Respir Med Case Rep. 2023 Apr 7;43:101846. doi: 10.1016/j.rmcr.2023.101846. eCollection 2023.

ABSTRACT

An 87-year-old man presented with dyspnea. Computed tomography revealed progressive subpleural consolidation in the apex, reticular shadows in the lower lobes, and bilateral ground glass opacifications. He died of respiratory failure on day 3. The post-mortem examination showed exudative stage diffuse alveolar damage and pulmonary edema. Intraalveolar collagenous fibrosis and subpleural elastosis were observed in the upper lobes, accompanied by interlobular septal and pleural thickening and lung architecture remodeling in the lower lobes. He was diagnosed with acute exacerbation of pleuroparenchymal fibroelastosis with lower lobe usual interstitial pneumonia, which can be fatal.

PMID:37077237 | PMC:PMC10106554 | DOI:10.1016/j.rmcr.2023.101846

Respir Res. 2023 Apr 7;24(1):101. doi: 10.1186/s12931-023-02403-8.

ABSTRACT

BACKGROUND: Cellular senescence is a cell fate in response to diverse forms of age-related damage and stress that has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). The associations between circulating levels of candidate senescence biomarkers and disease outcomes have not been specifically studied in IPF. In this study we assessed the circulating levels of candidate senescence biomarkers in individuals affected by IPF and controls and evaluated their ability to predict disease outcomes.

METHODS: We measured the plasma concentrations of 32 proteins associated with senescence in Lung Tissue Research Consortium participants and studied their relationship with the diagnosis of IPF, parameters of pulmonary and physical function, health-related quality of life, mortality, and lung tissue expression of P16, a prototypical marker of cellular senescence. A machine learning approach was used to evaluate the ability of combinatorial biomarker signatures to predict disease outcomes.

RESULTS: The circulating levels of several senescence biomarkers were significantly elevated in persons affected by IPF compared to controls. A subset of biomarkers accurately classified participants as having or not having the disease and was significantly correlated with measures of pulmonary function, health-related quality of life and, to an extent, physical function. An exploratory analysis revealed senescence biomarkers were also associated with mortality in IPF participants. Finally, the plasma concentrations of several biomarkers were associated with their expression levels in lung tissue as well as the expression of P16.

CONCLUSIONS: Our results suggest that circulating levels of candidate senescence biomarkers are informative of disease status, pulmonary and physical function, and health-related quality of life. Additional studies are needed to validate the combinatorial biomarkers signatures that emerged using a machine learning approach.

PMID:37029417 | DOI:10.1186/s12931-023-02403-8

Medicine (Baltimore). 2023 Apr 7;102(14):e33466. doi: 10.1097/MD.0000000000033466.

ABSTRACT

S100 protein family, which represents 25 relatively small calcium binding proteins, is involved in many intracellular and/or extracellular processes, including differentiation, apoptosis, migration/invasion, Ca2+ homeostasis, inflammation, and tissue repair. As an important member, S100A4 was reported to have an abnormal expression in several lung diseases, such as lung cancer, pulmonary hypertension, idiopathic pulmonary fibrosis (IPF), etc. For example, in lung cancer, S100A4 was demonstrated to be associated to metastatic tumor progression and epithelial to mesenchymal transition (EMT). In IPF, S100A4 was considered as a promising serum biomarker predicting disease progression. Various studies in recent years focused on the S100A4 function in lung diseases, showing researchers' interests on this protein. It is necessary to focuses on relative studies, and make a comprehensive understanding of S100A4 in common pulmonary diseases. By doing this, this paper provides a review of the evidence for S100A4 in lung cancer, chronic obstructive pulmonary disease (COPD), asthma, IPF and pulmonary hypertension.

PMID:37026957 | DOI:10.1097/MD.0000000000033466

Heliyon. 2023 Mar 25;9(4):e14768. doi: 10.1016/j.heliyon.2023.e14768. eCollection 2023 Apr.

ABSTRACT

BACKGROUND: The diagnostic process of pulmonary fibrosis (PF) is often challenging, requires a collaborative effort of several experts, and often requires bioptic material, which can be difficult to obtain, both in terms of quality and technique. The main procedures available to obtain such samples are transbronchial lung cryobiopsy (TBLC) and surgical lung biopsy (SLB).

OBJECTIVE: The purpose of this paper is to review the evidence for the role of TBLC in the diagnostic-therapeutic process of PF.

METHODS: A comprehensive review was performed to identify articles to date that addressed the role of TBLC in the diagnostic-therapeutic process of PF using the PubMed® database.

RESULTS: The reasoned search identified 206 papers, including 21 manuscripts (three reviews, one systematic review, two guidelines, two prospective studies, three retrospective studies, one cross-sectional study, one original article, three editorials, three clinical trials, and two unclassifiable studies), which were included in the final review.

CONCLUSIONS: TBLC is gaining increasing efficacy and improving safety profile; however, there are currently no clear data demonstrating its superiority over SLB. Therefore, the two techniques should be considered with careful rationalization on a case-by-case basis. Further research is needed to further optimize and standardize the procedure and to thoroughly study the histological and molecular characteristics of PF.

PMID:37025914 | PMC:PMC10070648 | DOI:10.1016/j.heliyon.2023.e14768

Front Endocrinol (Lausanne). 2023 Mar 21;14:1073878. doi: 10.3389/fendo.2023.1073878. eCollection 2023.

ABSTRACT

Type 2 diabetes mellitus (T2DM) is a widespread metabolic condition with a high global morbidity and mortality rate that affects the whole body. Their primary consequences are mostly caused by the macrovascular and microvascular bed degradation brought on by metabolic, hemodynamic, and inflammatory variables. However, research in recent years has expanded the target organ in T2DM to include the lung. Inflammatory lung diseases also impose a severe financial burden on global healthcare. T2DM has long been recognized as a significant comorbidity that influences the course of various respiratory disorders and their disease progress. The pathogenesis of the glycemic metabolic problem and endothelial microangiopathy of the respiratory disorders have garnered more attention lately, indicating that the two ailments have a shared history. This review aims to outline the connection between T2DM related endothelial cell dysfunction and concomitant respiratory diseases, including Coronavirus disease 2019 (COVID-19), asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

PMID:37025413 | PMC:PMC10071002 | DOI:10.3389/fendo.2023.1073878

Tanaffos. 2022 Mar;21(3):263-270.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a lung disease characterized by formation of fibroblast foci and honeycomb lesions in the pulmonary parenchyma. The physiopathological mechanisms involved in the development of fibrosis and architectural disorganization are still imperfectly elucidated. In fact, lesion formation is irreversible and no treatment, to date, has been shown to be effective (30% of patients die within 5 years of the onset of the disease). The long-held concept of chronic inflammation leading to fibrosis is still controversial. Indeed, recent data suggest that the physiopathology of this disease is the product of fibroblast dysfunction rather than the result of an inflammatory imbalance. This concept supports the parallel involvement of three main factors: epithelial damage, angiogenesis and oxidative stress. In this review we highlighted the different factors and the ethiopathogenic pathways involved in the fibrotic process, in order to increase our understanding of the mechanisms involved in this pulmonary pathology.

PMID:37025320 | PMC:PMC10073959

Pulm Circ. 2023 Apr 1;13(2):e12213. doi: 10.1002/pul2.12213. eCollection 2023 Apr.

ABSTRACT

Pulmonary hypertension (PH) is a frequent complication of interstitial lung disease (ILD). Although PH has mostly been described in idiopathic pulmonary fibrosis, it can manifest in association with many other forms of ILD. Associated pathogenetic mechanisms are complex and incompletely understood but there is evidence of disruption of molecular and genetic pathways, with panvascular histopathologic changes, multiple pathophysiologic sequelae, and profound clinical ramifications. While there are some recognized clinical phenotypes such as combined pulmonary fibrosis and emphysema and some possible phenotypes such as connective tissue disease associated with ILD and PH, the identification of further phenotypes of PH in ILD has thus far proven elusive. This statement reviews the current evidence on the pathogenesis, recognized patterns, and useful diagnostic tools to detect phenotypes of PH in ILD. Distinct phenotypes warrant recognition if they are characterized through either a distinct presentation, clinical course, or treatment response. Furthermore, we propose a set of recommendations for future studies that might enable the recognition of new phenotypes.

PMID:37025209 | PMC:PMC10071306 | DOI:10.1002/pul2.12213

Front Med (Lausanne). 2023 Apr 6;10:1160755. doi: 10.3389/fmed.2023.1160755. eCollection 2023.

ABSTRACT

The role of immunity in the pathogenesis of various pulmonary diseases, particularly interstitial lung diseases (ILDs), is being increasingly appreciated as mechanistic discoveries advance our knowledge in the field. Immune-mediated lung diseases demonstrate clinical and immunological heterogeneity and can be etiologically categorized into connective tissue disease (CTD)-associated, exposure-related, idiopathic, and other miscellaneous lung diseases including sarcoidosis, and post-lung transplant ILD. The immunopathogenesis of many of these diseases remains poorly defined and possibly involves either immune dysregulation, abnormal healing, chronic inflammation, or a combination of these, often in a background of genetic susceptibility. The heterogeneity and complex immunopathogenesis of ILDs complicate management, and thus a collaborative treatment team should work toward an individualized approach to address the unique needs of each patient. Current management of immune-mediated lung diseases is challenging; the choice of therapy is etiology-driven and includes corticosteroids, immunomodulatory drugs such as methotrexate, cyclophosphamide and mycophenolate mofetil, rituximab, or other measures such as discontinuation or avoidance of the inciting agent in exposure-related ILDs. Antifibrotic therapy is approved for some of the ILDs (e.g., idiopathic pulmonary fibrosis) and is being investigated for many others and has shown promising preliminary results. A dire need for advances in the management of immune-mediated lung disease persists in the absence of standardized management guidelines.

PMID:37089604 | PMC:PMC10117988 | DOI:10.3389/fmed.2023.1160755

BMC Pulm Med. 2023 Apr 6;23(1):113. doi: 10.1186/s12890-023-02396-6.

ABSTRACT

INTRODUCTION: The COVID-19 pandemic resulted in a rapid transformation of health services. This study aimed to understand the experiences of healthcare by people with interstitial lung disease (ILD), to inform future service delivery.

METHODS: Four specialist clinics in tertiary centres in Australia (Victoria:2 sites; New South Wales: 1 site; Western Australia: 1 site) recruited patients with ILD during an 8-week period from March 2021. Participants completed a COVID-specific questionnaire focused on health-related experiences during 2020.

RESULTS: Ninety nine (65% of 153) participants completed the questionnaire. 47% had idiopathic pulmonary fibrosis or connective tissue disease-associated ILD, 62% were female and the average age was 66 years. Whilst 56% rated their overall health in 2020 as the same as months prior, 38% indicated a worsening in health attributed to reduced physical activity and fear of contracting the virus. Access to healthcare professionals was 'good' in 61%, and 'fair-to-poor' for 37% due to missed respiratory assessments, with telehealth (mainly telephone) being perceived as less effective. 89% had contact with respiratory physicians, 68% with general practitioners, predominantly via telephone, with few video consultations. High satisfaction with care was reported by 78%, with lower satisfaction attributed to delays in assessments, disruption to usual services such as pulmonary rehabilitation, and dissatisfaction with telehealth.

CONCLUSION: People with ILD were generally satisfied with their care during 2020, however reduced access to healthcare professionals was challenging for those experiencing a deterioration in health. Telehealth was largely well received but did not always meet the needs of people with ILD particularly when unwell.

PMID:37024848 | DOI:10.1186/s12890-023-02396-6

Sci Rep. 2023 Apr 6;13(1):5670. doi: 10.1038/s41598-023-32715-0.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive lung disease that causes scarring and loss of lung function. Macrophages play a key role in fibrosis, but their responses to altered morphological and mechanical properties of the extracellular matrix in fibrosis is relatively unexplored. Our previous work showed functional changes in murine fetal liver-derived alveolar macrophages on fibrous or globular collagen morphologies. In this study, we applied differential proteomics to further investigate molecular mechanisms underlying the observed functional changes. Macrophages cultured on uncoated, fibrous, or globular collagen-coated plastic were analyzed by liquid chromatography-mass spectrometry. The presence of collagen affected expression of 77 proteins, while 142 were differentially expressed between macrophages grown on fibrous or globular collagen. Biological process and pathway enrichment analysis revealed that culturing on any type of collagen induced higher expression of enzymes involved in glycolysis. However, this did not lead to a higher rate of glycolysis, probably because of a concomitant decrease in activity of these enzymes. Our data suggest that macrophages sense collagen morphologies and can respond with changes in expression and activity of metabolism-related proteins. These findings suggest intimate interactions between macrophages and their surroundings that may be important in repair or fibrosis of lung tissue.

PMID:37024614 | DOI:10.1038/s41598-023-32715-0

Transplant Proc. 2023 Apr 4:S0041-1345(23)00108-2. doi: 10.1016/j.transproceed.2023.02.059. Online ahead of print.

ABSTRACT

PURPOSE: This study aims to assess the efficacy of current measurement strategies for lung sizing and the feasibility of future use of computed tomography (CT)-derived lung volumes to predict a donor-recipient lung size match during bilateral lung transplants.

METHODS: We reviewed the data of 62 patients who underwent bilateral lung transplantation for interstitial lung disease and/or idiopathic pulmonary fibrosis from 2018 to 2019. Data for recipients was retrieved from the department's transplant database and medical records, and the donor's data was retrieved from the DonorNet. The data included demographic data, lung heights, measured total lung capacity (TLC) from plethysmography for recipients and estimated TLC for donors, clinical data, and CT-derived lung volumes in both pre- and post-transplant recipients. The post-transplant CT-derived lung volume in recipients was used as a surrogate for donor lung CT volumes due to inadequate or poor donor CT data. Computed tomography-derived lung volumes were calculated using thresholding, region growing, and cutting techniques on Computer-Aided Design and Mimics (Materialise NV, Leuven, Belgium) programs. Preoperative CT-derived lung volumes in recipients were compared with the plethysmography TLC, Frustum Model, and donor-predicted TLC. The ratio of the recipient's pre-and postoperative CT-derived volumes, the ratio of preoperative CT-derived lung volume, and donor-estimated TLC were studied to detect a correlation with 1-year outcomes.

RESULTS: The recipient preoperative CT-derived volume correlated with the recipient preoperative plethysmography TLC (Pearson correlation coefficient [PCC] of 0.688) and with the recipient Frustum model volume (PCC of 0.593). The recipient postoperative CT-derived volume correlated with the recipient's postoperative plethysmography TLC (PCC of 0.651). There was no statistically significant correlation between recipients' CT-derived pre- or postoperative volume with donor-estimated TLC. The ratio of preoperative CT-derived volume to donor-estimated TLC correlated inversely with the length of ventilation (P value = .0031). The ratio of postoperative CT-derived volume to preoperative CT-derived volume correlated inversely with delayed sternal closure (P = .0039). No statistically significant correlations were found in evaluating outcomes related to lung oversizing in the recipient (defined as a postoperative to preoperative CT-derived lung volume ratio of >1.2).

CONCLUSIONS: Generating CT-derived lung volumes is a valid and convenient method for evaluating lung volumes for transplantation in patients with ILD and/or IPF. Donor-estimated TLC should be interpreted carefully. Further studies should derive donor lung volumes from CT scans for a more accurate evaluation of lung size matching.

PMID:37024309 | DOI:10.1016/j.transproceed.2023.02.059

J Pharmacol Exp Ther. 2023 Apr 6:JPET-AR-2022-001442. doi: 10.1124/jpet.122.001442. Online ahead of print.

ABSTRACT

Pulmonary fibroblasts are the primary producers of extracellular matrix (ECM) in the lungs, and their pathogenic activation drives scarring and loss of lung function in idiopathic pulmonary fibrosis (IPF). This uncontrolled production of ECM is stimulated by mechanosignaling and TGF-β1 signaling which together promote transcriptional programs including Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ). G protein-coupled receptors which couple to G alpha s have emerged as pharmacological targets to inactivate YAP/TAZ signaling and promote lung fibrosis resolution. Previous studies have shown a loss of expression of "antifibrotic GPCRs"- receptors which couple to G alpha s, in IPF patient-derived fibroblasts compared to non-IPF samples. Of the 14 G alpha s GPCRs we found to be expressed in lung fibroblasts, the dopamine receptor D1 (DRD1) was one of only two not repressed by TGF-β1 signaling, with the β2-adrenergic receptor being the most repressed. We compared the potency and efficacy of multiple D1 and β2 receptor agonists +/- TGF-β1 treatment in vitro for their ability to elevate cAMP, inhibit nuclear localization of YAP/TAZ, regulate expression of profibrotic and antifibrotic genes, and inhibit cellular proliferation and collagen deposition. Consistently, the activity of β2 receptor agonists was lost, while D1 receptor agonists was maintained, after stimulating cultured lung fibroblasts with TGF-β1. These data further support the therapeutic potential of the dopamine receptor D1 and highlight an orchestrated and pervasive loss of antifibrotic GPCRs mediated by TGF-β1 signaling. Significance Statement IPF is a deadly lung disease with limited therapies. GPCRs have emerged as a primary target for the development of novel antifibrotic drugs, however, a challenge to this approach is the dramatic changes in GPCR expression in response to profibrotic stimuli. Here we investigate the impact of TGF-β1 on the expression of antifibrotic GPCRs and show the D1 dopamine receptor expression is uniquely maintained in response to TGF-β1, further implicating it as a compelling target to treat IPF.

PMID:37024146 | DOI:10.1124/jpet.122.001442

Exp Ther Med. 2023 Mar 10;25(4):183. doi: 10.3892/etm.2023.11882. eCollection 2023 Apr.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a heterogeneous lung disease associated with high mortality. Disabled-2 (DAB2), an adapter protein, regulates cell-fibrinogen adhesion and fibrinogen uptake. DAB2 is differentially expressed in mouse fibrotic lungs induced by bleomycin according to a genome microarray analysis based on Gene Expression Omnibus database. However, the role of DAB2 in IPF has not been revealed. A bleomycin-induced mouse model of pulmonary fibrosis was constructed in the present study. It found that the expression of DAB2 was upregulated in bleomycin-induced fibrotic lung tissue with collagen fiber deposition and pulmonary interstitium thickening. Colocalization of DAB2 with α-smooth muscle actin (SMA) was observed in lung tissue sections. In vitro, human lung fibroblast MRC-5 cells were treated with TGF-β1 and the expression of DAB2 was increased. Knockdown of DAB2 suppressed cell proliferation and the expression of α-SMA, collagen I, collagen IV and fibronectin in TGF-β1-treated MRC-5 cells. The phosphorylation levels of PI3K and AKT were suppressed in DAB2-knockdown cells. IGF-1/IGF-1R has been reported to promote pulmonary fibrosis and activate the PI3K/Akt signaling. In the present study, the activation of IGF-1/IGF-1R signaling pathways in bleomycin-induced fibrotic lung tissues were positively associated with DAB2 expression. The phosphorylation level of IGF-1R was increased in MRC-5 cells with TGF-β1 treatment, and DAB2 expression was decreased by silencing of IGF-1R. This suggested that DAB2 might be a downstream target of the IGF-1R pathway and thus induced PI3K/AKT signaling activation and fibrogenesis. The current study demonstrated the importance of DAB2 in pulmonary fibrosis and suggested the potential of IGF-1R/DAB2/PI3K in the pathogenesis of IPF.

PMID:37021069 | PMC:PMC10067542 | DOI:10.3892/etm.2023.11882

Phytomedicine. 2023 Mar 20;114:154777. doi: 10.1016/j.phymed.2023.154777. Online ahead of print.

ABSTRACT

BACKGROUND AND PURPOSE: The pathological progression of lung injury (LI) to idiopathic pulmonary fibrosis (IPF) is a common feature of the development of lung disease. At present, effective strategies for preventing this progression are unavailable. Baicalin has been reported to specifically inhibit the progression of LI to IPF. Therefore, this meta-analysis aimed to assess its clinical application and its potential as a therapeutic drug for lung disease based on integrative analysis.

METHODS: We systematically searched preclinical articles in eight databases and reviewed them subjectively. The CAMARADES scoring system was used to assess the degree of bias and quality of evidence, whereas the STATA software (version 16.0 software) was used for statistical analysis, including a 3D analysis of the effects of dosage frequency of baicalin in LI and IPF. The protocol of this meta-analysis is documented in the PROSPERO database (CRD42022356152).

RESULTS: A total of 23 studies and 412 rodents were included after several rounds of screening. Baicalin was found to reduce the levels of TNF-α, IL-1β, IL-6, HYP, TGF-β and MDA and the W/D ratio and increase the levels of SOD. Histopathological analysis of lung tissue validated the regulatory effects of baicalin, and the 3D analysis of dosage frequency revealed that the effective dose of baicalin is 10-200 mg/kg. Mechanistically, baicalin can prevent the progression of LI to IPF by modulating p-Akt, p-NF-κB-p65 and Bcl-2-Bax-caspase-3 signalling. Additionally, baicalin is involved in signalling pathways closely related to anti-apoptotic activity and regulation of lung tissue and immune cells.

CONCLUSION: Baicalin at the dose of 10-200 mg/kg exerts protective effects against the progression of LI to IPF through anti-inflammatory and anti-apoptotic pathways.

PMID:37018850 | DOI:10.1016/j.phymed.2023.154777

J Med Chem. 2023 Apr 5. doi: 10.1021/acs.jmedchem.2c02087. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease characterized by lung fibrosis leading to an irreversible decline of lung function. Current antifibrotic drugs on the market slow down but do not prevent the progression of the disease and are associated with tolerability issues. The involvement of lysophosphatidic acid receptor 2 (LPA2) in IPF is supported by LPA2 knockdown studies. To further validate the role of LPA2 receptors in modulating IPF and potentially other fibrotic processes, a potent and selective LPA2 receptor antagonist with a good pharmacokinetic (PK) profile is needed. Herein, we report the medicinal chemistry exploration that led to the discovery of a new class of highly potent and selective LPA2 antagonists. Among them, compound 58 exhibits excellent potency, selectivity, and oral PK profile, making it a suitable tool for probing the involvement of LPA2 receptors in IPF and other fibrotic processes.

PMID:37017110 | DOI:10.1021/acs.jmedchem.2c02087

Respirology. 2023 Apr 5. doi: 10.1111/resp.14504. Online ahead of print.

NO ABSTRACT

PMID:37017098 | DOI:10.1111/resp.14504

Front Endocrinol (Lausanne). 2023 Apr 3;14:1079626. doi: 10.3389/fendo.2023.1079626. eCollection 2023.

ABSTRACT

Recent advances in aging research have provided novel insights for the development of senotherapy, which utilizes cellular senescence as a therapeutic target. Cellular senescence is involved in the pathogenesis of various chronic diseases, including metabolic and respiratory diseases. Senotherapy is a potential therapeutic strategy for aging-related pathologies. Senotherapy can be classified into senolytics (induce cell death in senescent cells) and senomorphics (ameliorate the adverse effects of senescent cells represented by the senescence-associated secretory phenotype). Although the precise mechanism has not been elucidated, various drugs against metabolic diseases may function as senotherapeutics, which has piqued the interest of the scientific community. Cellular senescence is involved in the pathogenesis of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF), which are aging-related respiratory diseases. Large-scale observational studies have reported that several drugs, such as metformin and statins, may ameliorate the progression of COPD and IPF. Recent studies have reported that drugs against metabolic diseases may exert a pharmacological effect on aging-related respiratory diseases that can be different from their original effect on metabolic diseases. However, high non-physiological concentrations are needed to determine the efficacy of these drugs under experimental conditions. Inhalation therapy may increase the local concentration of drugs in the lungs without exerting systemic adverse effects. Thus, the clinical application of drugs against metabolic diseases, especially through an inhalation treatment modality, can be a novel therapeutic approach for aging-related respiratory diseases. This review summarizes and discusses accumulating evidence on the mechanisms of aging, as well as on cellular senescence and senotherapeutics, including drugs against metabolic diseases. We propose a developmental strategy for a senotherapeutic approach for aging-related respiratory diseases with a special focus on COPD and IPF.

PMID:37077349 | PMC:PMC10106576 | DOI:10.3389/fendo.2023.1079626

Respir Res. 2023 Apr 1;24(1):99. doi: 10.1186/s12931-023-02400-x.

ABSTRACT

Honeycombing is a histological pattern consistent with Usual Interstitial Pneumonia (UIP). Honeycombing refers to cystic airways located at sites of dense fibrosis with marked mucus accumulation. Utilizing laser capture microdissection coupled mass spectrometry (LCM-MS), we interrogated the fibrotic honeycomb airway cells and fibrotic uninvolved airway cells (distant from honeycomb airways and morphologically intact) in specimens from 10 patients with UIP. Non-fibrotic airway cell specimens from 6 patients served as controls. Furthermore, we performed LCM-MS on the mucus plugs found in 6 patients with UIP and 6 patients with mucinous adenocarcinoma. The mass spectrometry data were subject to both qualitative and quantitative analysis and validated by immunohistochemistry. Surprisingly, fibrotic uninvolved airway cells share a similar protein profile to honeycomb airway cells, showing deregulation of the slit and roundabout receptor (Slit and Robo) pathway as the strongest category. We find that (BPI) fold-containing family B member 1 (BPIFB1) is the most significantly increased secretome-associated protein in UIP, whereas Mucin-5AC (MUC5AC) is the most significantly increased in mucinous adenocarcinoma. We conclude that fibrotic uninvolved airway cells share pathological features with fibrotic honeycomb airway cells. In addition, fibrotic honeycomb airway cells are enriched in mucin biogenesis proteins with a marked derangement in proteins essential for ciliogenesis. This unbiased spatial proteomic approach generates novel and testable hypotheses to decipher fibrosis progression.

PMID:37005656 | DOI:10.1186/s12931-023-02400-x

Thorax. 2023 Apr 3:thorax-2022-219792. doi: 10.1136/thorax-2022-219792. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is characterised by worsening dyspnoea and exercise intolerance.

RESEARCH QUESTION: Does a long-term pulmonary rehabilitation improve exercise tolerance in patients with IPF treated with standard antifibrotic drugs, which are expected to reduce disease progression?

METHODS: This open-label randomised controlled trial was performed at 19 institutions. Stable patients receiving nintedanib were randomised into pulmonary rehabilitation and control groups (1:1). The pulmonary rehabilitation group underwent initial rehabilitation which included twice-weekly sessions of monitored exercise training for 12 weeks, followed by an at-home rehabilitation programme for 40 weeks. The control group received usual care only, without pulmonary rehabilitation. Both groups continued to receive nintedanib. The primary and main secondary outcomes were change in 6 min walking distance (6MWD) and change in endurance time (using cycle ergometry) at week 52.

RESULTS: Eighty-eight patients were randomised into pulmonary rehabilitation (n=45) and control (n=43) groups. Changes in 6MWD were -33 m (95% CI -65 to -1) and -53 m (95% CI -86 to -21) in the pulmonary rehabilitation and control groups, respectively, with no statistically significant difference (mean difference, 21 m (95% CI -25 to 66), p=0.38). Changes in endurance time were significantly better in the pulmonary rehabilitation (64 s, 95% CI -42.3 to 171)) than in the control (-123 s (95% CI -232 to -13)) group (mean difference, 187 s (95% CI 34 to 153), p=0.019).

INTERPRETATION: Although pulmonary rehabilitation in patients taking nintedanib did not improve 6MWD in the long term, it led to prolonged improvement in endurance time.

TRIAL REGISTRATION NUMBER: UMIN000026376.

PMID:37012071 | DOI:10.1136/thorax-2022-219792

J Control Release. 2023 Apr 1:S0168-3659(23)00248-1. doi: 10.1016/j.jconrel.2023.03.057. Online ahead of print.

ABSTRACT

Mesenchymal stem cell (MSC) transplantation is emerging as a promising approach in the treatment of idiopathic pulmonary fibrosis (IPF), while it is still impeded by several challenges, including unsatisfactory treatment outcomes due to the poor survival of transplanted MSCs, and the lack of non-invasive and long-term imaging modality for tracking the behavior of MSCs. Herein, copper-based nanozyme (CuxO NPs) and gold nanoparticles (Au NPs) were encapsulated in oxidation-sensitive dextran (Oxi-Dex), a dextran derivative with reactive oxygen species (ROS)-responsiveness, forming a kind of novel nanocomposites (assigned as RSNPs) to act as ROS scavengers and computer tomography (CT) imaging tracers. After being internalized by MSCs, RSNPs enabled continuous CT imaging tracking of the transplanted MSCs for 21 days in IPF treatment, obtaining the location and distribution of the transplanted MSCs. Once MSCs were attacked by oxidative stress, the intracellular RSNPs can activate ROS clearance on demand by releasing CuxO NPs, thereby enhancing the therapeutic efficacy against IPF by improving cell survival. Taken together, a novel multifunctional RSNP was fabricated to label MSCs for CT imaging tracking and clearing superfluous ROS, presenting a promising high-efficient IPF therapy.

PMID:37011837 | DOI:10.1016/j.jconrel.2023.03.057