Front Immunol. 2023 Jun 2;14:1078055. doi: 10.3389/fimmu.2023.1078055. eCollection 2023.

ABSTRACT

BACKGROUND: There is still a lack of specific indicators to diagnose idiopathic pulmonary fibrosis (IPF). And the role of immune responses in IPF is elusive. In this study, we aimed to identify hub genes for diagnosing IPF and to explore the immune microenvironment in IPF.

METHODS: We identified differentially expressed genes (DEGs) between IPF and control lung samples using the GEO database. Combining LASSO regression and SVM-RFE machine learning algorithms, we identified hub genes. Their differential expression were further validated in bleomycin-induced pulmonary fibrosis model mice and a meta-GEO cohort consisting of five merged GEO datasets. Then, we used the hub genes to construct a diagnostic model. All GEO datasets met the inclusion criteria, and verification methods, including ROC curve analysis, calibration curve (CC) analysis, decision curve analysis (DCA) and clinical impact curve (CIC) analysis, were performed to validate the reliability of the model. Through the Cell Type Identification by Estimating Relative Subsets of RNA Transcripts algorithm (CIBERSORT), we analyzed the correlations between infiltrating immune cells and hub genes and the changes in diverse infiltrating immune cells in IPF.

RESULTS: A total of 412 DEGs were identified between IPF and healthy control samples, of which 283 were upregulated and 129 were downregulated. Through machine learning, three hub genes (ASPN, SFRP2, SLCO4A1) were screened. We confirmed their differential expression using pulmonary fibrosis model mice evaluated by qPCR, western blotting and immunofluorescence staining and analysis of the meta-GEO cohort. There was a strong correlation between the expression of the three hub genes and neutrophils. Then, we constructed a diagnostic model for diagnosing IPF. The areas under the curve were 1.000 and 0.962 for the training and validation cohorts, respectively. The analysis of other external validation cohorts, as well as the CC analysis, DCA, and CIC analysis, also demonstrated strong agreement. There was also a significant correlation between IPF and infiltrating immune cells. The frequencies of most infiltrating immune cells involved in activating adaptive immune responses were increased in IPF, and a majority of innate immune cells showed reduced frequencies.

CONCLUSION: Our study demonstrated that three hub genes (ASPN, SFRP2, SLCO4A1) were associated with neutrophils, and the model constructed with these genes showed good diagnostic value in IPF. There was a significant correlation between IPF and infiltrating immune cells, indicating the potential role of immune regulation in the pathological process of IPF.

PMID:37334348 | PMC:PMC10272521 | DOI:10.3389/fimmu.2023.1078055

Front Microbiol. 2023 Jun 2;14:1200937. doi: 10.3389/fmicb.2023.1200937. eCollection 2023.

ABSTRACT

INTRODUCTION: Growing evidence indicates that variations in the composition of the gut microbiota are linked to the onset and progression of chronic respiratory diseases (CRDs), albeit the causal relationship between the two remains unclear.

METHODS: We conducted a comprehensive two-sample Mendelian randomization (MR) analysis to investigate the relationship between gut microbiota and five main CRDs, including chronic obstructive pulmonary disease (COPD), asthma, idiopathic pulmonary fibrosis (IPF), sarcoidosis, and pneumoconiosis. For MR analysis, the inverse variance weighted (IVW) method was utilized as the primary method. The MR-Egger, weighted median, and MR-PRESSO statistical methods were used as a supplement. To detect heterogeneity and pleiotropy, the Cochrane and Rucker Q test, MR-Egger intercept test, and MR-PRESSO global test were then implemented. The leave-one-out strategy was also applied to assess the consistency of the MR results.

RESULTS: Based on substantial genetic data obtained from genome-wide association studies (GWAS) comprising 3,504,473 European participants, our study offers evidence that several gut microbial taxa, including 14 probable microbial taxa (specifically, 5, 3, 2, 3 and 1 for COPD, asthma, IPF, sarcoidosis, and pneumoconiosis, respectively) and 33 possible microbial taxa (specifically, 6, 7, 8, 7 and 5 for COPD, asthma, IPF, sarcoidosis, and pneumoconiosis, respectively) play significant roles in the formation of CRDs.

DISCUSSION: This work implies causal relationships between the gut microbiota and CRDs, thereby shedding new light on the gut microbiota-mediated prevention of CRDs.

PMID:37333634 | PMC:PMC10272395 | DOI:10.3389/fmicb.2023.1200937

bioRxiv. 2023 Jun 7:2023.06.07.544093. doi: 10.1101/2023.06.07.544093. Preprint.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by progressive scarring of the lungs and resulting in deterioration in lung function. Several profibrotic factors drive pulmonary fibrosis, with transforming growth factor-beta (TGF-beta) being the most established. TGF-beta promotes transformation of tissue fibroblasts to myofibroblasts, a key finding in the pathogenesis of pulmonary fibrosis. Anoctamin-1 (ANO1), also known as TMEM16A, is a calcium-activated chloride channel. We found that TGF-beta robustly upregulates ANO1 expression in human lung fibroblasts (HLF) at mRNA and protein levels. Consistent, ANO1 was readily detected in fibrotic areas of IPF lungs. TGF-beta treatment of HLF resulted in a significant increase in steady state accumulation of intracellular chloride concentration, which was prevented by a specific ANO1 inhibitor, T16A inh -A01, or by siRNA-mediated ANO1 knockdown. T16A inh -A01 or ANO1 siRNA significantly inhibited TGF-beta-induced myofibroblast differentiation as determined by the expression of smooth muscle alpha-actin, collagen-1 and fibronectin. Mechanistically, pharmacological or knockdown-mediated inhibition of ANO1 did not have an effect on the initial TGF-beta signaling (Smad2 phosphorylation), but it blocked downstream TGF-beta signaling including Rho pathway (assessed by phosphorylation of myosin light chain) and AKT activation. Together, these data demonstrate that ANO1 is a TGF-beta-inducible chloride channel that largely contributes to the increase in intracellular chloride concentration in TGF-beta-treated cells. Furthermore, ANO1 mediates TGF-beta-induced myofibroblast differntiation, at least partially through activation of Rho pathway and of AKT.

NEW & NOTEWORTHY: Pulmonary fibrosis is a devastating disease characterized by progressive scarring of the lungs and resulting in deterioration of lung function. Myofibroblasts are cells produced from tissue fibroblasts during this disease and are the key pathologic cells that contribute to lung scaring. Transforming growth factor-beta (TGF-beta) is the cytokine that drives myofibroblast differentiation. This study identifies a novel role of a chloride channel, Anoctamin-1, in the cellular mechanism TGF-beta-induced myofibroblast differentiation.

PMID:37333255 | PMC:PMC10274757 | DOI:10.1101/2023.06.07.544093

bioRxiv. 2023 Jun 7:2023.06.07.543956. doi: 10.1101/2023.06.07.543956. Preprint.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a chronic parenchymal lung disease characterized by repetitive alveolar cell injury, myofibroblast proliferation, and excessive extracellular matrix deposition for which unmet need persists for effective therapeutics. The bioactive eicosanoid, prostaglandin F2 α , and its cognate receptor FPr ( Ptfgr ) are implicated as a TGF β 1 independent signaling hub for IPF. To assess this, we leveraged our published murine PF model (I ER -Sftpc I 73 T ) expressing a disease-associated missense mutation in the surfactant protein C ( Sftpc ) gene. Tamoxifen treated I ER - Sftpc I 73 T mice develop an early multiphasic alveolitis and transition to spontaneous fibrotic remodeling by 28 days. I ER - Sftpc I 73 T mice crossed to a Ptgfr null (FPr - / - ) line showed attenuated weight loss and gene dosage dependent rescue of mortality compared to FPr +/+ cohorts. I ER - Sftpc I 73 T /FPr - / - mice also showed reductions in multiple fibrotic endpoints for which administration of nintedanib was not additive. Single cell RNA sequencing, pseudotime analysis, and in vitro assays demonstrated Ptgfr expression predominantly within adventitial fibroblasts which were reprogrammed to an "inflammatory/transitional" cell state in a PGF2 α / FPr dependent manner. Collectively, the findings provide evidence for a role for PGF2 α signaling in IPF, mechanistically identify a susceptible fibroblast subpopulation, and establish a benchmark effect size for disruption of this pathway in mitigating fibrotic lung remodeling.

PMID:37333249 | PMC:PMC10274762 | DOI:10.1101/2023.06.07.543956

Front Med (Lausanne). 2023 Jun 2;10:1151922. doi: 10.3389/fmed.2023.1151922. eCollection 2023.

ABSTRACT

RATIONALE: Therapies that slow idiopathic pulmonary fibrosis (IPF) progression are now available and recent studies suggest that the use of antifibrotic therapy may reduce IPF mortality.

OBJECTIVES: The aim of the study was to evaluate whether, to what extent, and for which factors the survival of IPF in a real-life setting has changed in the last 15 years.

METHODS: Historical eye is an observational study of a large cohort of consecutive IPF patients diagnosed and treated in a referral center for ILDs with prospective intention. We recruited all consecutive IPF patients seen at GB Morgagni Hospital, Forlì, Italy between January 2002 and December 2016 (15 years). We used survival analysis methods to describe and model the time to death or lung transplant and Cox regression to model prevalent and incident patient characteristics (time-dependent Cox models were fitted).

MEASUREMENTS AND MAIN RESULTS: The study comprised 634 patients. The year 2012 identifies the time point of mortality shift (HR 0.58, CI 0.46-0.63, p < 0.001). In the more recent cohort, more patients had better preserved lung function, underwent cryobiopsy instead of surgery, and were treated with antifibrotics. Highly significant negative prognostic factors were lung cancer (HR 4.46, 95% CI 3.3-6, p < 0.001), hospitalizations (HR 8.37, 95% CI 6.5-10.7, p < 0.001), and acute exacerbations (HR 8.37, 95% CI 6.52-10.7, p < 0.001). The average antifibrotic treatment effect estimated using propensity score matching showed a significant effect in the reduction of all-cause mortality (ATE coeff -0.23, SE 0.04, p < 0.001), acute exacerbations (ATE coeff -0.15, SE 0.04, p < 0.001), and hospitalizations (ATE coeff -0.15, SE 0.04, p < 0.001) but no effect on lung cancer risk (ATE coeff -0.03, SE 0.03, p = 0.4).

CONCLUSION: Antifibrotic drugs significantly impact hospitalizations, acute exacerbations, and IPF survival. After the introduction of cryobiopsy and antifibrotic drugs, the prognosis of IPF patients has significantly improved together with our ability to detect IPF at an earlier stage.

PMID:37332746 | PMC:PMC10273674 | DOI:10.3389/fmed.2023.1151922

Int Immunopharmacol. 2023 Jun 16;121:110493. doi: 10.1016/j.intimp.2023.110493. Online ahead of print.

ABSTRACT

Acute lung injury leads to the development of chronic conditions such as idiopathic pulmonary fibrosis (IPF), chronic obstructive pulmonary disease (COPD), asthma as well as alveolar sarcoma. Various investigations are being performed worldwide to understand the pathophysiology of these diseases, develop novel bioactive compounds and inhibitors to target the ailment. Generally, in vivo models are used to understand the disease outcome and therapeutic suppressing effects for which the animals are chemically or physically induced to mimic the onset of definite disease conditions. Amongst the chemical inducing agents, Bleomycin (BLM) is the most successful inducer. It is reported to target various receptors and activate inflammatory pathways, cellular apoptosis, epithelial mesenchymal transition leading to the release of inflammatory cytokines, and proteases. Mice is one of the most widely used animal model for BLM induced pulmonary associated studies apart from rat, rabbit, sheep, pig, and monkey. Although, there is considerable variation amongst in vivo studies for BLM induction which suggests a detailed study on the same to understand the mechanism of action of BLM at molecular level. Hence, herein we have reviewed various chemical inducers, mechanism of action of BLM in inducing lung injury in vivo, its advantages and disadvantages. Further, we have also discussed the rationale behind various in vivo models and recent development in BLM induction for various animals.

PMID:37331299 | DOI:10.1016/j.intimp.2023.110493

Eur J Intern Med. 2023 Jun 15:S0953-6205(23)00206-6. doi: 10.1016/j.ejim.2023.06.012. Online ahead of print.

ABSTRACT

OBJECTIVES: Antisynthetase syndrome (ASyS) is a rare autoimmune disease. We aimed to determine clinical, biological, radiological, and evolutive profiles of ASyS patients with anti-PL7 or anti-PL12 autoantibodies.

METHODS: We performed a retrospective study that included adults with overt positivity for anti-PL7/anti-PL12 autoantibodies and at least one Connors' criterion.

RESULTS: Among 72 patients, 69% were women, 29 had anti-PL7 and 43 anti-PL12 autoantibodies, median age was 60.3 years, and median follow-up period was 52.2 months. At diagnosis, 76% of patients had interstitial lung disease, 61% had arthritis, 39% myositis, 25% Raynaud's phenomenon, 18% mechanic's hands, and 17% had fever. The most frequent pattern on initial chest computed tomography was non-specific interstitial pneumonia and 67% had fibrosis at last follow-up. During follow-up, 12 patients had pericardial effusion (18%), 19 had pulmonary hypertension (29%), 9 (12.5%) had neoplasms, and 14 (19%) died. Sixty-seven patients (93%) received at least one steroid or immunosuppressive drug. Patients with anti-PL12 autoantibodies were younger (p=0.01) and more frequently exhibited anti-SSA autoantibodies (p=0.01); patients with anti-PL7 autoantibodies had more severe weakness and higher maximum creatine kinase levels (p=0.03 and 0.04, respectively). Initial severe dyspnoea was more common in patients from the West Indies (p=0.009), with lower predicted values of forced vital capacity, forced expiratory volume in 1s, and total lung capacity (p=0.01, p=0.02, p=0.01, respectively) contributing to a more severe 'respiratory' initial presentation.

CONCLUSIONS: The high mortality and significant numbers of cardiovascular events, neoplasms and lung fibrosis in anti-PL7/12 patients justify close monitoring and question addition of antifibrotic drugs.

PMID:37330316 | DOI:10.1016/j.ejim.2023.06.012

Cell Mol Biol (Noisy-le-grand). 2023 Apr 30;69(4):172-178. doi: 10.14715/cmb/2023.69.4.27.

ABSTRACT

This study aimed to investigate the mechanism of lung tissue YKL-40 promoting the interstitial transformation of alveolar epithelial cells in mice with idiopathic pulmonary fibrosis and its effect on the level of TGF-β1. For this purpose, Forty SPF SD mice were randomly divided into 4 groups. They were the blank control group (CK group), virus-negative control group (YKL-40-NC group), YKL-40 knockdown group (YKL-40-inhibitor group) and YKL-40 overexpression group (YKL-40-mimics group), respectively. The mRNA expressions of alveolar epithelial cell mesenchymal transformation-related proteins, pulmonary fibrosis-related factors and TGF-β1-related pathway proteins in the above four groups of mice were compared to determine the mechanism of the promotion of alveolar epithelial cell mesenchymal transformation by YKL-40 in the lung tissues of mice with idiopathic pulmonary fibrosis and the effect of YKL-40 on the level of TGF-β1. The results showed that in terms of lung wet/dry weight ratio, the YKL-40-NC group, YKL-40-inhibitor group and YKL-40-mimics group were significantly increased compared with the CK group (P<0.05). About YKL-40 protein expression, compared with the CK group, AOD value and YKL-40 protein expression in the YKL-40-NC group, YKL-40-inhibitor group and YKL-40-mimics group were significantly increased (P<0.05), and compared with YKL-40-NC group, The AOD value and YKL-40 protein expression in YKL-40-inhibitor group were significantly decreased, while the AOD value and YKL-40 protein expression in YKL-40-mimics group were significantly increased (P<0.05), suggesting successful lentivirus transfection. Compared with the CK group, β-catenin and E-cadherin in the alveolar epithelial cells were significantly increased, while Pro-SPC was significantly decreased (P<0.05). The mRNA expression of pulmonary fibrosis-related factors showed that compared with the CK group, the mRNA expression of vimimin and hydroxyproline was significantly increased, while the mRNA expression of E-cadherin was decreased (P<0.05). However, the mRNA expressions of vimimin and hydroxyproline in the YKL-40-inhibitor group were significantly decreased, but the mRNA expression of E-cadherin was significantly increased. Compared with CK group, the protein expressions of TGF-β1, Smad3, Smad7 and α-Sma in the CK group were significantly increased (P<0.05). The protein expressions of TGF-β1, Smad3, Smad7 and α-SMA in the YKL-40-mimics group were significantly increased, but the protein expressions of TGF-β1, Smad3, Smad7 and α-SMA in YKL-40-inhibitor group were significantly decreased (P<0.05). In general, overexpression of YKL-40 can promote the progression of pulmonary fibrosis and the interstitial transformation of alveolar epithelial cells in mice with idiopathic fibrosis.

PMID:37329529 | DOI:10.14715/cmb/2023.69.4.27

ACS Pharmacol Transl Sci. 2023 May 18;6(6):878-891. doi: 10.1021/acsptsci.3c00033. eCollection 2023 Jun 9.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a kind of life-threatening interstitial lung disease characterized by progressive dyspnea with accurate pathogenesis unknown. At present, heat shock protein inhibitors are gradually used to treat IPF. Silybin, a heat shock protein C-terminal inhibitor, has high safety and good application prospects. In this work, we have developed a silybin powder able to be used for inhalation administration for the treatment of IPF. Silybin powder was prepared by the spray drying method and identified using cascade impactometry, particle size, scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared (FT-IR) spectroscopy. A rat model of bleomycin-induced IPF was used to assess the effect of inhaled silybin spray-dried powder. Lung hydroxyproline content, wet weight, histology, inflammatory factor expression, and gene expression were examined. The results showed that inhaled silybin spray-dried powder alleviated inflammation and fibrosis, limited hydroxyproline accumulation in the lungs, modulated gene expression in the development of IPF, and improved postoperative survival. The results of this study suggest that silybin spray-dried powder is an attractive candidate for the treatment of IPF.

PMID:37325446 | PMC:PMC10262316 | DOI:10.1021/acsptsci.3c00033

Front Pharmacol. 2023 May 30;14:1219760. doi: 10.3389/fphar.2023.1219760. eCollection 2023.

ABSTRACT

[This corrects the article DOI: 10.3389/fphar.2022.838449.].

PMID:37324497 | PMC:PMC10263364 | DOI:10.3389/fphar.2023.1219760

Front Med (Lausanne). 2023 Jun 1;10:1195263. doi: 10.3389/fmed.2023.1195263. eCollection 2023.

NO ABSTRACT

PMID:37324135 | PMC:PMC10267469 | DOI:10.3389/fmed.2023.1195263

Ann Thorac Med. 2023 Apr-Jun;18(2):79-85. doi: 10.4103/atm.atm_264_22. Epub 2023 Apr 25.

ABSTRACT

BACKGROUND: The prognosis of idiopathic pulmonary fibrosis (IPF) can be predicted by the gender, age, and physiology (GAP) index. However, antifibrotic therapy (i.e., nintedanib and pirfenidone) may improve survival.

AIMS: This study aimed to compare the outcomes of antifibrotic-treated IPF with the survival predicted by the GAP index.

METHODS: A retrospective cohort study was conducted from March 2014 to January 2020. The electronic health-care records of all IPF patients treated with nintedanib or pirfenidone were reviewed. Besides standard demographic and mortality data, the variables required to calculate the GAP index were also extracted.

RESULTS: Eighty-one patients (male 55, 68%; age 71.4 ± 10.2 years) with IPF received antifibrotic therapy (nintedanib 44.4%; pirfenidone 55.6%; mean follow-up 35 ± 16.5 months). Cumulative mortality (whole cohort 3 years 12%; 4 years 26%; 5 years 33%) was significantly less than predicted by the GAP index.

CONCLUSIONS: The survival of antifibrotic-treated IPF is better than predicted by the GAP index. Novel systems for prognostication are required. The survival benefit from pirfenidone and nintedanib seem similar overall.

PMID:37323372 | PMC:PMC10263079 | DOI:10.4103/atm.atm_264_22

Respir Med. 2023 Jun 12:107329. doi: 10.1016/j.rmed.2023.107329. Online ahead of print.

ABSTRACT

OBJECTIVE: The clinical spectrum of connective tissue disease-associated interstitial lung disease (CTD-ILD) and rheumatoid arthritis-associated interstitial lung disease (RA-ILD) ranges from asymptomatic findings on radiographic imaging to a rapidly progressive illness leading to respiratory failure and death. The treatment is always challenging due to the paucity of proven effective treatments. Nintedanib and pirfenidone are recently approved antifibrotics in idiopathic pulmonary fibrosis. This study aimed to investigate the efficacy and safety of antifibrotic agents in the treatment of CTD-ILD and RA-ILD.

METHODS: Relevant databases were searched for randomized controlled trials that compared pirfenidone or nintedanib with placebo in patients with CTD-ILD and RA-ILD. The primary outcome was the change in forced vital capacity (FVC). The odds ratio or risk ratio with 95% confidence interval (CI) was estimated for categorical data, and the mean difference with 95% CI was estimated for continuous data. The I2 statistic was used to assess heterogeneity, and meta-analysis was performed when possible.

RESULTS: Ten studies with a total of 880 participants met the inclusion criteria. Of these, four studies were included in the meta-analysis. According to the pooled result, the annual decline of FVC was significantly decreased in the antifibrotic agent arm compared to that in the placebo arm (MD 70.58 mL/yr, 95% CI 40.55 to 100.61).

CONCLUSION: This review suggests a potential benefit and safety of antifibrotic treatment in slowing the decline of FVC in patients with CTD-ILD and RA-ILD. Further large-sample, random-controlled, high-quality trials are needed to provide more evidence in the decision-making regarding the use of antifibrotics in this group of patients.

CLINICAL TRIAL REGISTRATION: PROSPERO; No.: CRD42022369112; URL: https://www.crd.york.ac.uk/prospero/.

PMID:37315742 | DOI:10.1016/j.rmed.2023.107329

Int J Pharm. 2023 Jun 12:123117. doi: 10.1016/j.ijpharm.2023.123117. Online ahead of print.

ABSTRACT

The past decades have witnessed tremendous expansion in utilization of plant-derived medicines as resveratrol (RES) in treating several diseases like idiopathic pulmonary fibrosis (IPF). RES can exhibit its role in treating IPF via its outstanding antioxidant and anti-inflammatory activities. The goal of this work was to formulate RES-loaded spray-dried composite microparticles (SDCMs) suitable for pulmonary delivery via dry powder inhaler (DPI). They were prepared by spray drying of a previously prepared RES-loaded bovine serum albumin nanoparticles (BSA NPs) dispersion using different carriers. RES-loaded BSA NPs, prepared by the desolvation technique, acquired suitable particle size of 177.67±0.95 nm and entrapment efficiency of 98.7±0.35% with perfectly uniform size distribution and high stability. Considering the attributes of the pulmonary route, NPs were co-spray dried with compatible carriers viz. mannitol, dextran, trehalose, leucine, glycine, aspartic acid, and glutamic acid to fabricate SDCMs. All formulations showed suitable mass median aerodynamic diameter less than 5 µm; that is suitable for deep lung deposition. However, the best aerosolization behavior was attained from using leucine with fine particle fraction (FPF) of 75.74%, followed by glycine with FPF of 54.7%. Finally, a pharmacodynamic study was conducted on bleomycin-induced mice, and it strongly revealed the role of the optimized formulations in alleviating PF through suppressing the levels of hydroxyproline, tumor necrosis factor-α and matrix metalloproteinase-9 with obvious improvements in the treated lung histopathology. These findings indicate that in addition to leucine, the glycine amino acid, which is not commonly used yet, is very promising in the formulation of DPIs.

PMID:37315636 | DOI:10.1016/j.ijpharm.2023.123117

Elife. 2023 Jun 14;12:e85415. doi: 10.7554/eLife.85415. Online ahead of print.

ABSTRACT

Aging is a critical risk factor in idiopathic pulmonary fibrosis (IPF). Dysfunction and loss of type 2 alveolar epithelial cells (AEC2s) with failed regeneration is a seminal causal event in the pathogenesis of IPF, although the precise mechanisms for their regenerative failure and demise remain unclear. To systematically examine the genomic program changes of AEC2s in aging and after lung injury, we performed unbiased single-cell RNA-seq analyses of lung epithelial cells from uninjured or bleomycin-injured young and old mice, as well as from lungs of IPF patients and healthy donors. We identified three AEC2 subsets based on their gene signatures. Subset AEC2-1 mainly exist in uninjured lungs, while subsets AEC2-2 and AEC2-3 emerged in injured lungs and increased with aging. Functionally, AEC2 subsets are correlated with progenitor cell renewal. Aging enhanced the expression of the genes related to inflammation, stress responses, senescence, and apoptosis. Interestingly, lung injury increased aging-related gene expression in AEC2s even in young mice. The synergistic effects of aging and injury contributed to impaired AEC2 recovery in aged mouse lungs after injury. In addition, we also identified three subsets of AEC2s from human lungs that formed three similar subsets to mouse AEC2s. IPF AEC2s showed a similar genomic signature to AEC2 subsets from bleomycin-injured old mouse lungs. Taken together, we identified synergistic effects of aging and AEC2 injury in transcriptomic and functional analyses that promoted fibrosis. This study provides new insights into the interactions between aging and lung injury with interesting overlap with diseased IPF AEC2 cells.

PMID:37314162 | DOI:10.7554/eLife.85415

Am J Physiol Lung Cell Mol Physiol. 2023 Jun 13. doi: 10.1152/ajplung.00303.2022. Online ahead of print.

ABSTRACT

Vanadium is available as a dietary supplement and also is known to be toxic if inhaled, yet little information is available concerning effects of vanadium on mammalian metabolism when at concentrations found in food and water. Vanadium pentoxide (V+5) is representative of the most common dietary and environmental exposures, and prior research shows low-dose V+5 exposure causes oxidative stress measured by glutathione oxidation and protein S-glutathionylation. We examined the metabolic impact of V+5 at relevant dietary and environmental doses (0.01, 0.1, 1 ppm for 24 h) in human lung fibroblasts (HLF) and male C57BL/6J mice (0.02, 0.2, 2 ppm in drinking water for 7 months). Untargeted metabolomics using liquid chromatography-high-resolution mass spectrometry (LC-HRMS) showed that V+5 induced significant metabolic perturbations in both HLF cells and mouse lungs. We noted 30% of the significantly altered pathways in HLF cells, including pyrimidines and aminosugars, fatty acids, mitochondrial and redox pathways, showed similar dose-dependent patterns in mouse lung tissues. Alterations in lipid metabolism included leukotrienes and prostaglandins involved in inflammatory signaling, which have been associated with the pathogenesis of idiopathic pulmonary fibrosis (IPF) and other disease processes. Elevated hydroxyproline levels and excessive collagen deposition were also present in lungs from V+5-treated mice. Taken together, these results show that oxidative stress from environmental V+5, ingested at low levels, could alter metabolism to contribute to common human lung diseases.

PMID:37310758 | DOI:10.1152/ajplung.00303.2022

Rev Mal Respir. 2023 Jun;40(6):469-478. doi: 10.1016/j.rmr.2023.04.003. Epub 2023 May 31.

ABSTRACT

In some cases of interstitial lung disease (ILD), clinical and biological findings associated with CT scan pattern during multidisciplinary discussion (MDD) fail to yield a confident diagnosis. In these cases, histology may be necessary. Transbronchial lung cryobiopsy (TBLC) is a bronchoscopic procedure that has been developed in recent years and currently contributes to diagnostic work-up in patients with ILD. TBLC provides tissue samples for histological analysis with an acceptable risk of complications, consisting mainly in pneumothorax or bleeding. In addition to higher diagnostic yield than conventional forceps biopsies, the procedure shows a better safety profile than surgical biopsies. The indication to perform TBLC is decided during a 1st MDD and during a 2nd MDD, results can provide a diagnostic yield approximating 80%. TBLC appears to be an attractive, minimally invasive technique to be proposed as a first-line procedure in selected patients in experienced centers, while surgical lung biopsy may be considered as a second-line solution.

PMID:37308261 | DOI:10.1016/j.rmr.2023.04.003

BMJ Open Respir Res. 2023 Jun;10(1):e001291. doi: 10.1136/bmjresp-2022-001291.

ABSTRACT

Interstitial lung disease (ILD) is a collective term representing a diverse group of pulmonary fibrotic and inflammatory conditions. Due to the diversity of ILD conditions, paucity of guidance and updates to diagnostic criteria over time, it has been challenging to precisely determine ILD incidence and prevalence. This systematic review provides a synthesis of published data at a global level and highlights gaps in the current knowledge base. Medline and Embase databases were searched systematically for studies reporting incidence and prevalence of various ILDs. Randomised controlled trials, case reports and conference abstracts were excluded. 80 studies were included, the most described subgroup was autoimmune-related ILD, and the most studied conditions were rheumatoid arthritis (RA)-associated ILD, systemic sclerosis associated (SSc) ILD and idiopathic pulmonary fibrosis (IPF). The prevalence of IPF was mostly established using healthcare datasets, whereas the prevalence of autoimmune ILD tended to be reported in smaller autoimmune cohorts. The prevalence of IPF ranged from 7 to 1650 per 100 000 persons. Prevalence of SSc ILD and RA ILD ranged from 26.1% to 88.1% and 0.6% to 63.7%, respectively. Significant heterogeneity was observed in the reported incidence of various ILD subtypes. This review demonstrates the challenges in establishing trends over time across regions and highlights a need to standardise ILD diagnostic criteria.PROSPERO registration number: CRD42020203035.

PMID:37308252 | DOI:10.1136/bmjresp-2022-001291

Pneumologie. 2023 Jun 12. doi: 10.1055/a-2028-6100. Online ahead of print.

ABSTRACT

BACKGROUND: Welding, performed regularly by more than a million workers worldwide, is associated with exposures to irritative, fibrogenic and carcinogenic fumes and gases.

METHODS AND RESULTS: We present the case of a welder who had worked under extremely poor hygiene conditions for nearly 20 years and had developed end-stage lung fibrosis, finally requiring lung transplantation. Detailed histopathology and scanning electron microscopy/energy dispersive X-ray spectroscopy (SEM/EDS) analyses of his lungs showed advanced interstitial fibrosis and dust deposits in the lungs and in peribronchial lymph nodes containing welding type bodies, Fe, Si (silica), Ti (titanium), SiAl (aluminum silicates), Fe with Cr (Steel), and Zr (Zirkonium).

CONCLUSION: In the absence of a systemic disorder and the failure to meet the criteria for diagnosis of idiopathic pulmonary fibrosis (IPF), these findings suggest welder's lung fibrosis as the most likely diagnosis.

PMID:37308084 | DOI:10.1055/a-2028-6100

J Ethnopharmacol. 2023 Jun 10:116773. doi: 10.1016/j.jep.2023.116773. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive disease with limited therapy. Renshen Pingfei Formula (RPFF), a classic Chinese medicine derivative formula, has been shown to exert therapeutic effects on IPF.

AIM OF THE STUDY: The study aimed to explore the anti-pulmonary fibrosis mechanism of RPFF through network pharmacology, clinical plasma metabolomics, and in vitro experiment.

METHODS: Network pharmacology was used to study the holistic pharmacological mechanism of RPFF in the treatment of IPF. The differential plasma metabolites for RPFF in the treatment of IPF were identified by untargeted metabolomics analysis. By integrated analysis of metabolomics and network pharmacology, the therapeutic target of RPFF for IPF and the corresponding herbal ingredients were identified. In addition, the effects of the main components of the formula, kaempferol and luteolin, which regulate the adenosine monophosphate (AMP)-activated protein kinase (AMPK)/peroxisome proliferator-activated receptor γ (PPAR-γ) pathway were observed in vitro according to the orthogonal design.

RESULTS: A total of 92 potential targets for RPFF in the treatment of IPF were obtained. The Drug-Ingredients-Disease Target network showed that PTGS2, ESR1, SCN5A, PPAR-γ, and PRSS1 were associated with more herbal ingredients. The protein-protein interaction (PPI) network identified the key targets of RPFF in IPF treatment, including IL6, VEGFA, PTGS2, PPAR-γ, and STAT3. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis acquired the main enriched pathways, and PPAR-γ involved in multiple signaling pathways, including the AMPK signaling pathway. Untargeted clinical metabolomics analysis revealed plasma metabolite variations in patients with IPF versus controls and before versus after RPFF treatment for patients with IPF. Six differential metabolites were explored as differential plasma metabolites for RPFF in IPF treatment. Combined with network pharmacology, a therapeutic target PPAR-γ of RPFF in IPF treatment and the corresponding herbal components were identified. Based on the orthogonal experimental design, the experiments showed that kaempferol and luteolin can decrease the mRNA and protein expression of α-smooth muscle actin (α-SMA), and the combination of lower dose can inhibit α-SMA mRNA and protein expression by promoting the AMPK/PPAR-γ pathway in transforming growth factor beta 1 (TGF-β1)-treated MRC-5 cells.

CONCLUSIONS: This study revealed that the therapeutic effects of RPFF are due to multiple ingredients and have multiple targets and pathways, and PPAR-γ is one of therapeutic targets for RPPF in IPF and involved in the AMPK signaling pathway. Two ingredients of RPFF, kaempferol and luteolin, can inhibit fibroblast proliferation and the myofibroblast differentiation of TGF-β1, and exert a synergistic effect through AMPK/PPAR-γ pathway activation.

PMID:37308028 | DOI:10.1016/j.jep.2023.116773