J Respir Biol Transl Med. 2024 Jun;1(2):10006. doi: 10.35534/jrbtm.2024.10006. Epub 2024 Apr 30.

ABSTRACT

The molecular mechanisms that regulate progressive pulmonary fibrosis remain poorly understood. Type 2 alveolar epithelial cells (AEC2s) function as adult stem cells in the lung. We previously showed that there is a loss of AEC2s and a failure of AEC2 renewal in the lungs of idiopathic pulmonary fibrosis (IPF) patients. We also reported that beta-arrestins are the key regulators of fibroblast invasion, and beta-arrestin 1 and 2 deficient mice exhibit decreased mortality, decreased matrix deposition, and increased lung function in bleomycin-induced lung fibrosis. However, the role of beta-arrestins in AEC2 regeneration is unclear. In this study, we investigated the role and mechanism of Arrestin beta 1 (ARRB1) in AEC2 renewal and in lung fibrosis. We used conventional deletion as well as cell type-specific deletion of ARRB1 in mice and found that Arrb1 deficiency in fibroblasts protects mice from lung fibrosis, and the knockout mice exhibit enhanced AEC2 regeneration in vivo, suggesting a role of fibroblast-derived ARRB1 in AEC2 renewal. We further found that Arrb1-deficient fibroblasts promotes AEC2 renewal in 3D organoid assays. Mechanistically, we found that CCL7 is among the top downregulated cytokines in Arrb1 deficient fibroblasts and CCL7 inhibits AEC2 regeneration in 3D organoid experiments. Therefore, fibroblast ARRB1 mediates AEC2 renewal, possibly by releasing chemokine CCL7, leading to fibrosis in the lung.

PMID:38736470 | PMC:PMC11087074 | DOI:10.35534/jrbtm.2024.10006

J Med Invest. 2024;71(1.2):9-22. doi: 10.2152/jmi.71.9.

ABSTRACT

Patients with interstitial lung disease (ILD), especially those with idiopathic pulmonary fibrosis, are at increased risk of developing lung cancer (LC). Pharmacotherapy for advanced LC has dramatically progressed in recent years;however, management of LC with pre-existing ILD (LC-ILD) is challenging due to serious concerns about the risk of acute exacerbation of ILD (AE-ILD). As patients with LC-ILD have been excluded from most prospective clinical trials of advanced LC, optimal pharmacotherapy remains to be elucidated. Although the antitumor activity of first-line platinum-based cytotoxic chemotherapy appears to be similar in advanced LC patients with or without ILD, its impact on the survival of patients with LC-ILD is limited. Immune checkpoint inhibitors may hold promise for long-term survival, but many challenges remain, including safety and appropriate patient selection. Further understanding the predictive factors for AE-ILD after receiving pharmacotherapy in LC-ILD may lead to appropriate patient selection and lower treatment risk. The aim of this review was to summarize the current evidence related to pharmacotherapy for advanced LC-ILD and discuss emerging areas of research. J. Med. Invest. 71 : 9-22, February, 2024.

PMID:38735730 | DOI:10.2152/jmi.71.9

Mol Biotechnol. 2024 May 11. doi: 10.1007/s12033-024-01158-x. Online ahead of print.

ABSTRACT

We aim to screen and analyze the ferroptosis inflammation-related hub genes associated with idiopathic pulmonary fibrosis (IPF). The GSE52463 and GSE110147 datasets were obtained from the GEO database and merged. The DEGs were selected by differential analysis and intersected with inflammation-related genes and ferroptosis-related genes to acquire the ferroptosis-related differentially expressed genes (FRDEGs). GO, KEGG, GSEA, and GSVA were performed to investigate the features of FRDEGs. The key module genes were selected by WGCNA and employed to generate the PPI network using Cytoscape. Subsequently, the hub genes were identified using cytoHubba and validated by ROC curves generated by survivalROC. Finally, the correlations of hub genes were analyzed through Spearman and the subtypes of IPF were constructed using ConsensusClusterPlus. A total of 1814 DEGs were screened out and 18 FRDEGs were acquired from the intersection of DEGs, ferroptosis-related genes, and inflammation-related genes. GO and KEGG analysis revealed that FRDEGs were primarily involved in bacterial-origin molecular, response infectious disease, and iron ion transport. GSEA results suggested a predominant association with autoimmune diseases and GSVA identified ten different pathways between PF and control. Through WGCNA, three highly correlated modules were identified and ten key module genes were obtained by intersecting genes in the three modules with FRDEGs. Finally, employing three algorithms within the cytoHubba led to the identification of eight hub genes: CCND1, TP53, STAT3, CTNNB1 CDH1, ESR1, HSP90AA1, and EP300. Eventually, two distinct subtypes of IPF were identified. The present research successfully identified the hub genes associated with ferroptosis and inflammation and their biological effects on IPF. Furthermore, two disease subtypes of IPF were constructed.

PMID:38734841 | DOI:10.1007/s12033-024-01158-x

J Clin Med. 2024 May 6;13(9):2727. doi: 10.3390/jcm13092727.

ABSTRACT

Background: Pirfenidone and Nintedanib have significantly improved the prognosis of patients with idiopathic pulmonary fibrosis (IPF), reducing mortality risk and exacerbations. This study aimed to analyze antifibrotic treatment utilization and its association with clinical outcomes (i.e., acute exacerbation or death) during 2014-2021 in newly diagnosed IPF patients, using Healthcare Utilization Databases of the Marche Region, Italy. Methods: The first 12-month adherence to antifibrotic was estimated using the Proportion of Days Covered (PDC), defining adherence as PDC ≥ 75%. State Sequence Analysis over the initial 52 weeks of treatment was used to identify adherence patterns. The role of adherence patterns on acute exacerbations/death, adjusted by demographic, clinical features, and monthly adherence after the 52-week period (time-dependent variable), was assessed with Cox regression. Results: Among 667 new IPF cases, 296 received antifibrotic prescriptions, with 62.8% being adherent in the first year. Three antifibrotic utilization patterns emerged-high adherence (37.2%), medium adherence (42.5%), and low adherence (20.3%)-with median PDCs of 95.3%, 79.5%, and 18.6%, respectively. These patterns did not directly influence three-year mortality/exacerbation probability, but sustained adherence reduced risk over time. Conclusions: Good adherence was observed in in this population-based study, emphasizing the importance of continuous antifibrotics therapy over time to mitigate adverse outcomes.

PMID:38731256 | DOI:10.3390/jcm13092727

Respir Res. 2024 May 10;25(1):202. doi: 10.1186/s12931-024-02828-9.

ABSTRACT

BACKGROUND: Extracellular mitochondrial DNA (mtDNA) is released from damaged cells and increases in the serum and bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. While increased levels of serum mtDNA have been reported to be linked to disease progression and the future development of acute exacerbation (AE) of IPF (AE-IPF), the clinical significance of mtDNA in BALF (BALF-mtDNA) remains unclear. We investigated the relationships between BALF-mtDNA levels and other clinical variables and prognosis in IPF.

METHODS: Extracellular mtDNA levels in BALF samples collected from IPF patients were determined using droplet-digital PCR. Levels of extracellular nucleolar DNA in BALF (BALF-nucDNA) were also determined as a marker for simple cell collapse. Patient characteristics and survival information were retrospectively reviewed.

RESULTS: mtDNA levels in serum and BALF did not correlate with each other. In 27 patients with paired BALF samples obtained in a stable state and at the time of AE diagnosis, BALF-mtDNA levels were significantly increased at the time of AE. Elevated BALF-mtDNA levels were associated with inflammation or disordered pulmonary function in a stable state (n = 90), while being associated with age and BALF-neutrophils at the time of AE (n = 38). BALF-mtDNA ≥ 4234.3 copies/µL in a stable state (median survival time (MST): 42.4 vs. 79.6 months, p < 0.001) and ≥ 11,194.3 copies/µL at the time of AE (MST: 2.6 vs. 20.0 months, p = 0.03) were associated with shorter survival after BALF collection, even after adjusting for other known prognostic factors. On the other hand, BALF-nucDNA showed different trends in correlation with other clinical variables and did not show any significant association with survival time.

CONCLUSIONS: Elevated BALF-mtDNA was associated with a poor prognosis in both IPF and AE-IPF. Of note, at the time of AE, it sharply distinguished survivors from non-survivors. Given the trends shown by analyses for BALF-nucDNA, the elevation of BALF-mtDNA might not simply reflect the impact of cell collapse. Further studies are required to explore the underlying mechanisms and clinical applications of BALF-mtDNA in IPF.

PMID:38730452 | DOI:10.1186/s12931-024-02828-9

Respir Med. 2024 May 8:107659. doi: 10.1016/j.rmed.2024.107659. Online ahead of print.

ABSTRACT

Pulmonary Fibrosis (PF) describes a group of lung diseases characterised by progressive scarring (fibrosis). Symptoms worsen over time and include breathlessness, tiredness, and cough, giving rise to psychological distress. Significant morbidity accompanies PF, so ensuring patients' care needs are well defined and provided for, represents an important treatment strategy. The purpose of this systematic review was to synthesise what is currently known about the psychosocial morbidity, illness experience and needs of people with pulmonary fibrosis and their informal caregivers. Eight databases (MEDLINE, EMBASE, PUBMED, Cochrane database of Systematic reviews (CDSR), Web of Science Social Sciences Citation Index, PsycINFO, PsycARTICLES and CINAHL) were used to identify studies exploring the supportive needs of adults with PF and / or their caregivers. Methodological quality was assessed using the Mixed Methods Appraisal Tool. 53 studies were included, the majority using qualitative methodology (79%, 42/53), 6 as part of mixed methodological studies. Supportive care needs were mapped to eight domains using an a priori framework analysis. Findings highlight a lack of psychological support throughout the course of the illness, misconceptions about and barriers to, the provision of palliative care despite its potential positive impacts. Patients and caregivers express a desire for greater disease specific education and information provision throughout the illness. Trials of complex interventions are needed to address the unique set of challenges for patients and carers living with PF.

PMID:38729528 | DOI:10.1016/j.rmed.2024.107659

Medicine (Baltimore). 2024 May 10;103(19):e38133. doi: 10.1097/MD.0000000000038133.

ABSTRACT

BACKGROUND: Danhong injection, a compound injection of Chinese herbal medicine, has been widely used in idiopathic pulmonary fibrosis (IPF) at present as an adjuvant treatment. However, the clinical efficacy and molecular mechanism of IPF are still unclear. This study will evaluate and explore the clinical efficacy and molecular mechanism of Danhong injection in the treatment of IPF.

METHODS: In meta-analysis, the computer was used to search 8 databases (PubMed, EMbase, CENTRAL, MEDLINE, CBM, CNKI, WanFang, and VIP) to collect the RCTs, and RevMan 5.3 and Stata 14.0 were used for statistical analysis. It has been registered on PROSPERO: CRD42020221096. In network pharmacology, the main chemical components and targets of the chemical components of Danhong injection were obtained in TCMSP and Swiss Target Prediction databases. The main targets of IPF were obtained through Gencards, Disgenet, OMIM, TTD, and DRUGBANK databases. The String platform was used to construct PPI networks. Cytoscape 3.8.2 was used to construct the "Danhong components - IPF targets-pathways" network. The molecular docking verification was conducted by Auto Dock.

RESULTS: Twelve RCTs were finally included with a total of 896 patients. The meta-analysis showed that Danhong injection could improve the clinical efficiency ([OR] = 0.25, 95% CI [0.15, 0.41]), lung function, arterial blood gas analysis, inflammatory cytokines, and serum cytokines associated with pulmonary fibrosis of IPF patients, respectively (P < .05). The core active components of Danhong injection on IPF were Luteolin, Quercetin, and Kaempferol, and the core targets were PTGS2, AR, ESR1, PPARG, and RELA. Danhong injection mainly improved IPF through PD-L1 expression and PD-1 checkpoint path in cancer, pathways in cancer, PI3K-Akt signaling pathway, etc.

CONCLUSION: These results provided scientific basis for the clinical use of Danhong injection for the treatment of IPF, and provided a new direction to explore the potential mechanism of action of Danhong injection.

PMID:38728523 | DOI:10.1097/MD.0000000000038133

Adv Sci (Weinh). 2024 May 9:e2401327. doi: 10.1002/advs.202401327. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and ultimately fatal interstitial lung disease, with limited therapeutic options available. Impaired autophagy resulting from aberrant TRB3/p62 protein-protein interactions (PPIs) contributes to the progression of IPF. Restoration of autophagy by modulating the TRB3/p62 PPIs has rarely been reported for the treatment of IPF. Herein, peptide nanofibers are developed that specifically bind to TRB3 protein and explored their potential as a therapeutic approach for IPF. By conjugating with the self-assembling fragment (Ac-GFFY), a TRB3-binding peptide motif A2 allows for the formation of nanofibers with a stable α-helix secondary structure. The resulting peptide (Ac-GFFY-A2) nanofibers exhibit specific high-affinity binding to TRB3 protein in saline buffer and better capacity of cellular uptake to A2 peptide. Furthermore, the TRB3-targeting peptide nanofibers efficiently interfere with the aberrant TRB3/p62 PPIs in activated fibroblasts and fibrotic lung tissue of mice, thereby restoring autophagy dysfunction. The TRB3-targeting peptide nanofibers inhibit myofibroblast differentiation, collagen production, and fibroblast migration in vitro is demonstrated, as well as bleomycin-induced pulmonary fibrosis in vivo. This study provides a supramolecular method to modulate PPIs and highlights a promising strategy for treating IPF diseases by restoring autophagy.

PMID:38725147 | DOI:10.1002/advs.202401327

Eur Respir J. 2024 May 9;63(5):2400498. doi: 10.1183/13993003.00498-2024. Print 2024 May.

ABSTRACT

The novel concept of Sfrp1+ transitional fibroblasts has sparked novel points of interest: the mechanisms under which the Sfrp1+ transitional fibroblasts emerge and the in vivo functions of Sfrp1 and Sfrp1+ transitional fibroblasts in pulmonary fibrosis https://bit.ly/4aq6iAI

PMID:38724178 | PMC:PMC11079327 | DOI:10.1183/13993003.00498-2024

EBioMedicine. 2024 May 8;104:105136. doi: 10.1016/j.ebiom.2024.105136. Online ahead of print.

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 is an RNA sensor and 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 and 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.

FINDINGS: Sixty new anti-MDA5+, but not other MSAs surged between 2020 and 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 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.

INTERPRETATION: 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.

FUNDING: This work was supported in part by the National Institute for Health Research (NIHR) Leeds Biomedical Research Centre (BRC), and in part by the National Institutes of Health (NIH) grant R01-AI155696 and pilot awards from the UC Office of the President (UCOP)-RGPO (R00RG2628, R00RG2642 and R01RG3780) to P.G. S.S was supported in part by R01-AI141630 (to P.G) and in part through funds from the American Association of Immunologists (AAI) Intersect Fellowship Program for Computational Scientists and Immunologists.

PMID:38723554 | DOI:10.1016/j.ebiom.2024.105136

Respir Investig. 2024 May 8;62(4):631-637. doi: 10.1016/j.resinv.2024.04.021. Online ahead of print.

ABSTRACT

BACKGROUND: Acute exacerbation (AE) is a potentially lethal event in patients with usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF). However, to date, no pathological predictors of AE have been identified. This retrospective study aimed to elucidate the pathological features that could predict AE in patients with UIP.

METHODS: We reviewed the pathological findings of 91 patients with UIP/IPF and correlated these findings with AE events. Thirteen histological variables related to acute lung injury were evaluated by three independent observers and classified as positive or negative. The patients' clinical data during follow-up were collected and reviewed for AE. A recursive partition using the Gini index for the prediction of AE was performed, with each pathological finding as a candidate for branching.

RESULTS: Twenty patients (22%) developed AE during the median follow-up duration of 40 months. Thirty-eight patients died (15 due to AE and 23 for other reasons). The median time interval from surgical lung biopsy to AE onset was 497 (interquartile range: 901-1657) days. Histologically, squamous metaplasia was positively associated with AE (odds ratio: 4.7, P = 0.015) and worse event-free survival in patients with UIP (P = 0.04). Leaf scoring based on the Gini index for recursive partition, including five positive findings (squamous metaplasia, neutrophilic infiltration, septal widening, Kuhn's hyaline, and fibrin), showed a sensitivity of 90% with a specificity of 74.7% (area under curve: 0.89).

CONCLUSIONS: We found that squamous metaplasia is an important histopathological finding that predicts AE events and tends to unfavorable outcome in patients with UIP/IPF.

PMID:38723442 | DOI:10.1016/j.resinv.2024.04.021

Physiol Rep. 2024 May;12(9):e16032. doi: 10.14814/phy2.16032.

ABSTRACT

INPP4A has been shown to be involved in the regulation of cell proliferation and apoptosis of multiple cell types including fibroblasts. Previous reports from our group have demonstrated the role of inositol polyphosphate 4-phosphatase Type I A (INPP4A) in these functions. Though existing evidences suggest a critical role for INPP4A in the maintenance of lung homeostasis, its role in chronic lung diseases is relatively under explored. In the current study, we made an attempt to understand the regulation of INPP4A in idiopathic pulmonary fibrosis (IPF). Through integration of relevant INPP4A gene expression data from public repositories with our results from in vitro experiments and mouse models, we show that INPP4A is altered in IPF. Interestingly, the direction of the change is dependent both on the disease stage and the region of the lung used. INPP4A was found to be upregulated when analyzed in lung sample representative of the whole lung, but was downregulated in the fibrotic regions of the lung. Similarly, INPP4A was found to be high, compared to controls, only in the early stage of the disease. Though the observed increase in INPP4A was found to be negatively correlated to physiological indices, FVC, and DLCO, of lung function, treatment with anti-INPP4A antibody worsened the condition in bleomycin treated mice. These contrasting results taken together are suggestive of a nuanced regulation of INPP4A in IPF which is dependent on the disease stage, cellular state and extent of fibrosis in the lung region being analyzed.

PMID:38720166 | DOI:10.14814/phy2.16032

Mol Biotechnol. 2024 May 8. doi: 10.1007/s12033-024-01171-0. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a debilitating, life-threatening irreversible lung disease characterized by the excessive accumulation of fibrotic tissue in the lungs, impairing their function. The exact mechanisms underlying Pulmonary fibrosis (PF) are multifaceted and not yet fully understood. Reports show that during COVID-19 pandemic, PF was dramatically increased due to the hyperactivation of the immune system. Neutrophils and macrophages are the patrolling immune cells that keep the microenvironment balanced. Neutrophil extracellular traps (NETs) are a normal protective mechanism of neutrophils. The chief components of the NETs include DNA, citrullinated histones, and anti-microbial peptides which are released by the activated neutrophils. However, it is becoming increasingly evident that hyperactivation of immune cells can also turn into criminals when it comes to pathological state. Dysregulated NETosis may contribute to sustained inflammation, overactivation of fibroblasts, and ultimately promoting collagen deposition which is the characteristic feature of PF. The role of NETs along with inflammation is attaining greater attention. However, seldom researches are related to the relationship between NETs causing PF. This review highlights the cellular mechanism of NETs-induced pulmonary fibrosis, which could give a better understanding of molecular targets which may be helpful for treating NETs-induced PF.

PMID:38717537 | DOI:10.1007/s12033-024-01171-0

Mol Biol Rep. 2024 May 8;51(1):627. doi: 10.1007/s11033-024-09576-5.

ABSTRACT

MicroRNAs (miRNAs) are short, non-coding single-stranded RNA molecules approximately 22 nucleotides in length, intricately involved in post-transcriptional gene expression regulation. Over recent years, researchers have focused keenly on miRNAs, delving into their mechanisms in various diseases such as cancers. Among these, miR-26a emerges as a pivotal player in respiratory ailments such as pneumonia, idiopathic pulmonary fibrosis, lung cancer, asthma, and chronic obstructive pulmonary disease. Studies have underscored the significance of miR-26a in the pathogenesis and progression of respiratory diseases, positioning it as a promising therapeutic target. Nevertheless, several challenges persist in devising medical strategies for clinical trials involving miR-26a. In this review, we summarize the regulatory role and significance of miR-26a in respiratory diseases, and we analyze and elucidate the challenges related to miR-26a druggability, encompassing issues such as the efficiency of miR-26a, delivery, RNA modification, off-target effects, and the envisioned therapeutic potential of miR-26a in clinical settings.

PMID:38717532 | DOI:10.1007/s11033-024-09576-5

Am J Respir Crit Care Med. 2024 May 8. doi: 10.1164/rccm.202306-0979OC. Online ahead of print.

ABSTRACT

RATIONALE: Changes in peripheral blood cell populations have been observed but not detailed at single-cell resolution in idiopathic pulmonary fibrosis (IPF).

OBJECTIVES: To provide an atlas of the changes in the peripheral immune system in stable and progressive IPF.

METHODS: Peripheral blood mononuclear cells (PBMCs) from IPF patients and controls were profiled using 10x Chromium 5' single-cell RNA sequencing (scRNA-seq). Flow cytometry was used for validation. Protein concentrations of Regulatory T-cells (Tregs) and Monocytes chemoattractants were measured in plasma and lung homogenates from patients and controls.

MEASUREMENTS AND MAIN RESULTS: Thirty-eight PBMC samples from 25 patients with IPF and 13 matched controls yielded 149,564 cells that segregated into 23 subpopulations. Classical monocytes were increased in progressive and stable IPF compared to controls (32.1%, 25.2%, 17.9%, respectively, p<0.05). Total lymphocytes were decreased in IPF vs controls, and in progressive vs stable IPF (52.6% vs 62.6%, p=0.035). Tregs were increased in progressive vs stable IPF (1.8% vs 1.1% of all PBMC, p=0.007), although not different than controls, and may be associated with decreased survival (P=0.009 in Kaplan-Meier analysis; P=0.069 after adjusting for age, sex, and baseline FVC). Flow cytometry analysis confirmed this finding in an independent cohort of IPF patients. Fraction of Tregs out of all T cells was also increased in two cohorts of lung scRNA-seq. CCL22 and CCL18, ligands for CCR4 and CCR8 Treg chemotaxis receptors, were increased in IPF.

CONCLUSIONS: The single-cell atlas of the peripheral immune system in IPF, reveals an outcome-predictive increase in classical monocytes and Tregs, as well as evidence for a lung-blood immune recruitment axis involving CCL7 (for classical monocytes) and CCL18/CCL22 (for Tregs).

PMID:38717443 | DOI:10.1164/rccm.202306-0979OC

Multimed Man Cardiothorac Surg. 2024 May 8;2024. doi: 10.1510/mmcts.2024.018.

ABSTRACT

In this video tutorial, we present a comprehensive step-by-step operative technique for a bilateral orthotopic lung transplant using a bilateral transverse thoracosternotomy in a patient with idiopathic pulmonary fibrosis lung disease. The donor lungs were exposed to extended cold static ischaemic storage at 10° C for the semi-elective operation.

PMID:38716640 | DOI:10.1510/mmcts.2024.018

bioRxiv [Preprint]. 2024 Apr 28:2024.04.24.589970. doi: 10.1101/2024.04.24.589970.

ABSTRACT

Rationale: While rodent lung fibrosis models are routinely used to evaluate novel antifibrotics, these models have largely failed to predict clinical efficacy of novel drug candidates for Idiopathic Pulmonary Fibrosis (IPF). Moreover, single target therapeutic strategies for IPF have failed and current multi-target standard of care drugs are not curative. Caveolin-1 (CAV-1) is an integral membrane protein, which, via its caveolin scaffolding domain (CSD), interacts with caveolin binding domains (CBD). CAV-1 regulates homeostasis, and its expression is decreased in IPF lungs. LTI-03 is a seven amino acid peptide derived from the CSD and formulated for dry powder inhalation; it was well tolerated in normal volunteers ( NCT04233814 ) and a safety trial is underway in IPF patients ( NCT05954988 ). Objectives: Anti-fibrotic efficacy of LTI-03 and other CSD peptides has been observed in IPF lung monocultures, and rodent pulmonary, dermal, and heart fibrosis models. This study aimed to characterize progressive fibrotic activity in IPF PCLS explants and to evaluate the antifibrotic effects of LTI-03 and nintedanib in this model. Methods: First, CBD regions were identified in IPF signaling proteins using in silico analysis. Then, IPF PCLS (n=8) were characterized by COL1A1 immunostaining, multiplex immunoassays, and bulk RNA sequencing following treatment every 12hrs with LTI-03 at 0.5, 3.0, or 10 μM; nintedanib at 0.1 μM or 1 μM; or control peptide (CP) at 10 μM. Measurements and Main Results: CBDs were present in proteins implicated in IPF, including VEGFR, FGFR and PDGFR. Increased expression of profibrotic mediators indicated active fibrotic activity in IPF PCLS over five days. LTI-03 dose dependently decreased COL1A1 staining, and like nintedanib, decreased profibrotic proteins and transcripts. Unlike nintedanib, LTI-03 did not induce cellular necrosis signals. Conclusion: IPF PCLS explants demonstrate molecular activity indicative of fibrosis during 5 days in culture and LTI-03 broadly attenuated pro-fibrotic proteins and pathways, further supporting the potential therapeutic effectiveness of LTI-03 for IPF.

PMID:38712072 | PMC:PMC11071419 | DOI:10.1101/2024.04.24.589970

Nan Fang Yi Ke Da Xue Xue Bao. 2024 Apr 20;44(4):644-651. doi: 10.12122/j.issn.1673-4254.2024.04.04.

ABSTRACT

OBJECTIVE: To observe the effect of Shenqi Chongcao (SQCC) Formula on the ASS1/src/STAT3 signaling pathway in a rat model of lung fibrosis and explore its therapeutic mechanism.

METHODS: A total of 120 male SD rats were divided equally into 5 groups, including a blank control group with saline treatment and 4 groups of rat models of idiopathic pulmonary fibrosis induced by intratracheal instillation of bleomycin. One day after modeling, the rat models were treated with daily gavage of 10 mL/kg saline, SQCC decoction (0.423 g/kg), pirfenidone (10 mL/kg), or intraperitoneal injection of arginine deiminase (ADI; 2.25 mg/kg, every 3 days) for 28 days. After the treatments, the lung tissues of the rats were collected for calculating the lung/body weight ratio, observing histopathology using HE and Masson staining, and analyzing the inflammatory cells in BALF using Giemsa staining. Serum chemokine ligand 2 (CCL2) and transforming growth factor-β1 (TGF-β1) levels were measured with ELISA. The protein expressions of src, p-srcTry529, STAT3, and p-STAT3Try705 and the mRNA expressions of ASS1, src and STAT3 in the lung tissues were detected using Western blotting and RT-qPCR.

RESULTS: The neutrophil, macrophage and lymphocyte counts and serum levels of CCL2 and TGF-β1 were significantly lower in SQCC, pirfenidone and ADI treatment groups than in the model group at each time point of measurement (P < 0.05). P-srcTry529 and p-STAT3Try705 protein expression levels and ASS1, src, and STAT3 mRNA in the lung tissues were also significantly lower in the 3 treatment groups than in the model group (P < 0.05).

CONCLUSION: SQCC Formula can alleviate lung fibrosis in rats possibly by activating the ASS1/src/STAT3 signaling pathway in the lung tissues.

PMID:38708496 | DOI:10.12122/j.issn.1673-4254.2024.04.04

Respir Res. 2024 May 4;25(1):195. doi: 10.1186/s12931-024-02825-y.

ABSTRACT

BACKGROUND: Lipocalin-2 (LCN2) is a secretory glycoprotein upregulated by oxidative stress; moreover, patients with idiopathic pulmonary fibrosis (IPF) have shown increased LCN2 levels in bronchoalveolar lavage fluid (BALF). This study aimed to determine whether circulatory LCN2 could be a systemic biomarker in patients with IPF and to investigate the role of LCN2 in a bleomycin-induced lung injury mouse model.

METHODS: We measured serum LCN2 levels in 99 patients with stable IPF, 27 patients with acute exacerbation (AE) of IPF, 51 patients with chronic hypersensitivity pneumonitis, and 67 healthy controls. Further, LCN2 expression in lung tissue was evaluated in a bleomycin-induced lung injury mouse model, and the role of LCN2 was investigated using LCN2-knockout (LCN2 -/-) mice.

RESULTS: Serum levels of LCN2 were significantly higher in patients with AE-IPF than in the other groups. The multivariate Cox proportional hazards model showed that elevated serum LCN2 level was an independent predictor of poor survival in patients with AE-IPF. In the bleomycin-induced lung injury mouse model, a higher dose of bleomycin resulted in higher LCN2 levels and shorter survival. Bleomycin-treated LCN2 -/- mice exhibited increased BALF cell and protein levels as well as hydroxyproline content. Moreover, compared with wild-type mice, LCN2-/- mice showed higher levels of circulatory 8-isoprostane as well as lower Nrf-2, GCLC, and NQO1 expression levels in lung tissue following bleomycin administration.

CONCLUSIONS: Our findings demonstrate that serum LCN2 might be a potential prognostic marker of AE-IPF. Moreover, LCN2 expression levels may reflect the severity of lung injury, and LCN2 may be a protective factor against bleomycin-induced acute lung injury and oxidative stress.

PMID:38704585 | DOI:10.1186/s12931-024-02825-y

Pulmonology. 2024 May 3:S2531-0437(24)00045-X. doi: 10.1016/j.pulmoe.2024.03.004. Online ahead of print.

ABSTRACT

INTRODUCTION AND AIMS: Workplace exposures are widely known to cause specific occupational diseases such as silicosis and asbestosis, but they also can contribute substantially to causation of common respiratory diseases. In 2019, the American Thoracic Society (ATS) and the European Respiratory Society (ERS) published a joint statement on the occupational burden of respiratory diseases. Our aim on this narrative review is to summarise the most recent evidence published after the ATS/ERS statement as well as to provide information on traditional occupational lung diseases that can be useful for clinicians and researchers.

RESULTS: Newer publications confirm the findings of the ATS/ERS statement on the role of workplace exposure in contributing to the aetiology of the respiratory diseases considered in this review (asthma, COPD, chronic bronchitis, idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, infectious pneumonia). Except for COPD, chronic bronchitis and infectious pneumonia, the number of publications in the last 5 years for the other diseases is limited. For traditional occupational lung diseases such as silicosis and asbestosis, there are old as well as novel sources of exposure and their burden continues to be relevant, especially in developing countries.

CONCLUSIONS: Occupational exposure remains an important risk factor for airways and interstitial lung diseases, causing occupational lung diseases and contributing substantially in the aetiology of common respiratory diseases. This information is critical for public health professionals formulating effective preventive strategies but also for clinicians in patient care. Effective action requires shared knowledge among clinicians, researchers, public health professionals, and policy makers.

PMID:38704309 | DOI:10.1016/j.pulmoe.2024.03.004