Cell Death Differ. 2021 Aug 20. doi: 10.1038/s41418-021-00840-w. Online ahead of print.

ABSTRACT

The mitochondrial calcium uniporter (MCU) regulates metabolic reprogramming in lung macrophages and the progression of pulmonary fibrosis. Fibrosis progression is associated with apoptosis resistance in lung macrophages; however, the mechanism(s) by which apoptosis resistance occurs is poorly understood. Here, we found a marked increase in mitochondrial B-cell lymphoma-2 (Bcl-2) in lung macrophages from subjects with idiopathic pulmonary fibrosis (IPF). Similar findings were seen in bleomycin-injured wild-type (WT) mice, whereas Bcl-2 was markedly decreased in mice expressing a dominant-negative mitochondrial calcium uniporter (DN-MCU). Carnitine palmitoyltransferase 1a (Cpt1a), the rate-limiting enzyme for fatty acid β-oxidation, directly interacted with Bcl-2 by binding to its BH3 domain, which anchored Bcl-2 in the mitochondria to attenuate apoptosis. This interaction was dependent on Cpt1a activity. Lung macrophages from IPF subjects had a direct correlation between CPT1A and Bcl-2, whereas the absence of binding induced apoptosis. The deletion of Bcl-2 in macrophages protected mice from developing pulmonary fibrosis. Moreover, mice had resolution when Bcl-2 was deleted or was inhibited with ABT-199 after fibrosis was established. These observations implicate an interplay between macrophage fatty acid β-oxidation, apoptosis resistance, and dysregulated fibrotic remodeling.

PMID:34413485 | DOI:10.1038/s41418-021-00840-w

Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2021 Jul;33(7):832-837. doi: 10.3760/cma.j.cn121430-20200729-00550.

ABSTRACT

OBJECTIVE: To investigate the main postoperative complications, causes of death and the risk factors for survival in patient with benign end-stage lung diseases within 1 year after lung transplantation.

METHODS: A retrospective analysis was conducted to collect the clinical data of 200 patients with benign end-stage lung disease who underwent lung transplantation admitted to Wuxi People's Hospital Affiliated to Nanjing Medical University from May 2017 to October 2018. The main postoperative complications, survival and causes of death within 1 year after operation were analyzed. The Kaplan-Meier method was used to plot survival curves, and the Log-Rank test was used to compare the influence of factors, including recipient's gender, use of marginal donor lung, primary disease, preoperative combination of moderate to severe pulmonary hypertension (PAH), intraoperative extracorporeal membrane oxygenation (ECMO) support, surgical methods, intraoperative massive blood loss, postoperative complications [infection, primary graft dysfunction (PGD), acute rejection], on 1-year survival in patients who underwent lung transplantation. The multivariate Cox proportional hazards regression model was used to evaluate the risk factors of death within 1 year after lung transplantation.

RESULTS: Two hundred patients underwent successful lung transplantation. The major postoperative complications within 1 year after transplantation included infection in 131 patients, PGD in 20 patients, acute rejection in 57 patients, anastomotic complication in 26 patients and others (new onset diabetes, osteoporosis, etc.) in 53 patients. The 3-month, 6-month, and 1-year postoperative cumulative survival rates were 81.5%, 80.0% and 77.5%, respectively. Forty-five patients died during 1 year after operation, among whom 14 died of infection, 7 died of PGD, 8 died of acute rejection, 4 died of anastomotic complication, 3 died of cardio-cerebrovascular accident, 3 died of multiple organ failure, 2 died of respiratory failure and 4 died of other causes (traffic accident, etc.). The Kaplan-Meier survival analysis showed that recipient's gender, idiopathic pulmonary fibrosis (IPF) as the primary disease, preoperative combination of moderate and severe PAH, intraoperative ECMO support, intraoperative massive blood loss, postoperative complications (infection, PGD, acute rejection) were influencing factors for postoperative 1-year survival rate. The multivariate Cox regression model showed that male was the protective factor [hazard ratio (HR) = 0.481, 95% confidence interval (95%CI) was 0.244-0.947, P = 0.034], IPF as the primary disease (HR = 2.667, 95%CI was 1.222-5.848, P = 0.014), intraoperative use of ECMO support (HR = 1.538, 95%CI was 0.787-3.012, P = 0.028), massive blood loss during surgery (HR = 2.026, 95%CI was 0.976-4.205, P = 0.045) and postoperative infection (HR = 3.138, 95%CI was 1.294-7.608, P = 0.011), PGD (HR = 1.604, 95%CI was 0.464-5.539, P = 0.004), and acute rejection (HR = 1.897, 95%CI was 0.791-4.552, P = 0.015) were the independent risk factors for death within 1 year after transplantation.

CONCLUSIONS: One-year survival rates after lung transplantation are affected by recipient's gender, primary disease, preoperative combination of moderate and severe PAH, intraoperative ECMO support, intraoperative massive blood loss, and postoperative complications (infection, PGD, acute rejection). The male is the protective factor, while IPF as the primary disease, intraoperative ECMO support, massive blood loss during surgery and postoperative complications (infection, PGD, acute rejection) are independent risk factors for death within 1 year after lung transplantation.

PMID:34412753 | DOI:10.3760/cma.j.cn121430-20200729-00550

Semin Arthritis Rheum. 2021 Jul 10;51(5):996-1004. doi: 10.1016/j.semarthrit.2021.07.002. Online ahead of print.

ABSTRACT

BACKGROUND: The major risk factor for idiopathic pulmonary fibrosis (IPF), MUC5B rs35705950, was found to be associated with rheumatoid arthritis-associated interstitial lung disease (RA-ILD). Whilst the MUC5B rs35705950 T risk allele has been associated with better survival in IPF, its impact on RA-ILD prognosis remains to be determined. Our objective was to explore the influence of MUC5B rs35705950 on survival and progression in RA-ILD.

METHODS: Through an international retrospective observational study, patients with RA-ILD were genotyped for the MUC5B rs35705950 variant and consecutive pulmonary function tests (PFTs) findings were collected. Longitudinal data up to a 10-year follow-up were considered and analyzed using mixed regression models. Proportional hazards and joint proportional hazards models were used to analyze the association of baseline and longitudinal variables with lung transplant-free survival. Significant progression of RA-ILD was defined as at least an absolute or relative 10% decline of forced vital capacity at 2 years from baseline.

RESULTS: Out of 321 registered patients, 261 were included in the study: 139 women (53.3%), median age at RA-ILD diagnosis 65 years (interquartile range [IQR] 57 to 71), 151 ever smokers (59.2%). Median follow-up was 3.5 years (IQR 1.3 to 6.6). Mortality rate was 32% (95%CI 19 to 42) at 10 years. The MUC5B rs35705950 variant did not impact lung transplant-free survival (HR for the T risk allele carriers=1.26; 95%CI 0.61 to 2.62; P=0.53). Decline in pulmonary function at 2 years was not influenced by MUC5B rs35705950 (OR=0.95; 95%CI 0.44 to 2.05; P=0.89), irrespective of the HRCT pattern.

CONCLUSION: In this study, the MUC5B rs35705950 promoter variant did not influence transplant- free survival or decline in pulmonary function in patients with RA-ILD.

PMID:34411838 | DOI:10.1016/j.semarthrit.2021.07.002

Ann Am Thorac Soc. 2021 Aug 19. doi: 10.1513/AnnalsATS.202101-044OC. Online ahead of print.

ABSTRACT

RATIONALE: There is a growing need to accurately estimate the prognosis of idiopathic pulmonary fibrosis (IPF) in clinical practice, given the development of effective drugs for treating IPF.

OBJECTIVE: To develop artificial intelligence-based image analysis software to detect parenchymal and airway abnormalities on chest computed tomography (CT) and to explore their prognostic importance in patients with IPF.

METHODS: A novel artificial intelligence-based quantitative CT image analysis software (AIQCT) was developed by applying 304 HRCT scans from patients with diffuse lung diseases as the training set. AIQCT automatically categorized and quantified ten types of parenchymal patterns as well as airways, expressing the volumes as percentages of the total lung volume. To validate the software, the area percentages of each lesion quantified by AIQCT were compared with those of the visual scores using 30 plain HRCT images with lung diseases. In addition, three-dimensional analysis for similarity with ground truth was performed using HRCT images from 10 patients with IPF. AIQCT was then applied to 120 patients with IPF who underwent chest HRCT scanning at our institute. Associations between the measured volumes and survival were analyzed.

RESULTS: The correlations between AIQCT and the visual scores were moderate to strong (correlation coefficient 0.44 to 0.95) depending on the parenchymal pattern. The Dice indexes for similarity between AIQCT data and ground truth were 0.67, 0.76, and 0.64 for reticulation, honeycomb, and bronchi, respectively. During a median follow-up period of 2,184 days, 66 patients died, and 1 underwent lung transplantation. In multivariable Cox regression analysis, bronchial volumes [adjusted hazard ratio (HR), 1.33; 95% confidence interval (CI), 1.16 to 1.53] and normal lung volumes (adjusted HR, 0.97; 95% CI, 0.94 to 0.99) were independently associated with survival after adjusting for the GAP stage of IPF.

CONCLUSIONS: Our newly developed artificial intelligence-based image analysis software successfully quantified parenchymal lesions and airway volumes. Bronchial and normal lung volumes on chest HRCT may provide additional prognostic information on the GAP stage of IPF.

PMID:34410886 | DOI:10.1513/AnnalsATS.202101-044OC

Ann Thorac Surg. 2021 Aug 14:S0003-4975(21)01428-4. doi: 10.1016/j.athoracsur.2021.07.038. Online ahead of print.

ABSTRACT

BACKGROUND: Diagnosis of interstitial lung disease is based on the analysis of clinical, biological, radiological and pathological findings during a multidisciplinary discussion (MDD). When a definitive diagnosis is not possible, guidelines recommend obtaining lung samples through surgical lung biopsy (SLB). We sought to determine morbidity, mortality, diagnostic yield, and therapeutic impact of SLB in the management of patients with interstitial lung disease.

METHODS: We retrospectively analyzed morbidity, mortality, diagnostic yield, and therapeutic changes following SLB for interstitial lung disease performed electively from January 2015 to May 2019 in a reference center. Each case was reviewed during two MDD, first without (MDD1) and then with (MDD2) the result of the SLB.

RESULTS: Study group included 73 patients (male 56%, age 66 years [57-70], FVC 79% [69-91], DLCO 52% [46-63]). Median postoperative hospital length of stay was 2 days [0-11]. Thirteen patients (17%) experienced at least one complication, including pain at 1 month (n=8) and residual pneumothorax (n=6). No serious complication or postoperative death was noticed. After MMD1, the working diagnosis was idiopathic non-specific interstitial pneumonia in 20 (27%), idiopathic pulmonary fibrosis in 18 (25%), fibrotic hypersensitivity pneumonitis in 15 (21%), unclassifiable interstitial lung disease in 5 (7%) and other diagnosis in 15 patients (21%). After SLB and MDD2, the final diagnosis was modified in 35 patients (48%) and led to therapeutic changes in 33 patients (45%).

CONCLUSIONS: SLB is associated with no serious complication or death and notably changes the diagnosis and treatment of interstitial lung disease.

PMID:34403693 | DOI:10.1016/j.athoracsur.2021.07.038

Respir Med Case Rep. 2021 Jun 1;33:101443. doi: 10.1016/j.rmcr.2021.101443. eCollection 2021.

ABSTRACT

Short telomere syndrome (STS) is characterized as multiorgan dysfunction presenting with unexplained cytopenias, cryptogenic cirrhosis and pulmonary fibrosis. We present a liver transplant recipient that gradually developed hypoxic respiratory failure attributed to idiopathic pulmonary fibrosis associated telomere disease that culminated in a successful single lung transplantation.

PMID:34401283 | PMC:PMC8349085 | DOI:10.1016/j.rmcr.2021.101443

Respir Med Case Rep. 2021 May 11;33:101427. doi: 10.1016/j.rmcr.2021.101427. eCollection 2021.

ABSTRACT

BACKGROUND: Amyloidosis is an uncommon condition, which results from accumulation of misfolded extracellular insoluble protein in tissues and organs of the body, causing its damage and dysfunction. Histologically, after staining with Congo red, the amyloid deposits show an apple-green birefringence under polarized light microscope. Amyloidosis can affect all organ systems and is classified into hereditary or acquired, localized or systemic. Respiratory involvement occurs in 50% of the patients with amyloidosis and it may take tracheobronchial, nodular parenchymal, diffuse alveolar septal and lymphatic forms.

METHODS: We report four cases of pulmonary amyloidosis. A female patient with localized form of tracheobronchial and nodular parenchymal pulmonary amyloidosis, which was initially misdiagnosed as sarcoidosis. A male patient who was referred to our department for further evaluation of multiple tumors in lungs accompanied by mediastinal lymphadenopathy, liver and peritoneal tumors. A male patient with suspect of lung malignancy. A male patient with diagnosed idiopathic pulmonary fibrosis and the possibility of malignancy.

RESULTS: All the diagnoses were established by demonstration of amyloid protein in tissue specimens obtained in transbronchial or open lung biopsies.

CONCLUSIONS: Due to its nonspecific clinical and radiological findings, amyloidosis can often mimic other diseases and should be considered as one of the differential diagnoses. In order to confirm the diagnosis, proving the presence of amyloid deposition with positive Congo red staining in respiratory specimen is mandatory.

PMID:34401273 | PMC:PMC8348153 | DOI:10.1016/j.rmcr.2021.101427

Curr Mol Biol Rep. 2021 Aug 12:1-10. doi: 10.1007/s40610-021-00145-4. Online ahead of print.

ABSTRACT

Cellular senescence (CS) is increasingly implicated in the etiology of age-related diseases. While CS can facilitate physiological processes such as tissue repair and wound healing, senescent cells also contribute to pathophysiological processes involving macromolecular damage and metabolic dysregulation that characterize multiple morbid and prevalent diseases, including Alzheimer's disease, osteoarthritis, atherosclerotic vascular disease, diabetes mellitus, and idiopathic pulmonary fibrosis (IPF). Preclinical studies targeting senescent cells and the senescence-associated secretory phenotype (SASP) with "senotherapeutics" have demonstrated improvement in age-related morbidity associated with these disease states. Despite promising results from these preclinical trials, few human clinical trials have been conducted. A first-in-human, open-label, pilot study of the senolytic combination of dasatinib and quercetin (DQ) in patients with IPF showed improved physical function and mobility. In this review, we will discuss our current understanding of cellular senescence, its role in age-associated diseases, with a specific focus on IPF, and potential for senotherapeutics in the treatment of fibrotic lung diseases.

PMID:34401216 | PMC:PMC8358258 | DOI:10.1007/s40610-021-00145-4

Front Immunol. 2021 Jul 30;12:699722. doi: 10.3389/fimmu.2021.699722. eCollection 2021.

ABSTRACT

PURPOSE: To develop a novel method to quantify the amount of fibrosis in the salivary gland and to investigate the relationship between fibrosis and specific symptoms associated with Sjögren's syndrome (SS) using this method.

MATERIALS AND METHODS: Paraffin-embedded labial salivary gland (LSG) slides from 20 female SS patients and their clinical and LSG pathology data were obtained from the Sjögren's International Collaborative Clinical Alliance. Relative interstitial fibrosis area (RIFA) in Masson's trichrome-stained LSG sections was quantified from digitally scanned slides and used for correlation analysis. Gene expression levels were assessed by microarray analysis. Core promoter accessibility for RIFA-correlated genes was determined using DNase I hypersensitive sites sequencing analysis.

RESULTS: RIFA was significantly correlated with unstimulated whole saliva flow rate in SS patients. Sixteen genes were significantly and positively correlated with RIFA. In a separate analysis, a group of differentially expressed genes was identified by comparing severe and moderate fibrosis groups. This combined set of genes was distinct from differentially expressed genes identified in lung epithelium from idiopathic pulmonary fibrosis patients compared with controls. Single-cell RNA sequencing analysis of salivary glands suggested most of the RIFA-correlated genes are expressed by fibroblasts in the gland and are in a permissive chromatin state.

CONCLUSION: RIFA quantification is a novel method for assessing interstitial fibrosis and the impact of fibrosis on SS symptoms. Loss of gland function may be associated with salivary gland fibrosis, which is likely to be driven by a unique set of genes that are mainly expressed by fibroblasts.

PMID:34400910 | PMC:PMC8363566 | DOI:10.3389/fimmu.2021.699722

Sci Rep. 2021 Aug 16;11(1):16525. doi: 10.1038/s41598-021-96152-7.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a severe disorder leading to progressive and irreversible loss of pulmonary function. In this study we investigated the anti-fibrotic effect of vitamin D using a mouse model of IPF. Lung fibrosis was induced with bleomycin in vitamin D-sufficient and vitamin D-deficient C57BL/6 mice. We found that treatment with active vitamin D analog paricalcitol prevented mouse body weight loss and alleviated lung fibrosis, whereas vitamin D deficiency severely aggravated lung injury. At the molecular level, paricalcitol treatment suppressed the induction of fibrotic inducer TGF-β and extracellular matrix proteins α-SMA, collagen type I and fibronectin in the lung, whereas vitamin D deficiency exacerbated the induction of these proteins. Interestingly, bleomycin treatment activated the local renin-angiotensin system (RAS) in the lung, manifested by the induction of renin, angiotensinogen, angiotensin II and angiotensin receptor type 1 (AT1R). Paricalcitol treatment suppressed the induction of these RAS components, whereas vitamin D deficiency enhanced the activation of the lung RAS. We also showed that treatment of bleomycin-induced vitamin D-deficient mice with AT1R antagonist losartan relieved weight loss, substantially ameliorated lung fibrosis and markedly blocked TGF-β induction in the lung. Moreover, we demonstrated that in lung fibroblast cultures, TGF-β and angiotensin II synergistically induced TGF-β, AT1R, α-SMA, collagen type I and fibronectin, whereas 1,25-dihydroxyvitamin D markedly suppressed the induction of these fibrotic markers. Collectively, these observations strongly suggest that vitamin D mitigates lung fibrosis by blocking the activation of the lung RAS in this mouse model of IPF.

PMID:34400742 | DOI:10.1038/s41598-021-96152-7

Thorax. 2021 Aug 16:thoraxjnl-2021-216882. doi: 10.1136/thoraxjnl-2021-216882. Online ahead of print.

ABSTRACT

BACKGROUND: The role of club cells in the pathology of idiopathic pulmonary fibrosis (IPF) is not well understood. Protein disulfide isomerase A3 (PDIA3), an endoplasmic reticulum-based redox chaperone required for the functions of various fibrosis-related proteins; however, the mechanisms of action of PDIA3 in pulmonary fibrosis are not fully elucidated.

OBJECTIVES: To examine the role of club cells and PDIA3 in the pathology of pulmonary fibrosis and the therapeutic potential of inhibition of PDIA3 in lung fibrosis.

METHODS: Role of PDIA3 and aberrant club cells in lung fibrosis was studied by analyses of human transcriptome dataset from Lung Genomics Research Consortium, other public resources, the specific deletion or inhibition of PDIA3 in club cells and blocking SPP1 downstream of PDIA3 in mice.

RESULTS: PDIA3 and club cell secretory protein (SCGB1A1) signatures are upregulated in IPF compared with control patients. PDIA3 or SCGB1A1 increases also correlate with a decrease in lung function in patients with IPF. The bleomycin (BLM) model of lung fibrosis showed increases in PDIA3 in SCGB1A1 cells in the lung parenchyma. Ablation of Pdia3, specifically in SCGB1A1 cells, decreases parenchymal SCGB1A1 cells along with fibrosis in mice. The administration of a PDI inhibitor LOC14 reversed the BLM-induced parenchymal SCGB1A1 cells and fibrosis in mice. Evaluation of PDIA3 partners revealed that SPP1 is a major interactor in fibrosis. Blocking SPP1 attenuated the development of lung fibrosis in mice.

CONCLUSIONS: Our study reveals a new relationship with distally localised club cells, PDIA3 and SPP1 in lung fibrosis and inhibition of PDIA3 or SPP1 attenuates lung fibrosis.

PMID:34400514 | DOI:10.1136/thoraxjnl-2021-216882

Respir Res. 2021 Aug 16;22(1):229. doi: 10.1186/s12931-021-01815-8.

ABSTRACT

BACKGROUND: The multidimensional and complex care needs of patients with idiopathic pulmonary fibrosis (IPF) call for appropriate care models. This systematic review aimed to identify care models or components thereof that have been developed for patients with IPF in the outpatient clinical care, to describe their characteristics from the perspective of chronic integrated care and to describe their outcomes.

METHODS: A systematic review was conducted using state-of-the-art methodology with searches in PubMed/Medline, Embase, CINAHL and Web Of Science. Researchers independently selected studies and collected data, which were described according to the Chronic Care Model (CCM).

RESULTS: Eighteen articles were included describing 13 new care models or components. The most commonly described CCM elements were 'delivery system design' (77%) and 'self-management support' (69%), with emphasis on team-based and multidisciplinary care provision and education. The most frequently described outcome was health-related quality of life.

CONCLUSIONS: Given the high need for integrated care and the scarcity and heterogeneity of data, developing, evaluating and implementing new models of care for patients with IPF and the comprehensive reporting of these endeavours should be a priority for research and clinical care.

PMID:34399748 | DOI:10.1186/s12931-021-01815-8

Chin Med J (Engl). 2021 Aug 5;134(15):1792-1794. doi: 10.1097/CM9.0000000000001464.

NO ABSTRACT

PMID:34397584 | PMC:PMC8367049 | DOI:10.1097/CM9.0000000000001464

Front Mol Biosci. 2021 Jul 29;8:664913. doi: 10.3389/fmolb.2021.664913. eCollection 2021.

ABSTRACT

Pulmonary fibrosis is a group of progressive, fibrotic, and fatal lung diseases, and the role of autophagy in pulmonary fibrosis is controversial. In the current research, we dynamically observed a bleomycin-induced pulmonary fibrosis mouse model after 3, 7, 14, 21, and 28 days and investigated the expression of autophagy markers. We found that autophagy markers were not significantly changed on the indicated days in the mouse lung tissue. Then, RNA-Seq was used to analyze the gene expression and associated functions and pathways in fibrotic lung tissue on different days post-bleomycin. In addition, short time series expression miner (STEM) analysis was performed to explore the temporal post-bleomycin gene expression. Through STEM, continually up- or downregulated profiles did not demonstrate the critical role of autophagy in the development of fibrosis. Furthermore, gene ontology (GO) annotations showed that continually upregulated profiles were mainly related to fibrosis synthesis, extracellular space, and inflammation, while enriched pathways were mainly related to the PI3K-Akt signaling pathway, ECM-receptor interactions, and focal adhesion signaling pathway. For continually downregulated profiles, GO annotations mainly involved sarcomere organization, muscle contraction, and muscle fiber development. The enriched KEGG signaling pathways were the cAMP signaling pathway, cGMP-PKG signaling pathway, calcium signaling pathway, and cardiac muscle contraction. Moreover, we analyzed autophagy-related genes' expression in specific cells from a publicly available database of three human and one animal study of pulmonary fibrosis using single-cell sequencing technology. All results consistently demonstrated no critical role of autophagy in the pathogenesis of pulmonary fibrosis. In summary, autophagy may not critically and consistently change during the development of pulmonary fibrosis at different stages post-bleomycin in a mouse model. These continually up- or downregulated profiles, including gene profiles, and the corresponding functions and pathways may provide mechanistic insights into IPF therapy.

PMID:34395518 | PMC:PMC8358296 | DOI:10.3389/fmolb.2021.664913

Front Pharmacol. 2021 Jul 28;12:670146. doi: 10.3389/fphar.2021.670146. eCollection 2021.

ABSTRACT

Background: Idiopathic pulmonary fibrosis (IPF) is disease with high mortality, and its effective treatment is limited. Shenfu injection is a traditional Chinese medicine which can improve circulation and protect cells. In this study, we aimed to investigate the feasibility and mechanism of Shenfu injection in the treatment of IPF. Methods: The components and targets of Shenfu injection were mainly retrieved from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) database. The targets of Shenfu injection were standardized by UniProt database. The Genecards and OMIM databases was used to search for IPF-related genes. The Venn diagram of gene intersection was drawn using the OmicStudio tools, and the protein-protein interaction network was visualized using the Cytoscape 3.7.2 software. Moreover, the metascape online software was applied to explore the enriched Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, and the Cytoscape 3.7.2 software was used to construct the target-pathway network. Molecular docking was used to visualize the interactions between the main active compounds and targeted proteins. Animal experiments were performed to validate the effects and mechanisms of Shenfu injection. Results: We obtained 46 co-targets of Shenfu injection and IPF. Among the hub target genes, several genes with important functions were enriched, including TNF, IL-6, IL-1B, TP53, JUN, CASP3 and CASP8. The pathway enrichment analysis for the hub target genes identified pathways in infection/inflammation, apoptosis and cancer. Molecular docking results showed that the main active compound Ginsenoside Re had high affinity to the core target proteins. These results suggested that Shenfu injection may have a positive effect in the treatment of IPF. Consistent with this finding, animal experiments showed that Shenfu injection significantly reduced pulmonary fibrosis in a mouse model with inhibition of apoptosis and inflammation by downregulating IL-1β, caspase-3 and phosphorylated NF-κB. Conclusion: Our results demonstrated that Shenfu injection efficiently alleviate bleomycin-induced pulmonary fibrosis through multi-targets in inflammation-, apoptosis- and cancer-related pathways, which provided first evidence and reference to the feasibility of Shenfu injection in the treatment of IPF.

PMID:34393772 | PMC:PMC8356043 | DOI:10.3389/fphar.2021.670146

Front Pharmacol. 2021 Jul 28;12:669037. doi: 10.3389/fphar.2021.669037. eCollection 2021.

ABSTRACT

Introduction: Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease characterized by excess deposition and altered structure of extracellular matrix (ECM) in the lungs. The fibrotic ECM is paramount in directing resident cells toward a profibrotic phenotype. Collagens, an important part of the fibrotic ECM, have been shown to be structurally different in IPF. To further understand the disease to develop better treatments, the signals from the ECM that drive fibrosis need to be identified. Adipose tissue-derived stromal cell conditioned medium (ASC-CM) has demonstrated antifibrotic effects in animal studies but has not been tested in human samples yet. In this study, the collagen structural integrity in (fibrotic) lung tissue, its interactions with fibroblasts and effects of ASC-CM treatment hereon were studied. Methods: Native and decellularized lung tissue from patients with IPF and controls were stained for denatured collagen using a collagen hybridizing peptide. Primary lung fibroblasts were seeded into decellularized matrices from IPF and control subjects and cultured for 7 days in the presence or absence of ASC-CM. Reseeded matrices were fixed, stained and analyzed for total tissue deposition and specific protein expression. Results: In both native and decellularized lung tissue, more denatured collagen was observed in IPF tissue compared to control tissue. Upon recellularization with fibroblasts, the presence of denatured collagen was equalized in IPF and control matrices, whereas total ECM was higher in IPF matrices than in the control. Treatment with ASC-CM resulted in less ECM deposition, but did not alter the levels of denatured collagen. Discussion: Our data showed that ASC-CM can inhibit fibrotic ECM-induced profibrotic behavior of fibroblasts. This process was independent of collagen structural integrity. Our findings open up new avenues for ASC-CM to be explored as treatment for IPF.

PMID:34393771 | PMC:PMC8355988 | DOI:10.3389/fphar.2021.669037

Acad Radiol. 2021 Aug 12:S1076-6332(21)00304-4. doi: 10.1016/j.acra.2021.06.017. Online ahead of print.

ABSTRACT

RATIONALE: There is no agreed upon method for quantifying ventilation defect percentage (VDP) with high sensitivity and specificity from hyperpolarized (HP) gas ventilation MR images in multiple pulmonary diseases for both pediatrics and adults, yet identifying such methods will be necessary for future multi-site trials. Most HP gas MRI ventilation research focuses on a specific pulmonary disease and utilizes one quantification scheme for determining VDP. Here we sought to determine the potential of different methods for quantifying VDP from HP 129Xe images in multiple pulmonary diseases through comparison of the most utilized quantification schemes: linear binning and thresholding.

MATERIALS AND METHODS: HP 129Xe MRI was performed in a total of 176 subjects (125 pediatrics and 51 adults, age 20.98±16.48 years) who were either healthy controls (n = 23) or clinically diagnosed with cystic fibrosis (CF) (n = 37), lymphangioleiomyomatosis (LAM) (n = 29), asthma (n = 22), systemic juvenile idiopathic arthritis (sJIA) (n = 11), interstitial lung disease (ILD) (n = 7), or were bone marrow transplant (BMT) recipients (n = 47). HP 129Xe ventilation images were acquired during a ≤16 second breath-hold using a 2D multi-slice gradient echo sequence on a 3T Philips scanner (TR/TE 8.0/4.0ms, FA 10-12°, FOV 300 × 300mm, voxel size≈3 × 3 × 15mm). Images were analyzed using 5 different methods to quantify VDPs: linear binning (histogram normalization with binning into 6 clusters) following either linear or a variant of a nonparametric nonuniform intensity normalization algorithm (N4ITK) bias-field correction, thresholding ≤60% of the mean signal intensity with linear bias-field correction, and thresholding ≤60% and ≤75% of the mean signal intensity following N4ITK bias-field correction. Spirometry was successfully obtained in 84% of subjects.

RESULTS: All quantification schemes were able to label visually identifiable ventilation defects in similar regions within all subjects. The VDPs of control subjects were significantly lower (p<0.05) compared to BMT, CF, LAM, and ILD subjects for most of the quantification methods. No one quantification scheme was better able to differentiate individual disease groups from the control group. Advanced statistical modeling of the VDP quantification schemes revealed that in comparing controls to the combined disease group, N4ITK bias-field corrected 60% thresholding had the highest predictive efficacy, sensitivity, and specificity at the VDP cut-point of 2.3%. However, compared to the thresholding quantification schemes, linear binning was able to capture and label subtle low-ventilation regions in subjects with milder obstruction, such as subjects with asthma.

CONCLUSION: The difference in VDP between healthy controls and patients varied between the different disease states for all quantification methods. Although N4ITK bias-field corrected 60% thresholding was superior in separating the combined diseased group from controls, linear binning is able to better label low-ventilation regions unlike the current, 60% thresholding scheme. For future clinical trials, a consensus will need to be reached on which VDP scheme to utilize, as there are subtle advantages for each for specific disease.

PMID:34393064 | DOI:10.1016/j.acra.2021.06.017

J Ethnopharmacol. 2021 Aug 12:114522. doi: 10.1016/j.jep.2021.114522. Online ahead of print.

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Firstly prescribed in the ancient Chinese book Jingui Yaolue, Gancao Ganjiang decoction (GGD) is a traditional Chinese herbal formula that has been widely used to treat "atrophic lung disease". GGD is a popular and widely used traditional Chinese medicine. The decoction is extracted from the dried rhizomes and roots of Glycyrrhiza uralensis Fisch. and Zingiber officinale Roscoe (2:1).

AIM OF STUDY: To investigate the therapeutic effect of idiopathic pulmonary fibrosis (IPF) of GGD, a bleomycin-induced IPF murine model was used in this study.

MATERIALS AND METHODS: Mice were induced by bleomycin instillation and GGD was orally administered. Changes on mice weight were recorded during the experiment. Lung weight was recorded on days 14 and 28, and pulmonary index was calculated accordingly. Pathological evaluation, including fibrosis analysis of lung tissue, was assessed by H&E and Masson staining. The expression of PD-1, p-STAT3 and IL-17A were detected by immunohistochemistry (IHC). The expression of p-STAT3 in lung tissues of mice were detected by Western blot. The level of IL-17A in lung tissue were detected by ELISA. The expression of PD-1 in CD4+ T cells in peripheral blood of mice was detected by flow cytometry. The levels of hydroxyproline and TGF-β1 in lung tissue were detected by ELISA. The expression of E-cadherin, vimentin and α-SMA in lung tissues of mice were detected by qRT-PCR and Western blot.

RESULTS: GGD can increase body weight and reduce pulmonary index in mice with pulmonary fibrosis. As such, GGD can significantly improve the inflammatory and alleviate IPF in the lung tissue of mice. GGD treatment was capable of reducing the content of PD-1 in lung tissue as well as the expression of PD-1 in CD4+ T cells in peripheral blood. Likewise, GGD was able to reduce the content of p-STAT3, IL-17A and TGF-β1. In addition, GGD stimulation could inhibit epithelial-mesenchymal transformation (EMT) by increasing the expression of E-cadherin and reducing vimentin and α-SMA, thus reducing extracellular matrix (ECM) deposition.

CONCLUSION: Our results indicate that GGD positively affects IPF by regulating PD-1/TGF-β1/IL-17A pathway.

PMID:34391863 | DOI:10.1016/j.jep.2021.114522

Respir Res. 2021 Aug 14;22(1):228. doi: 10.1186/s12931-021-01821-w.

ABSTRACT

BACKGROUND: Transbronchial cryobiopsy in the evaluation of patients with interstitial lung diseases (ILD) is expected to reduce the need for surgical lung biopsy (SLB).

OBJECTIVE: To evaluate the diagnostic value of cryobiopsy in combination with bronchoalveolar lavage (BAL), radiologic and clinical data in patients with ILD.

METHODS: Between 08/15 and 01/20 patients with ILD underwent cryobiopsy if they: did not have (i) an usual interstitial pneumonia (UIP)-pattern on CT, (ii) predominant ground-glass opacities suggesting alveolitis, (iii) findings suggestive of sarcoidosis on CT, or if they had (i) a CT showing UIP-pattern, but had findings suggesting alternative diagnosis than idiopathic pulmonary fibrosis (IPF), or (ii) had previous non-diagnostic conventional transbronchial forceps biopsy. Histological findings were integrated into the multidisciplinary team discussion (MDTD) and a diagnostic consensus was sought.

RESULTS: One hundred patients underwent cryobiopsy. In 88/100 patients, cryobiopsy was representative with diagnostic findings in 45/88 and non-specific histological findings in 43/88 patients. In 25/43 with non-specific findings, a consensus diagnosis was reached after MDTD integrating BAL, radiologic and clinical data; eight of the remaining 18 patients with non-specific findings were referred to SLB. In 12/100 patients cryobiopsy was not representative and three of these patients were also referred to SLB. In 7/11 patients (64%) SLB was diagnostic. Complications of cryobiopsy included pneumothorax (14%) and locally controlled bleeding (24%).

CONCLUSIONS: The diagnostic yield of cryobiopsy was 70%:45% of cryobiopsies were diagnostic based on histology alone and an additional 25% provided non-specific, but valuable findings allowing a consensus diagnosis after MDTD. Our data demonstrate that the diagnostic value of cryobiopsy is high if combined with BAL, radiologic and clinical data.

PMID:34391420 | DOI:10.1186/s12931-021-01821-w

Sci Rep. 2021 Aug 13;11(1):16481. doi: 10.1038/s41598-021-95728-7.

ABSTRACT

The purpose of this study was to evaluate the implications of the 2018 updated guideline for the diagnosis of idiopathic pulmonary fibrosis (IPF) in clinical practice compared to 2011 guideline. This study involved 535 patients including 339 IPF and 196 non-IPF, and we retrospectively evaluated CT classifications of usual interstitial pneumonia (UIP) by two guidelines. Interobserver agreement of 2018 criteria showed moderate reliability (κ = 0.53) comparable to 2011 (κ = 0.56) but interobserver agreement for probable UIP was fair (κ = 0.40). CT pattern of indeterminate for UIP was associated with better prognosis compared with the other groups (adjusted hazard ratio [HR] = 0.36, p < 0.001). Compared to possible UIP, probable UIP demonstrated a lower positive predictive value (PPV, 62.9% vs 65.8%). In analysis of patients with CT patterns of non-definite UIP, diagnosing IPF when CT pattern showed probable UIP with lymphocyte count ≤ 15% in BAL fluid, and either male sex or age ≥ 60 years showed a high specificity of 90.6% and a PPV of 80.8% in the validation cohort. The 2018 criteria provide better prognostic stratification than the 2011 in patients with possible UIP. BAL fluid analysis can improve the diagnostic certainty for IPF diagnosis in patients with probable UIP CT pattern.

PMID:34389774 | DOI:10.1038/s41598-021-95728-7