activation of the NLRP3 inflammasome and EndoMT (decreased vascular endothelial cadherin with increased alpha-smooth muscle actin and vimentin) in the lung samples after bleomycin. However, inhibition of the NLRP3 inflammasome significantly reduces EndoMT via inhibiting focal adhesion kinase (FAK). In vitro studies also confirmed these findings. In conclusion, NLRP3 inflammasome inhibition could reduce lung inflammation and fibrosis via the regulation of EndoMT by the FAK pathway.

PMID:37958797 | DOI:10.3390/ijms242115813

Int J Mol Sci. 2023 Oct 31;24(21):15811. doi: 10.3390/ijms242115811.

ABSTRACT

The extracellular matrix (ECM) is a dynamic complex protein network that provides structural integrity and plays an active role in shaping fibroblast behavior both in health and disease. Despite its essential functions, the impact of age-associated post-translational modifications on ECM-driven fibroblast activities such as proliferation, survival, fibroblast-to-myofibroblast transformation (FMT), and extracellular matrix production remains largely unknown. Nε-carboxymethyl-lysine (CML) is one of the well-characterized advanced glycation end-products (AGEs) that can occur on lysine residues within ECM proteins through non-enzymatic glycation. In this study, we determined the accumulation and the effects of the CML-modified ECM (CML-ECM) on fibroblast activation. Immunostainings and immunoblot analysis demonstrated significant increases in CML-AGE content in idiopathic pulmonary fibrosis (IPF) compared to age-matched healthy lungs. Gene expression analysis and fibroblast activation assays collectively implicate the ECM as a negative regulator of fibroblast activation. Notably, the CML modification of the ECM resulted in a significant decrease in its anti-fibrotic effects including proliferation, FMT, apoptosis, and ECM production. Together, the results of this study revealed an unexplored pathological role played by the CML-ECM on fibroblast activation, which has wide implications in IPF and other fibrotic diseases.

PMID:37958795 | DOI:10.3390/ijms242115811

Cureus. 2023 Oct 10;15(10):e46816. doi: 10.7759/cureus.46816. eCollection 2023 Oct.

ABSTRACT

INTRODUCTION: To investigate the feasibility of early surgical treatment and perioperative steroid use in patients with interstitial lung disease (ILD) complicated by pneumothorax.

METHODS: We retrospectively examined data, including patient characteristics, laboratory findings, surgical treatment details, postoperative complications, and deaths, of nine patients with ILD complicated by secondary pneumothorax. The patients had been treated at our hospital during the past 10 years.

RESULTS: All nine patients were male (median age, 69.0 years). A total of nine patients had a histopathologic diagnosis of ILD after surgery. Of these, five were clinically diagnosed with ILD before surgery. Collagen disease was diagnosed in one case, drug-induced in one case, and idiopathic ILD (IILD) in three cases. All nine patients were diagnosed with postoperative ILD, including one case of collagen disease, one case of drug-induced, three cases of idiopathic pulmonary fibrosis (IPF)/cryptogenic fibrosing alveolitis, one case of nonspecific interstitial pneumonia (NSIP), and three cases of cryptogenic organizing pneumonia (COP). Regarding preoperative clinical characteristics, the performance status (PS) was 0 or 1 in all patients. Overall, three patients received oxygen (0-3 L/min), whereas steroids were administered to five patients. The mean drainage period was 23.5 days, and this was consistent with the time taken from pneumothorax occurrence to surgery. Video-assisted thoracic surgery (VATS) and thoracoscopic-assisted surgery were performed in seven and two patients, respectively. No postoperative recurrence or surgery-related deaths occurred.

CONCLUSIONS: Early surgery for secondary pneumothorax complicated by ILD may be a viable option for patients in good preoperative condition. For patients who are preoperatively treated with steroids, continued use of steroids should be carefully considered.

PMID:37954808 | PMC:PMC10636492 | DOI:10.7759/cureus.46816

Expert Opin Emerg Drugs. 2023 Nov 12:1-14. doi: 10.1080/14728214.2023.2281416. Online ahead of print.

ABSTRACT

INTRODUCTION: Currently approved drug treatments for idiopathic pulmonary fibrosis (IPF), pirfenidone and nintedanib, have been shown to slow lung function decline and improve clinical outcomes. Since significant advances in the understanding of pathogenetic mechanisms in IPF, novel potential agents are being tested to identify new targeted and better tolerated therapeutic strategies.

AREAS COVERED: This review describes the evidence from IPF phase II and III clinical trials that have been completed or are ongoing in recent years. The literature search was performed using Medline and Clinicaltrials.org databases. Particular attention is paid to the new inhibitor of phosphodiesterase 4B (BI 1015550), being studied in a more advanced research phase. Some emerging critical issues of the pharmacological research are highlighted considering the recent outstanding failures of several phase III trials.

EXPERT OPINION: An exponential number of randomized clinical trials are underway testing promising new molecules to increase treatment choices for patients with IPF and improve patients' quality of life. The next goals should aim at a deeper understanding of the pathogenic pathways of the disease with the challenging goal of being able not only to stabilize but also to reverse the ongoing fibrotic process in patients with IPF.

PMID:37953604 | DOI:10.1080/14728214.2023.2281416

Phytother Res. 2023 Nov 12. doi: 10.1002/ptr.8070. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), as the most common idiopathic interstitial pneumonia, is caused by a complex interaction of pathological mechanisms. Interestingly, IPF frequently occurs in the middle-aged and elderly populations but rarely affects young people. Salvianolic acid B (SAB) exerts antioxidant, antiinflammatory, and antifibrotic bioactivities and is considered a promising drug for pulmonary disease treatment. However, the pharmacological effects and mechanisms of SAB on cellular senescence of lung cells and IPF development remain unclear. We used bleomycin (BLM)-induced pulmonary fibrosis mice and different lung cells to investigate the antisenescence impact of SAB and explain its underlying mechanism by network pharmacology and the Human Protein Atlas database. Here, we found that SAB significantly prevented pulmonary fibrosis and cellular senescence in mice, and reversed the senescence trend and typical senescence-associated secretory phenotype (SASP) factors released from lung macrophages and alveolar type II (AT2) epithelial cells, which further reduced lung fibroblasts activation. Additionally, SAB alleviated the epithelial-mesenchymal transition process of AT2 cells induced by transforming growth factor beta. By predicting potential targets of SAB that were then confirmed by chromatin immunoprecipitation-qPCR technology, we determined that SAB directly hampered the binding of transcription factor stimulating protein 1 to the promoters of SASPs (P21 and P16), thus halting lung cell senescence. We demonstrated that SAB reduced BLM-induced AT2 and macrophage senescence, and the subsequent release of SASP factors that activated lung fibroblasts, thereby dual-relieving IPF. This study provides a new scientific foundation and perspective for pulmonary fibrosis therapy.

PMID:37953063 | DOI:10.1002/ptr.8070

Pharmacol Ther. 2023 Nov 10:108562. doi: 10.1016/j.pharmthera.2023.108562. Online ahead of print.

ABSTRACT

The pathogenesis of pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and other forms of interstitial lung disease, involves a complex interplay of various factors including host genetics, environmental pollutants, infection, aberrant repair and dysregulated immune responses. Highly variable clinical outcomes of some ILDs, in particular IPF, have made it difficult to identify the precise mechanisms involved in disease pathogenesis and thus the development of a specific cure or treatment to halt and reverse the decline in patient health. With the advent of in-depth molecular diagnostics, it is becoming evident that the pathogenesis of IPF is unlikely to be the same for all patients and therefore will likely require different treatment approaches. Chronic inflammation is a cardinal feature of IPF and is driven by both innate and adaptive immune responses. Inflammatory cells and activated fibroblasts secrete various pro-inflammatory cytokines and chemokines that perpetuate the inflammatory response and contribute to the recruitment and activation of more immune cells and fibroblasts. The balance between pro-inflammatory and regulatory immune cell subsets, as well as the interactions between immune cell types and resident cells within the lung microenvironment, ultimately determines the extent of fibrosis and the potential for resolution. This review examines the role of the innate and adaptive immune responses in pulmonary fibrosis, with an emphasis on IPF. The role of different immune cell types is discussed as well as novel anti-inflammatory and immunotherapy approaches currently in clinical trial or in preclinical development.

PMID:37952904 | DOI:10.1016/j.pharmthera.2023.108562

J Transl Med. 2023 Nov 11;21(1):805. doi: 10.1186/s12967-023-04668-5.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common idiopathic interstitial lung disease. Clinical models to accurately evaluate the prognosis of IPF are currently lacking. This study aimed to construct an easy-to-use and robust prediction model for transplant-free survival (TFS) of IPF based on clinical and radiological information.

METHODS: A multicenter prognostic study was conducted involving 166 IPF patients who were followed up for 3 years. The end point of follow-up was death or lung transplantation. Clinical information, lung function tests, and chest computed tomography (CT) scans were collected. Body composition quantification on CT was performed using 3D Slicer software. Risk factors in blood routine examination-radiology-pulmonary function (BRP) were identified by Cox regression and utilized to construct the "BRP Prognosis Model". The performance of the BRP model and the gender-age-physiology variables (GAP) model was compared using time-ROC curves, calibration curves, and decision curve analysis (DCA). Furthermore, histopathology fibrosis scores in clinical specimens were compared between the different risk stratifications identified by the BRP model. The correlations among body composition, lung function, serum inflammatory factors, and profibrotic factors were analyzed.

RESULTS: Neutrophil percentage > 68.3%, pericardial adipose tissue (PAT) > 94.91 cm3, pectoralis muscle radiodensity (PMD) ≤ 36.24 HU, diffusing capacity of the lung for carbon monoxide/alveolar ventilation (DLCO/VA) ≤ 56.03%, and maximum vital capacity (VCmax) < 90.5% were identified as independent risk factors for poor TFS among patients with IPF. We constructed a BRP model, which showed superior accuracy, discrimination, and clinical practicability to the GAP model. Median TFS differed significantly among patients at different risk levels identified by the BRP model (low risk: TFS > 3 years; intermediate risk: TFS = 2-3 years; high risk: TFS ≈ 1 year). Patients with a high-risk stratification according to the BRP model had a higher fibrosis score on histopathology. Additionally, serum proinflammatory markers were positively correlated with visceral fat volume and infiltration.

CONCLUSIONS: In this study, the BRP prognostic model of IPF was successfully constructed and validated. Compared with the commonly used GAP model, the BRP model had better performance and generalization with easily obtainable indicators. The BRP model is suitable for clinical promotion.

PMID:37951977 | DOI:10.1186/s12967-023-04668-5

Trends Immunol. 2023 Nov 9:S1471-4906(23)00210-7. doi: 10.1016/j.it.2023.10.003. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal chronic interstitial lung disease (ILD) that affects lung mechanical functions and gas exchange. IPF is caused by increased fibroblast activity and collagen deposition that compromise the alveolar-capillary barrier. Identifying an effective therapy for IPF remains a clinical challenge. Chemokines are key proteins in cell communication that have functions in immunity as well as in tissue homeostasis, damage, and repair. Chemokine receptor signaling induces the activation and proliferation of lung-resident cells, including alveolar macrophages (AMs) and fibroblasts. AMs are an important source of chemokines and cytokines during IPF. We highlight the complexity of this system and, based on insights from genetic and transcriptomic studies, propose a new role for homeostatic chemokine imbalance in IPF, with implications for putative therapeutic targets.

PMID:37951789 | DOI:10.1016/j.it.2023.10.003

Cell Mol Life Sci. 2023 Nov 11;80(12):357. doi: 10.1007/s00018-023-05005-1.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a progressively fatal and incurable disease characterized by the loss of alveolar structures, increased epithelial-mesenchymal transition (EMT), and aberrant tissue repair. In this study, we investigated the role of Nuclear Factor I-B (NFIB), a transcription factor critical for lung development and maturation, in IPF. Using both human lung tissue samples from patients with IPF, and a mouse model of lung fibrosis induced by bleomycin, we showed that there was a significant reduction of NFIB both in the lungs of patients and mice with IPF. Furthermore, our in vitro experiments using cultured human lung cells demonstrated that the loss of NFIB was associated with the induction of EMT by transforming growth factor beta (TGF-β). Knockdown of NFIB promoted EMT, while overexpression of NFIB suppressed EMT and attenuated the severity of bleomycin-induced lung fibrosis in mice. Mechanistically, we identified post-translational regulation of NFIB by miR-326, a miRNA with anti-fibrotic effects that is diminished in IPF. Specifically, we showed that miR-326 stabilized and increased the expression of NFIB through its 3'UTR target sites for Human antigen R (HuR). Moreover, treatment of mice with either NFIB plasmid or miR-326 reversed airway collagen deposition and fibrosis. In conclusion, our study emphasizes the critical role of NFIB in lung development and maturation, and its reduction in IPF leading to EMT and loss of alveolar structures. Our study highlights the potential of miR-326 as a therapeutic intervention for IPF. The schema shows the role of NFIB in maintaining the normal epithelial cell characteristics in the lungs and how its reduction leads to a shift towards mesenchymal cell-like features and pulmonary fibrosis. A In normal lungs, NFIB is expressed abundantly in the epithelial cells, which helps in maintaining their shape, cell polarity and adhesion molecules. However, when the lungs are exposed to factors that induce pulmonary fibrosis, such as bleomycin, or TGF-β, the epithelial cells undergo epithelial to mesenchymal transition (EMT), which leads to a decrease in NFIB. B The mesenchymal cells that arise from EMT appear as spindle-shaped with loss of cell junctions, increased cell migration, loss of polarity and expression of markers associated with mesenchymal cells/fibroblasts. C We designed a therapeutic approach that involves exogenous administration of NFIB in the form of overexpression plasmid or microRNA-326. This therapeutic approach decreases the mesenchymal cell phenotype and restores the epithelial cell phenotype, thus preventing the development or progression of pulmonary fibrosis.

PMID:37950757 | DOI:10.1007/s00018-023-05005-1

Chest. 2023 Nov 8:S0012-3692(23)05703-3. doi: 10.1016/j.chest.2023.11.008. Online ahead of print.

NO ABSTRACT

PMID:37949294 | DOI:10.1016/j.chest.2023.11.008

ASAIO J. 2023 Nov 7. doi: 10.1097/MAT.0000000000002055. Online ahead of print.

ABSTRACT

Single lung transplantation (LUTX) can be the last therapeutic option for a growing cohort of patients suffering from end-stage respiratory failure. Postoperative ventilatory management of single LUTX recipients is challenged by the coexistence of the diseased native lung and a healthy-but fragile-graft. In this case report, in a single LUTX recipient with idiopathic pulmonary fibrosis, regional ventilation (), perfusion (), and / matching and subsequent measurement of shunt fraction (Qs/Qt) and alveolar dead space (Vd/Vt) were obtained by integrating electrical impedance tomography (EIT) with volumetric capnography and pulmonary thermodilution technique. Although the preoperative pulmonary scintigraphy showed predominant right lung perfusion (79.8% vs. 20.2%), the EIT documented the postoperative re-establishment of between the lungs (demonstrating the adequate functioning of vascular anastomoses), the diversion of to the graft and similar global Qs/Qt (17%) and Vd/Vt (29%) between native and graft lung. Electrical impedance tomography mapping allowed regional Qs/Qt and Vd/Vt assessment: the native right lung had a completely deranged distribution of and (Qs/Qt 25%, Vd/Vt 46%), whereas the graft showed normal coupling of and (Qs/Qt 8%, Vd/Vt 12%). Electrical impedance tomography may allow noninvasive, repeatable, bedside assessments of the lung / coupling after single LUTX.

PMID:37949061 | DOI:10.1097/MAT.0000000000002055

Clin Radiol. 2023 Oct 29:S0009-9260(23)00493-2. doi: 10.1016/j.crad.2023.10.013. Online ahead of print.

ABSTRACT

AIM: To review histologically confirmed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) cases and carry out a detailed pathological-radiological correlation to see if computed tomography (CT) can be used to confidently identify DIPNECH.

MATERIALS AND METHODS: Twenty-three histologically confirmed DIPNECH patients in the shared database of two NHS Trusts were reviewed. CT images were reviewed by two independent radiologists, each of them with >10 years of experience in thoracic imaging. All histological specimens were reviewed by a single pathologist with >25 years of experience. The diagnosis of DIPNECH was made according to the current World Health Organization (WHO) definition included in the WHO 2015 classification of pulmonary tumours. The results on histology were compared to the presence of nodules and air trapping on CT. Demographic information and, when available, molecular imaging studies and pulmonary function tests were also considered.

RESULTS: There are prototypal clinical and radiological findings reflecting the presence of underlying histological DIPNECH: middle-aged women with multiple small and scattered nodules due to the clustering and proliferation of neuroendocrine cells. At least one larger, dominant, lung nodule reflecting a carcinoid tumour is very common and mosaic attenuation/air trapping is seen approximately in 50% of cases in inspiratory scans. Airflow obstruction is rarely associated with histological bronchial or peribronchial fibrosis, which suggests other mechanisms must be involved in its development.

CONCLUSION: CT can be used to predict pathological DIPNECH in the appropriate clinical setting. It is important to consider DIPNECH to avoid overdiagnosis of more sinister conditions such as lung cancer or metastases.

PMID:37945436 | DOI:10.1016/j.crad.2023.10.013

BMJ Open Respir Res. 2023 Nov;10(1):e001568. doi: 10.1136/bmjresp-2022-001568.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis is a progressive fibrotic lung disease with limited therapeutic options and high lethality, related to alveolar type II epithelial (ATII) cell dysregulation, the abnormal repair of alveolar epithelial cells and activation of fibroblasts promote the development of pulmonary fibrosis. Fatty acid binding protein 1 (FABP1) was significantly downregulated in the fibrotic state by proteomics screening in our previous date, and the ATII cell dysregulation can be mediated by FABP1 via regulating fatty acid metabolism and intracellular transport. The aim of this study was to evaluate the role and potential mechanism of FABP1 in the development of pulmonary fibrosis.

METHODS: Proteomics screening was used to detect changes of the protein profiles in two different types (induced by bleomycin and silica, respectively) of pulmonary fibrosis models. The localisation of FABP1 in mouse lung was detected by Immunofluorescence and immunohistochemistry. Experimental methods such as lung pathology, micro-CT, western blotting, small animal imaging in vivo, EdU, etc were used to verify the role of FABP1 in pulmonary fibrosis.

RESULTS: The expression of FABP1 in the mouse lung was significantly reduced in the model of pulmonary fibrosis from our proteomic analysis and immunological methods, the double immunofluorescence staining showed that FABP1 was mainly localised in type II alveolar epithelial cells. Additionally, the expression of FABP1 was negatively correlated with the progression of pulmonary fibrosis. Further in vivo and in vitro experiments showed that overexpression of FABP1 alleviated pulmonary fibrosis by protecting alveolar epithelium from injury and promoting cell survival.

CONCLUSION: Our findings provide a proof-of-principle that FABP1 may represent an effective treatment for pulmonary fibrosis by regulating alveolar epithelial regeneration, which may be associated with the fatty acid metabolism in ATII cells.

PMID:37940355 | DOI:10.1136/bmjresp-2022-001568

RMD Open. 2023 Nov;9(4):e003426. doi: 10.1136/rmdopen-2023-003426.

ABSTRACT

Objective The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable and different from continuously progressive idiopathic pulmonary fibrosis (IPF). Most proposed definitions of progressive pulmonary fibrosis or SSc-ILD severity are based on the research data from patients with IPF and are not validated for patients with SSc-ILD. Our study aimed to gather the current evidence for severity, progression and outcomes of SSc-ILD.Methods A systematic literature review to search for definitions of severity, progression and outcomes recorded for SSc-ILD was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in Medline, Embase, Web of Science and Cochrane Library up to 1 August 2023.Results A total of 9054 papers were reviewed and 342 were finally included. The most frequent tools used for the definition of SSc-ILD progression and severity were combined changes of carbon monoxide diffusing capacity (DLCO) and forced vital capacity (FVC), isolated FVC or DLCO changes, high-resolution CT (HRCT) extension and composite algorithms including pulmonary function test, clinical signs and HRCT data. Mortality was the most frequently reported long-term event, both from all causes or ILD related.Conclusions The studies presenting definitions of SSc-ILD 'progression', 'severity' and 'outcome' show a large heterogeneity. These results emphasise the need for developing a standardised, consensus definition of severe SSc-ILD, to link a disease specific definition of progression as a surrogate outcome for clinical trials and clinical practice.PROSPERO registration number CRD42022379254.Cite Now.

PMID:37940340 | DOI:10.1136/rmdopen-2023-003426

Purinergic Signal. 2023 Nov 8. doi: 10.1007/s11302-023-09973-8. Online ahead of print.

ABSTRACT

Adenosine receptor (AR) suppresses inflammation and fibrosis by activating cyclic adenosine monophosphate (cAMP) signaling. We investigated whether altered AR expression contributes to the development of fibrotic diseases and whether A2AAR and A2BAR upregulation inhibits fibrotic responses. Primary human lung fibroblasts (HLFs) from normal (NHLFs) or patients with idiopathic pulmonary fibrosis (DHLF) were used for in vitro testing. Murine models of fibrotic liver or pulmonary disease were developed by injecting thioacetamide intraperitoneally, by feeding a high-fat diet, or by intratracheal instillation of bleomycin. Modafinil, which activates cAMP signaling via A2AAR and A2BAR, was administered orally. The protein amounts of A2AAR, A2BAR, and exchange protein directly activated by cAMP (Epac) were reduced, while collagen and α-smooth muscle actin (α-SMA) were elevated in DHLFs compared to NHLFs. In liver or lung tissue from murine models of fibrotic diseases, A2AAR and A2BAR were downregulated, but A1AR and A3AR were not. Epac amounts decreased, and amounts of collagen, α-SMA, KCa2.3, and KCa3.1 increased compared to the control. Modafinil restored the amounts of A2AAR, A2BAR, and Epac, and reduced collagen, α-SMA, KCa2.3, and KCa3.1 in murine models of fibrotic diseases. Transforming growth factor-β reduced the amounts of A2AAR, A2BAR, and Epac, and elevated collagen, α-SMA, KCa2.3, and KCa3.1 in NHLFs; however, these alterations were inhibited by modafinil. Our investigation revealed that A2AAR and A2BAR downregulation induced liver and lung fibrotic diseases while upregulation attenuated fibrotic responses, suggesting that A2AAR and A2BAR-upregulating agents, such as modafinil, may serve as novel therapies for fibrotic diseases.

PMID:37938538 | DOI:10.1007/s11302-023-09973-8

Sci Rep. 2023 Nov 8;13(1):19393. doi: 10.1038/s41598-023-46733-5.

ABSTRACT

Abnormal deposition of extracellular matrix (ECM) in lung tissue is a characteristic of idiopathic pulmonary fibrosis (IPF). Increased collagen deposition is also accompanied by altered collagen organization. Collagen type XIV, a fibril-associated collagen, supports collagen fibril organization. Its status in IPF has not been described at the protein level yet. In this study, we utilized publicly available datasets for single-cell RNA-sequencing for characterizing collagen type XIV expression at the gene level. For protein level comparison, we applied immunohistochemical staining for collagen type XIV on lung tissue sections from IPF patients and compared it to lung tissue sections from never smoking and ex-smoking donors. Analyzing the relative amounts of collagen type XIV at the whole tissue level, as well as in parenchyma, airway wall and bronchial epithelium, we found consistently lower proportions of collagen type XIV in all lung tissue compartments across IPF samples. Our study suggests proportionally lower collagen type XIV in IPF lung tissues may have implications for the assembly of the ECM fibers potentially contributing to progression of fibrosis.

PMID:37938243 | DOI:10.1038/s41598-023-46733-5