Respir Res. 2023 Mar 20;24(1):87. doi: 10.1186/s12931-023-02396-4.

ABSTRACT

SARS-CoV2 infection has a poor prognosis in patients affected of idiopathic pulmonary fibrosis (IPF). Autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) are found in the blood of at least 15% of patients with life-threatening COVID-19 pneumonia. Because of the elevated prevalence of some auto-Abs in IPF patients, we hypothesize that the prevalence of auto-Abs neutralizing type I IFNs might be increased in the IPF population and then explained specific poor outcome after COVID-19. We screened the plasma of 247 consecutive IPF patients for the presence of auto-Abs neutralizing type I IFNs. Three patients displayed auto-Abs neutralizing type I IFNs. Among them, the only patient with documented SARS-CoV-2 infection experienced life threatening COVID-19 pneumonia. The prevalence of auto-Abs neutralizing type I IFNs in this cohort of IPF patients was not significantly different from the one of the general population. Overall, this study did not suggest any association between auto-Abs neutralizing type I IFNs and IPF.

PMID:36941652 | DOI:10.1186/s12931-023-02396-4

Heliyon. 2023 Jan 2;9(2):e12694. doi: 10.1016/j.heliyon.2022.e12694. eCollection 2023 Feb.

ABSTRACT

[This corrects the article DOI: 10.1016/j.heliyon.2022.e09773.].

PMID:36937035 | PMC:PMC10014439 | DOI:10.1016/j.heliyon.2022.e12694

Front Immunol. 2023 Mar 1;14:1117749. doi: 10.3389/fimmu.2023.1117749. eCollection 2023.

ABSTRACT

Immunoglobulin A (IgA) is the most abundant Ig in mucosae where it plays key roles in host defense against pathogens and in mucosal immunoregulation. Whereas intense research has established the different roles of secretory IgA in the gut, its function has been much less studied in the lung. This review will first summarize the state-of-the-art knowledge on the distribution and phenotype of IgA+ B cells in the human lung in both homeostasis and disease. Second, it will analyze the studies looking at cellular and molecular mechanisms of homing and priming of IgA+ B cells in the lung, notably following immunization. Lastly, published data on observations related to IgA and IgA+ B cells in lung and airway disease such as asthma, cystic fibrosis, idiopathic pulmonary fibrosis, or chronic rhinosinusitis, will be discussed. Collectively it provides the state-of-the-art of our current understanding of the biology of IgA-producing cells in the airways and identifies gaps that future research should address in order to improve mucosal protection against lung infections and chronic inflammatory diseases.

PMID:36936934 | PMC:PMC10014553 | DOI:10.3389/fimmu.2023.1117749

Front Genet. 2023 Mar 2;14:1114601. doi: 10.3389/fgene.2023.1114601. eCollection 2023.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease of unknown etiology, characterized by diffuse alveolitis and alveolar structural damage. Due to the short median survival time and poor prognosis of IPF, it is particularly urgent to find new IPF biomarkers. Previous studies have shown that basement membranes (BMs) are associated with the development of IPF and tumor metastasis. However, there is still a lack of research on BMs-related genes in IPF. Therefore, we investigated the expression level of BMs genes in IPF and control groups, and explored their potential as biomarkers for IPF diagnosis. In this study, the GSE32537 and GSE53845 datasets were used as training sets, while the GSE24206, GSE10667 and GSE101286 datasets were used as validation sets. In the training set, seven immune biomarkers related to BMs were selected by differential expression analysis, machine learning algorithm (LASSO, SVM-RFE, Randomforest) and ssGSEA analysis. Further ROC analysis confirmed that seven BMs-related genes played an important role in IPF. Finally, four immune-related Hub genes (COL14A1, COL17A1, ITGA10, MMP7) were screened out. Then we created a logistic regression model of immune-related hub genes (IHGs) and used a nomogram to predict IPF risk. The nomogram model was evaluated to have good reliability and validity, and ROC analysis showed that the AUC value of IHGs was 0.941 in the training set and 0.917 in the validation set. Pan-cancer analysis showed that IHGs were associated with prognosis, immune cell infiltration, TME, and drug sensitivity in 33 cancers, suggesting that IHGs may be potential targets for intervention in human diseases including IPF and cancer.

PMID:36936416 | PMC:PMC10017543 | DOI:10.3389/fgene.2023.1114601

Front Endocrinol (Lausanne). 2023 Mar 3;14:1126397. doi: 10.3389/fendo.2023.1126397. eCollection 2023.

ABSTRACT

BACKGROUND: Insulin-like growth factor-1 (IGF-1) display a vital role in in the pathogenesis of lung diseases, however, the relationship between circulating IGF-1 and lung disease remains unclear.

METHODS: Single nucleotide polymorphisms (SNPs) associated with the serum levels of IGF-1 and the outcomes data of lung diseases including asthma, chronic obstructive pulmonary disease (COPD), lung cancer and idiopathic pulmonary fibrosis (IPF) were screened from the public genome-wide association studies (GWAS). Two-sample Mendelian randomization (MR) analysis was then performed to assess the independent impact of IGF-1 exposure on these lung diseases.

RESULTS: Totally, 416 SNPs related to circulating IGF-1 levels among 358,072 participants in UK Biobank. According to a primary casual effects model with MR analyses by the inverse variance weighted (IVW) method, the circulating IGF-1 was demonstrated a significantly related with the risk of asthma (OR, 0.992; 95% CI, 0.985-0.999, P=0.0324), while circulating IGF-1 showed no significant correlation with CODP (OR, 1.000; 95% CI, 0.999-1.001, P=0.758), lung cancer (OR, 0.979, 95% CI, 0.849-1.129, P=0.773), as well as IPIGFF (OR, 1.100, 95% CI, 0.794-1.525, P=0.568).

CONCLUSION: The present study demonstrated that circulating IGF-1 may be causally related to lower risk of asthma.

PMID:36936149 | PMC:PMC10020499 | DOI:10.3389/fendo.2023.1126397

Biomed Pharmacother. 2023 Mar 17;161:114553. doi: 10.1016/j.biopha.2023.114553. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible lung disease with a poor prognosis. There is currently no definitive cure for IPF. The present study establishes a platform for the development of a novel therapeutic approach for the treatment of PF using the atypical antidepressant, mirtazapine. In the endotracheal bleomycin rat model, mirtazapine interfered with the activation of NLRP3 inflammasome via downregulating the NLRP3 on the gene and protein expression levels. Accordingly, the downstream mediators IL-1β and IL-18 were repressed. Such observation is potentially a direct result of the reported improvement in oxidative stress. Additionally, mirtazapine corrected the bleomycin-induced disparities in the levels of the fibrogenic mediators TGF-β, PDGF-BB, and TIMP-1, in consequence, the lung content of hydroxyproline and the expression of α-SMA were reduced. Besides, mirtazapine curbed the ICAM-1 and the chemotactic cytokines MCP-1 and CXCL4. This protective property of mirtazapine resulted in improving the BALF total and differential cell counts, diminishing LDH activity, and reducing the BALF total protein. Moreover, the inflammation and fibrosis scores were accordingly lower. To conclude, we reveal for the first time the efficacy of mirtazapine as a potential treatment for PF. The combination of social isolation, sleep problems, breathing difficulties, and fear of death can lead to psychological distress and depression in patients with IPF. Hence, mirtazapine is a promising treatment option that may improve the prognosis for IPF patients due to its antifibrotic effects, as well as its ability to alleviate depressive episodes.

PMID:36934553 | DOI:10.1016/j.biopha.2023.114553

Respir Res. 2023 Mar 19;24(1):86. doi: 10.1186/s12931-023-02362-0.

ABSTRACT

BACKGROUND: Interstitial lung disease is frequently comorbid with dermatomyositis and has a poor prognosis, especially in patients with the anti-melanoma differentiation-associated gene 5 (MDA5) autoantibody. However, the pathogenesis of dermatomyositis-related interstitial lung disease remains unclear.

METHODS: We examined 18 and 19 patients with dermatomyositis-related interstitial lung disease and idiopathic pulmonary fibrosis (control), respectively. Lung tissues obtained from these patients were semi-quantitatively evaluated by immunohistochemical staining with in-house anti-human MDA5 monoclonal antibodies, as well as anti-human immunoglobulin (Ig) G, IgM, IgA, and complement component 3(C3) antibodies. We established human MDA5 transgenic mice and treated them with rabbit anti-human MDA5 polyclonal antibodies, and evaluated lung injury and Ig and C3 expression.

RESULTS: MDA5 was moderately or strongly expressed in the lungs of patients in both groups, with no significant differences between the groups. However, patients with dermatomyositis-related interstitial lung disease showed significantly stronger expression of C3 (p < 0.001), IgG (p < 0.001), and IgM (p = 0.001) in the lungs than control. Moreover, lung C3, but IgG, IgA, nor IgM expression was significantly stronger in MDA5 autoantibody-positive dermatomyositis-related interstitial lung disease (n = 9) than in MDA5 autoantibody-negative dermatomyositis-related interstitial lung disease (n = 9; p = 0.022). Treatment with anti-MDA5 antibodies induced lung injury in MDA5 transgenic mice, and strong immunoglobulin and C3 expression was observed in the lungs of the mice.

CONCLUSION: Strong immunoglobulin and C3 expression in the lungs involve lung injury related to dermatomyositis-related interstitial lung disease. Enhanced immune complex formation in the lungs may contribute to the poor prognosis of MDA5 autoantibody-positive dermatomyositis-related interstitial lung disease.

PMID:36934274 | DOI:10.1186/s12931-023-02362-0

Biochim Biophys Acta Mol Basis Dis. 2023 Mar 16:166692. doi: 10.1016/j.bbadis.2023.166692. Online ahead of print.

NO ABSTRACT

PMID:36933847 | DOI:10.1016/j.bbadis.2023.166692

Ann Diagn Pathol. 2023 Mar 16;64:152131. doi: 10.1016/j.anndiagpath.2023.152131. Online ahead of print.

NO ABSTRACT

PMID:36933389 | DOI:10.1016/j.anndiagpath.2023.152131

Respir Investig. 2023 Mar 16;61(3):339-346. doi: 10.1016/j.resinv.2023.02.006. Online ahead of print.

ABSTRACT

BACKGROUND: Patients with idiopathic pulmonary fibrosis (IPF) have a slowly progressive clinical course, although some develop acute exacerbations (AEs). An easily obtained composite score is desirable for predicting the survival rate in patients with AE of IPF (AE-IPF). We investigated the quick sequential organ failure assessment (qSOFA), originally developed to identify sepsis, as a predictor of mortality in patients with AE-IPF and compared it to other composite assessments.

METHODS: Consecutive patients with IPF admitted for their first AE between 2008 and 2019 were recruited retrospectively. The association between the qSOFA score obtained at admission and mortality was investigated.

RESULTS: During the study period, 97 patients with AE-IPF were hospitalized. The hospital mortality was 30.9%. Multivariate logistic regression analysis revealed that both the qSOFA and the Japanese Association for Acute Medicine (JAAM)-disseminated intravascular coagulation (DIC) scores were significant predictors of hospital mortality (odds ratio [OR] 3.86, 95% confidence interval [CI] 1.43-10.3; p = 0.007 and OR 2.71, 95% CI 1.56-4.67; p = 0.0004; respectively). Kaplan-Meier survival curves showed that both scores were consistently associated with survival. Furthermore, the sum of the two scores was a more effective predictor than the individual scores.

CONCLUSIONS: The qSOFA score of patients admitted with AE-IPF was associated with both in-hospital and long-term mortality, which was also true for the JAAM-DIC score. The qSOFA score plus the JAAM-DIC score should be determined during the diagnostic evaluation of a patient with AE-IPF. Both scores combined may be more effective at predicting outcomes than individual scores.

PMID:36933282 | DOI:10.1016/j.resinv.2023.02.006

Respir Investig. 2023 Mar 16;61(3):335-338. doi: 10.1016/j.resinv.2023.02.005. Online ahead of print.

ABSTRACT

BACKGROUND: Gastro-esophageal reflux disease (GORD) has been associated with a greater risk of idiopathic pulmonary fibrosis (IPF) in observational studies, but results are limited by confounding. We used multivariable Mendelian randomization to examine their causal relationship, adjusting for BMI.

METHODS: We selected genetic instruments for GORD from genome-wide association studies of 80,265 cases and 305,011 controls. Genetic association data for IPF were obtained from 2668 cases and 8591 controls, and BMI from 694,649 individuals. We used the inverse-variance weighted method and a series of sensitivity analyses including weak instrument robust methods.

RESULTS: Although genetic liability to GORD increased IPF risk (OR 1.58; 95% CI 1.10-2.25), this result was attenuated to include the null after adjusting for BMI (OR 1.14; 95% CI 0.85-1.52).

CONCLUSION: Intervention for GORD alone is unlikely to reduce the risk of IPF, whereas reducing obesity may be a better approach.

PMID:36933281 | DOI:10.1016/j.resinv.2023.02.005

Sci Rep. 2023 Mar 17;13(1):4422. doi: 10.1038/s41598-023-31470-6.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is characterised by progressive fibrosing interstitial pneumonia with an associated irreversible decline in lung function and quality of life. IPF prevalence increases with age, appearing most frequently in patients aged > 50 years. Pulmonary vessel-like volume (PVV) has been found to be an independent predictor of mortality in IPF and other interstitial lung diseases, however its estimation can be impacted by artefacts associated with image segmentation methods and can be confounded by adjacent fibrosis. This study compares PVV in IPF patients (N = 21) with PVV from a healthy cohort aged > 50 years (N = 59). The analysis includes a connected graph-based approach that aims to minimise artefacts contributing to calculation of PVV. We show that despite a relatively low extent of fibrosis in the IPF cohort (20% of the lung volume), PVV is 2-3 times higher than in controls. This suggests that a standardised method to calculate PVV that accounts for tree connectivity could provide a promising tool to provide early diagnostic or prognostic information in IPF patients and other interstitial lung disease.

PMID:36932117 | DOI:10.1038/s41598-023-31470-6

Transplant Proc. 2023 Mar 15:S0041-1345(23)00084-2. doi: 10.1016/j.transproceed.2023.01.023. Online ahead of print.

ABSTRACT

A heart-lung transplant is considered in patients with end-stage heart and lung disease. However, there is no report of a patient receiving a staged heart transplant followed by a lung transplant. Our case report describes a successful left single lung transplant for idiopathic pulmonary fibrosis 6 years after a heart transplant. This case illustrates that this approach can avoid significantly increased wait time until transplant, and it shows that early interstitial lung disease may not be a contraindication for the heart transplant.

PMID:36931954 | DOI:10.1016/j.transproceed.2023.01.023

PLoS One. 2023 Mar 17;18(3):e0283288. doi: 10.1371/journal.pone.0283288. eCollection 2023.

ABSTRACT

No biomarkers have been identified in bronchoalveolar lavage fluid (BALF) for predicting fibrosis progression or prognosis in progressive fibrosing interstitial lung disease (PF-ILD). We investigated BALF biomarkers for PF-ILD diagnosis and prognosis assessment. Overall, 120 patients with interstitial pneumonia who could be diagnosed with PF-ILD or non PF-ILD were enrolled in this retrospective study. PF-ILD was diagnosed according to Cottin's definition. All patients underwent bronchoscopy and BALF collection. We evaluated blood and BALF parameters, high-resolution computed tomography (HRCT) patterns, and spirometry data to identify factors influencing PF-ILD diagnosis and prognosis. On univariate logistic analysis, age, sex, the BALF white blood cell fraction (neutrophil, lymphocyte, eosinophil, and neutrophil-to-lymphocyte ratio), BALF flow cytometric analysis (CD8), and an idiopathic pulmonary fibrosis/usual interstitial pneumonia pattern on HRCT were correlated with PF-ILD diagnosis. Multivariate logistic regression analysis revealed that sex (male), age (cut-off 62 years, area under the curve [AUC] 0.67; sensitivity 0.80; specificity 0.47), white blood cell fraction in BALF (NLR, neutrophil, and lymphocyte), and CD8 in BALF (cut-off 34.2; AUC 0.66; sensitivity, 0.74; specificity, 0.62) were independent diagnostic predictors for PF-ILD. In BALF, the NLR (cut-off 8.70, AUC 0.62; sensitivity 0.62; specificity 0.70), neutrophil count (cut-off 3.0, AUC 0.59; sensitivity 0.57; specificity 0.63), and lymphocyte count (cut-off 42.0, AUC 0.63; sensitivity 0.77; specificity 0.53) were independent diagnostic predictors. In PF-ILD patients (n = 77), lactate dehydrogenase (cut-off 275, AUC 0.69; sensitivity 0.57; specificity 0.78), Krebs von den Lungen-6 (cut-off 1,140, AUC 0.74; sensitivity 0.71; specificity 0.76), baseline forced vital capacity (FVC) (cut-off 1.75 L, AUC 0.71; sensitivity, 0.93; specificity, 0.46), and BALF neutrophil ratio (cut-off 6.0, AUC 0.72; sensitivity 0.79; specificity 0.80) correlated with death within 3 years. The BALF cellular ratio, particularly the neutrophil ratio, correlated with the diagnosis and prognosis of PF-ILD. These findings may be useful in the management of patients with interstitial pneumonia.

PMID:36930615 | DOI:10.1371/journal.pone.0283288

Medicine (Baltimore). 2023 Mar 17;102(11):e33330. doi: 10.1097/MD.0000000000033330.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a lung disease that is both chronic and progressive and is characterized by glycolysis. However, glycolysis's function and its clinical significance in IPF are still not well understood. We accessed the Gene Expression Omnibus database to retrieve mRNA expression information for lung tissue and other samples. We identified genes associated with glycolysis that had differential expression levels between IPF and controls. In this work, we conducted a comprehensive bioinformatic analysis to systematically examine the glycolysis-associated genes with differential expression and subsequently investigated the possible prognostic significance of these genes. Additionally, the expression profiles of the associated prognostic genes were further investigated via quantitative real-time polymerase chain reaction in our cohort. In this investigation, we found that the expression of 16 genes involved in glycolysis was differentially expressed. Among them, 12 were upregulated and 4 were downregulated. We found that 3 glycolysis-related genes (stanniocalcin 2, transketolase like 1, artemin) might serve as hub genes for anticipating patient prognosis. The data from these genes were used to generate the prognostic models. The findings confirmed that high-risk IPF patients recorded a shorter overall survival relative to low-risk patients. This prognostic model yielded 1-, 2-, and 3-year survival rates of 0.666, 0.651, and 0.717, correspondingly, based on the area under the curve of the survival-dependent receiver operating characteristic. The GSE27957 and GSE70866 cohorts validated these findings, indicating the model has a good predictive performance. All 3 glycolysis-associated genes were validated to be expressed in our cohort. Finally, we used mRNA levels from 3 genes to produce a nomogram to quantitatively predict the prognosis of IPF individuals. As possible indicators for the prognosis of IPF, the glycolysis-related genes stanniocalcin 2, transketolase like 1, and artemin were shown to be promising candidate markers.

PMID:36930085 | DOI:10.1097/MD.0000000000033330

Eur Radiol. 2023 Mar 16. doi: 10.1007/s00330-023-09534-y. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the prognostic value of deep learning (DL)-driven CT fibrosis quantification in idiopathic pulmonary fibrosis (IPF).

METHODS: Patients diagnosed with IPF who underwent nonenhanced chest CT and spirometry between 2005 and 2009 were retrospectively collected. Proportions of normal (CT-Norm%) and fibrotic lung volume (CT-Fib%) were calculated on CT using the DL software. The correlations of CT-Norm% and CT-Fib% with forced vital capacity (FVC) and diffusion capacity of carbon monoxide (DLCO) were evaluated. The multivariable-adjusted hazard ratios (HRs) of CT-Norm% and CT-Fib% for overall survival were calculated with clinical and physiologic variables as covariates using Cox regression. The feasibility of substituting CT-Norm% for DLCO in the GAP index was investigated using time-dependent areas under the receiver operating characteristic curve (TD-AUCs) at 3 years.

RESULTS: In total, 161 patients (median age [IQR], 68 [62-73] years; 104 men) were evaluated. CT-Norm% and CT-Fib% showed significant correlations with FVC (Pearson's r, 0.40 for CT-Norm% and - 0.37 for CT-Fib%; both p < 0.001) and DLCO (0.52 for CT-Norm% and - 0.46 for CT-Fib%; both p < 0.001). On multivariable Cox regression, both CT-Norm% and CT-Fib% were independent prognostic factors when adjusted to age, sex, smoking status, comorbid chronic diseases, FVC, and DLCO (HRs, 0.98 [95% CI 0.97-0.99; p < 0.001] for CT-Norm% at 3 years and 1.03 [1.01-1.05; p = 0.01] for CT-Fib%). Substituting CT-Norm% for DLCO showed comparable discrimination to the original GAP index (TD-AUC, 0.82 [0.78-0.85] vs. 0.82 [0.79-0.86]; p = 0.75).

CONCLUSION: CT-Norm% and CT-Fib% calculated using chest CT-based deep learning software were independent prognostic factors for overall survival in IPF.

KEY POINTS: • Normal and fibrotic lung volume proportions were automatically calculated using commercial deep learning software from chest CT taken from 161 patients diagnosed with idiopathic pulmonary fibrosis. • CT-quantified volumetric parameters from commercial deep learning software were correlated with forced vital capacity (Pearson's r, 0.40 for normal and - 0.37 for fibrotic lung volume proportions) and diffusion capacity of carbon monoxide (Pearson's r, 0.52 and - 0.46, respectively). • Normal and fibrotic lung volume proportions (hazard ratios, 0.98 and 1.04; both p < 0.001) independently predicted overall survival when adjusted for clinical and physiologic variables.

PMID:36928568 | DOI:10.1007/s00330-023-09534-y

Adv Ther. 2023 Mar 16. doi: 10.1007/s12325-023-02454-9. Online ahead of print.

ABSTRACT

Nintedanib is a tyrosine kinase inhibitor approved for the treatment of idiopathic pulmonary fibrosis (IPF) and other progressive fibrosing interstitial lung diseases. Placebo-controlled trials showed that the adverse event profile of nintedanib was characterised mainly by gastrointestinal events, particularly diarrhoea. We review the data from all published real-world studies of the safety of nintedanib in patients with IPF. These real-world data were consistent with the safety profile observed in clinical trials and described in the product label. The most common adverse events were diarrhoea, nausea and vomiting, but these infrequently led to permanent treatment discontinuation. Liver enzyme elevations were observed, supporting the recommendation for regular monitoring of liver enzymes, particularly in the first few months of treatment. Bleeding and cardiovascular adverse events were rarely reported. As in clinical trials, in real-world studies, reductions of the nintedanib dose, treatment interruptions and use of anti-diarrhoeal medications were frequently employed to manage adverse events. Few data are available on the use of nintedanib in patients who are elderly or have advanced disease, but there are some data to suggest a greater rate of treatment discontinuation in these patients. Effective management of adverse events associated with nintedanib is important to minimise their impact.

PMID:36928494 | DOI:10.1007/s12325-023-02454-9

Drug Metab Dispos. 2023 Mar 16:DMD-AR-2022-001113. doi: 10.1124/dmd.122.001113. Online ahead of print.

ABSTRACT

Nintedanib, which is used to treat idiopathic pulmonary fibrosis and non-small cell lung cancer, is metabolized to a pharmacologically inactive carboxylate derivative, BIBF1202, via hydrolysis and subsequently by glucuronidation to BIBF1202 acyl-glucuronide (BIBF1202-G). Since BIBF1202-G contains an ester bond, it can be hydrolytically cleaved to BIBF1202. In this study, we sought to characterize these metabolic reactions in the human liver and intestine. Nintedanib hydrolysis was detected in human liver microsomes (HLM) (CL int: 102.8 {plus minus} 18.9 µL/min/mg protein) but not in small intestinal preparations. CES1 was suggested to be responsible for nintedanib hydrolysis according to experiments using recombinant hydrolases and hydrolase inhibitors as well as proteomic correlation analysis using 25 individual HLM. BIBF1202 glucuronidation in HLM (3.6 {plus minus} 0.3 µL/min/mg protein) was higher than that in human intestinal microsomes (1.5 {plus minus} 0.06 µL/min/mg protein). UGT1A1 and gastrointestinal UGT1A7, UGT1A8, and UGT1A10 were able to mediate BIBF1202 glucuronidation. The impact of UGT1A1 on glucuronidation was supported by the finding that liver microsomes from subjects homozygous for the UGT1A1*28 allele showed significantly lower activity than those from subjects carrying the wild-type UGT1A1 allele. Interestingly, BIBF1202-G was converted to BIBF1202 in HLS9 at 70-fold higher rates than the rates of BIBF1202 glucuronidation. An inhibition study and proteomic correlation analysis suggested that b-glucuronidase is responsible for hepatic BIBF1202-G deglucuronidation. In conclusion, the major metabolic reactions of nintedanib in the human liver and intestine were quantitatively and thoroughly elucidated. This information could be helpful to understand the inter- and intraindividual variability in the efficacy of nintedanib. Significance Statement To our knowledge, this is the first study to characterize the enzymes responsible for each step of nintedanib metabolism in the human body. We found that β-glucuronidase may contribute to BIBF1202-G deglucuronidation.

PMID:36927840 | DOI:10.1124/dmd.122.001113

Am J Respir Crit Care Med. 2023 Mar 16. doi: 10.1164/rccm.202303-0402LE. Online ahead of print.

NO ABSTRACT

PMID:36927480 | DOI:10.1164/rccm.202303-0402LE

Am J Respir Cell Mol Biol. 2023 Mar 16. doi: 10.1165/rcmb.2022-0292OC. Online ahead of print.

ABSTRACT

Progressive pulmonary fibrosis results from a dysfunctional tissue repair response and is characterized by fibroblast proliferation, activation, invasion, and extracellular matrix accumulation. Lung fibroblast heterogeneity is well recognized. With single cell RNA-sequencing (scRNA-seq), fibroblast subtypes have been reported by recent studies. However, the roles of fibroblast subtypes in effector functions in lung fibrosis are not well understood. In this study, we incorporated the recently published scRNA-seq datasets on murine lung samples of fibrosis models and human lung samples of fibrotic diseases and analyzed fibroblast gene signatures. We identified and confirmed the novel fibroblast subtypes we reported recently across all samples of both mouse models and human lung fibrotic diseases including idiopathic pulmonary fibrosis, systemic sclerosis associated interstitial lung disease, and COVID-19. Furthermore, we identified specific cell surface proteins for each fibroblast subtype through differential gene expression analysis which enabled us to isolate primary cells representing distinct fibroblast subtypes by flow cytometry sorting. We compared matrix production including fibronectin, collagen, and hyaluronan after pro-fibrotic factor stimulation and assessed invasive capacity of each fibroblast subtype. Our results suggested that in addition to myofibroblasts, lipofibroblasts and Ebf1+ fibroblasts are two important fibroblast subtypes that contribute to matrix deposition and also have enhanced invasive, proliferative, and contraction phenotypes. The histological locations of fibroblast subtypes are identified in healthy and fibrotic lungs by these cell surface proteins. This study provides new insights to inform approaches to targeting lung fibroblast subtypes to promote the development of therapeutics for lung fibrosis.

PMID:36927333 | DOI:10.1165/rcmb.2022-0292OC