Idiopathic Pulmonary Fibrosis
Genetic overlap between idiopathic pulmonary fibrosis and COVID-19
Eur Respir J. 2022 May 20:2103132. doi: 10.1183/13993003.03132-2021. Online ahead of print.
NO ABSTRACT
PMID:35595312 | DOI:10.1183/13993003.03132-2021
The influence of green tea extract on nintedanib's bioavailability in patients with pulmonary fibrosis
Biomed Pharmacother. 2022 May 17;151:113101. doi: 10.1016/j.biopha.2022.113101. Online ahead of print.
ABSTRACT
Nintedanib is an oral small-molecule kinase inhibitor and first-line treatment for idiopathic pulmonary fibrosis. Nintedanib is a substrate of the drug efflux transporter ABCB1. Green tea flavonoids --especially epigallocatechin gallate (EGCG)-- are potent ABCB1 modulators. We investigated if concomitant administration of green tea extract (GTE) could result in a clinically relevant herb-drug interaction. Patients were randomized between A-B and B-A, with A being nintedanib alone and B nintedanib with GTE. Both periods lasted 7 days, in which nintedanib was administered twice daily directly after a meal. In period B, patients additionally received capsules with GTE (500 mg BID, >60% EGCG). Pharmacokinetic sampling for 12 h was performed at day 7 of each period. Primary endpoint was change in geometric mean for the area under the curve (AUC0-12 h). A linear mixed model was used to analyse AUCs and maximal concentration (Cmax). In 26 included patients, the nintedanib AUC0-12 h was 21% lower (95% CI -29% to -12%; P < 0.001) in period B (with GTE) compared to period A. Cmax did not differ significantly between periods; - 14% (95% CI -29% to +4%; P = 0.12). The detrimental effect was predominant in patients with the ABCB1 3435 C>T wild type variant. No differences in toxicities were observed. Exposure to nintedanib decreased with 21% when administered 60 min after GTC for only 7 days. This is a statistically significant interaction which could potentially impair treatment efficacy. Before patients and physicians should definitely be warned to avoid this combination, prospective clinical validation of an exposure-response relationship is necessary.
PMID:35594703 | DOI:10.1016/j.biopha.2022.113101
Collagen 3D matrices as a model for the study of cell behavior in pulmonary fibrosis
Exp Lung Res. 2022 May 20:1-11. doi: 10.1080/01902148.2022.2067265. Online ahead of print.
ABSTRACT
Purpose: Idiopathic pulmonary fibrosis (IPF) is a complex progressive chronic lung disease where epithelial to mesenchymal interaction, extracellular matrix (ECM) contact, and pro-fibrotic cytokines dynamics take part in the development of the disease. The study of IPF in the widespread in vitro two-dimensional (2 D) culture fails to explain the interaction of cells with the changing environment that occurs in fibrotic lung tissue. A three-dimensional (3 D) co-culture model might shed light on the pathogenesis of IPF by mimicking the fibrotic environment. Materials and Methods: Fibroblasts from nine IPF were isolated and embedded in collagen matrices with the alveolar epithelial human cell line (A549) on the top. Cells were also cultured in 2 D with and without TGF-β1 as a conventional model to compare with. Both types of cells were isolated separately. Protein and gene expression of the main fibrotic markers were measured by qPCR, Western blot, and ELISA. Results: IPF fibroblasts to myofibroblasts differentiation was observed in the 3 D model and in cells stimulated with TGF-β1. In addition, ECM-related genes were highly up-regulated in the 3 D collagen matrix. A549 co-cultured 3 D with IPF fibroblasts showed EMT activation, with down-regulation of E-cadherin (CDH1). However, other pro-fibrotic genes as VIM, TGFB1, and MMP7 were up-regulated in A549 co-cultured 3 D with fibroblasts. Conclusions: 3 D-collagen matrices might induce fibroblasts' fibrotic phenotype as in the classic TGF-β1 model, by up-regulating genes associated with matrix production. In addition, IPF lung fibroblasts seem to exert a pro-fibrotic influence in A549 cells when they are co-cultured. These results suggest that an improved 3 D co-culture model might serve as an important tool to study the fibrotic process and its regulation.
PMID:35594338 | DOI:10.1080/01902148.2022.2067265
Role of low-dose radiation in senescence and aging: A beneficial perspective
Life Sci. 2022 May 16:120644. doi: 10.1016/j.lfs.2022.120644. Online ahead of print.
ABSTRACT
Cellular senescence refers to the permanent arrest of cell cycle caused by intrinsic and/or extrinsic stressors including oncogene activation, irradiation, DNA damage, oxidative stress, and certain cytokines (including senescence associated secretory phenotype). Cellular senescence is an important factor in aging. Accumulation of senescent cells has been implicated in the causation of various age-related organ disorders, tissue dysfunction, and chronic diseases. It is widely accepted that the biological effects triggered by low-dose radiation (LDR) are different from those caused by high-dose radiation. Experimental evidence suggests that LDR may promote growth and development, enhance longevity, induce embryo production, and delay the progression of chronic diseases. The underlying mechanisms of these effects include modulation of immune response, stimulation of hematopoietic system, antioxidative effect, reduced DNA damage and improved ability for DNA damage repair. In this review, we discuss the possible mechanisms by which LDR prevents senescence and aging from the perspectives of inhibiting cellular senescence and promoting the removal of senescent cells. We review a wide broad of evidence about the beneficial impact of LDR in senescence and aging models (including cardiovascular diseases, neurological diseases, arthritis and osteoporosis, chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis) to highlight the potential value of LDR in preventing aging and age-related diseases. However, there is no consensus on the effect of LDR on human health, and several important aspects require further investigation.
PMID:35588864 | DOI:10.1016/j.lfs.2022.120644
CRTH2 Mediates Pro-fibrotic Macrophage Differentiation and Promotes Lung Fibrosis
Am J Respir Cell Mol Biol. 2022 May 18. doi: 10.1165/rcmb.2021-0504OC. Online ahead of print.
ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is a particularly deadly form of pulmonary fibrosis with unknown reason. In patients with IPF, high serum and lung levels of CHI3L1 can be detected and are associated with poor survival. However, the roles of CHI3L1 in these diseases have not been fully elucidated. We hypothesize that CHI3L1 interacts with CRTH2 to stimulate pro-fibrotic macrophage differentiation and the development of pulmonary fibrosis and that circulating blood monocytes from patients with IPF are hyperresponsive to CHI3L1-CRTH2 signaling. We used murine pulmonary fibrosis models to investigate the role of CRTH2 on pro-fibrotic macrophage differentiation and fibrosis development, and primary human PBMC cell culture to detect the difference of monocytes in the responses to CHI3L1 stimulation and CRTH2 inhibition between IPF patients and normal controls. Our results showed that null mutation or small molecule inhibition of CRTH2 prevents the development of pulmonary fibrosis in murine models. Furthermore, CHI3L1 stimulation induces a greater increase in CD206 expression in IPF monocytes than control monocytes. These results demonstrated that monocytes from IPF patients appear to be hyperresponsive to CHI3L1 stimulation. These studies support targeting CHI3L1-CRTH2 pathway as a promising therapeutic approach in IPF and that the sensitivity of blood monocytes to CHI3L1-induced pro-fibrotic differentiation may serve as a biomarker that predicts responsiveness to CHI3L1 or CRTH2 based interventions.
PMID:35585756 | DOI:10.1165/rcmb.2021-0504OC
DOCK2 contributes to pulmonary fibrosis by promoting lung fibroblast to myofibroblast transition
Am J Physiol Cell Physiol. 2022 May 18. doi: 10.1152/ajpcell.00067.2022. Online ahead of print.
ABSTRACT
Idiopathic pulmonary fibrosis (IPF) is the most common chronic interstitial lung disease and is characterized by the progressive scarring of the lung. Transforming growth factor-β (TGF-β) signaling plays an essential role in IPF and drives fibroblast to myofibroblast transition (FMT). Dedicator of cytokinesis 2 (DOCK2) is known to regulate diverse immune functions by activating Rac and has been recently implicated in pleural fibrosis. We now report a novel role of DOCK2 in pulmonary fibrosis development by mediating FMT. In primary normal and IPF human lung fibroblasts (HLFs), TGF-β induced DOCK2 expression concurrent with FMT markers, α-SMA, collagen-1, and fibronectin. Knockdown of DOCK2 significantly attenuated TGF-β induced expression of these FMT markers. In addition, we found that the upregulation of DOCK2 by TGF-β is dependent on both Smad3 and ERK pathways as their respective inhibitors blocked TGF-β mediated induction. TGF-β also stabilized DOCK2 protein which contributes to increased DOCK2 expression. In addition, DOCK2 was also dramatically induced in the lungs of patients with IPF and in bleomycin and TGF-β induced pulmonary fibrosis in C57BL/6 mice. Further, increased lung DOCK2 expression co-localized with the FMT marker α-SMA in the bleomycin-induced pulmonary fibrosis model, implicating DOCK2 in the regulation of lung fibroblast phenotypic changes. Importantly, DOCK2 deficiency also attenuated bleomycin-induced pulmonary fibrosis and α-SMA expression. Taken together, our study demonstrates a novel role of DOCK2 in pulmonary fibrosis by modulating FMT and suggests that targeting DOCK2 may present a potential therapeutic strategy for the prevention or treatment of IPF.
PMID:35584329 | DOI:10.1152/ajpcell.00067.2022
Perceptions of Genetic Testing: A Mixed-methods Study of Patients with Pulmonary Fibrosis and their First-degree Relatives
Ann Am Thorac Soc. 2022 May 18. doi: 10.1513/AnnalsATS.202111-1300OC. Online ahead of print.
ABSTRACT
RATIONALE: Genetic testing is an emerging tool in interstitial lung disease (ILD) as several ILD subtypes have potential genetic causes or predispositions with resultant clinical implications. There is a need to understand patients' and their first-degree relatives' perceptions of genetic testing for ILD.
OBJECTIVES: The objective of this study was to investigate patients with ILD and their first-degree family members' understanding about the genetic risks associated with ILD and their interest and/or concerns about genetic testing.
METHODS: This mixed-methods study included patients with ILD and their first-degree relatives. Data were obtained from an online survey and three focus groups. Categorical data were reported with descriptive frequencies. Chi-squared analyses were used to measure associations. Focus group discussions were transcribed, coded and analysed according to the grounded theory principle.
RESULTS: A total of 188 respondents completed the survey; 119 patients, 52 first-degree relatives and 17 who were both patients and who also reported being a first-degree relative to someone with ILD. Most (79%) patients had idiopathic pulmonary fibrosis. The majority of patients and first-degree relatives were unsure if there was a genetic cause, whereas 71% of those who were both patient and first-degree relative thought there could be a genetic cause to their ILD. 59% of respondents worried their family members could be affected, and 72% of respondents were interested in genetic testing. Interest in genetic testing was associated with sex (p=0.03), post-secondary education (p=0.047), and having a family member with ILD (p=0.02). The main motivators were understanding family members' risk and contributing to research. First-degree relatives were concerned about insurance issues (60%) and personal stress (60%) more often than patients (40% and 28%, respectively); 29% of first-degree relatives anticipated changing their health behaviour based on results. Focus group themes included disease knowledge, understanding the role of genetics in ILD, testing concerns, and how to use genetic testing information.
CONCLUSIONS: This study provides insight into patients' and first-degree relatives' perceptions of ILD-related genetic testing. These findings inform the need for additional patient resources, yet better understanding of the clinical applications of ILD genetic testing, and how testing may impact diagnostics, therapeutics and prognostication.
PMID:35584322 | DOI:10.1513/AnnalsATS.202111-1300OC
Malnutrition and decreased food intake at diagnosis are associated with hospitalization and mortality of idiopathic pulmonary fibrosis patients
Clin Nutr. 2022 May 6;41(6):1335-1342. doi: 10.1016/j.clnu.2022.05.001. Online ahead of print.
ABSTRACT
INTRODUCTION AND AIMS: Malnutrition is frequent in patients with idiopathic pulmonary fibrosis (IPF). We examined the relationship between malnutrition at diagnosis and all-cause hospitalization, survival, and acute exacerbation in newly diagnosed IPF patients.
METHODS: In this prospective cohort study, the nutritional status of 153 consecutive newly-diagnosed IPF outpatients was evaluated by measuring body mass index (BMI), fat-free mass index (FFMI) with bioelectrical impedance analysis, and food intake with the Self Evaluation of Food Intake (SEFI)®. Diagnosis was taken as the baseline date and malnutrition was defined as an FFMI below 17 (men) or 15 kg/m2 (women). To determine the factors associated with all-cause hospitalization and mortality, univariate Cox regression analyses were performed and variables with P < 0.2 were included in a stepwise multivariable analysis.
RESULTS: A quarter (26%; 40/153) of the patients were suffering from malnutrition at baseline, which was more frequent (62%) in patients whose BMI was <25 kg/m2. Patients whose baseline FFMI was low were more likely to be hospitalized (Hazard Ratio (HR) = 1.98 [95% confidence interval, 1.15; 3.41], P = 0.0139) and/or die (HR = 1.79 [1.11; 2.89], P = 0.0165), but their acute exacerbation rate was similar to that of patients with normal FFMIs. Decreased food intake (SEFI®<7) at baseline was associated with all-cause hospitalization (P = 0.003) and mortality (P < 0.0001) during follow-up. Baseline higher gender-age-physiology (GAP) scores (HR = 1.24 [1.01; 1.52], P = 0.0434; HR = 1.71 [1.37; 2.14], P < 0.0001, respectively), lower BMI (HR = 0.89 [0.83; 0.96], P = 0.003; HR = 0.89 [0.82; 0.96], P = 0.003), and decreased food intake (SEFI® score) (HR = 0.81 [0.71; 0.93], P = 0.003; HR = 0.72 [0.64; 0.81], P < 0.0001), but not FFMI, were independently associated with all-cause hospitalization and mortality rates during follow-up.
CONCLUSIONS: Malnutrition and decreased food intake at IPF diagnosis are associated with all-cause hospitalization and mortality. Future studies will determine whether dedicated interventions to improve food intake and nutritional status could improve outcomes for IPF patients.
PMID:35580539 | DOI:10.1016/j.clnu.2022.05.001
The state of the art for artificial intelligence in lung digital pathology
J Pathol. 2022 May 17. doi: 10.1002/path.5966. Online ahead of print.
ABSTRACT
Lung diseases carry a significant burden of morbidity and mortality worldwide. The advent of digital pathology (DP) and an increase in computational power have led to the development of artificial intelligence (AI) based tools that can assist pathologists and pulmonologists in improving clinical workflow and patient management. While previous works have explored the advances in computational approaches for breast, prostate, and head and neck cancers, there has been a growing interest in applying these technologies to lung diseases as well. The application of AI tools on radiology images for better characterization of indeterminate lung nodules, fibrotic lung disease, and lung cancer risk stratification has been well documented. In this article, we discuss methodologies used to build AI tools in lung digital pathology, describing the various hand-crafted and deep learning-based unsupervised feature approaches. Next, we review AI tools across a wide spectrum of lung diseases including cancer, tuberculosis, idiopathic pulmonary fibrosis, and COVID-19. We discuss the utility of novel imaging biomarkers for different types of clinical problems including quantification of biomarkers like PD-L1, lung disease diagnosis, risk stratification, and prediction of response to treatments such as immune checkpoint inhibitors. We also look briefly at some emerging applications of AI tools in lung digital pathology such as multimodal data analysis, 3D pathology, and transplant rejection. Lastly, we discuss the future of DP-based AI tools, describing the challenges with regulatory approval, developing reimbursement models, planning clinical deployment, and addressing AI biases. This article is protected by copyright. All rights reserved.
PMID:35579955 | DOI:10.1002/path.5966
Efficacy of Qingfei oral liquid for idiopathic pulmonary fibrosis in rats and related network pharmacology study
Zhejiang Da Xue Xue Bao Yi Xue Ban. 2022 Feb 25;51(1):53-61. doi: 10.3724/zdxbyxb-2021-0203.
ABSTRACT
To investigate the therapeutic effect and mechanism of Qingfei oral liquid in idiopathic pulmonary fibrosis. Seventy-two male SD rats were divided into control group, model group, pirofenidone group and Qingfei group with 18 animals in each group. The idiopathic pulmonary fibrosis was induced in last three groups by intratracheal injection of bleomycin; pirofenidone group was given oral administration of pirofenidone b.i.d for 21 d, and Qingfei group was given Qingfei oral liquid 3.6 mL/kg q.d for Lung tissues were obtained for HE staining, Masson staining and transforming growth factor (TGF)-β immunohistochemical staining. Superoxide dismutase (SOD), malondialdehyde (MDA) and glutathione (GSH) were detected in tissue homogenates. The BATMAN-TCM database was used to retrieve the chemical components and their corresponding targets of Qingfei oral solution by network pharmacology method, and then the component-target-disease network diagram was constructed. Finally, the pathway enrichment analysis was carried out to explore the molecular mechanism of Qingfei oral liquid against idiopathic fibrosis. Histopathology results showed that Qingfei oral liquid had a similar relieving effect on pulmonary fibrosis as the positive drug pirfenidone; TGF-β secretion had a significant reduction in lung tissues of Qingfei group; and Qingfei oral liquid had better regulatory effect on SOD, MDA and GSH than pirfenidone. The results of component-target-disease network and pathway enrichment analysis showed that the related molecular pathways were concentrated in inflammation, extracellular matrix and cytokines. Qingfei oral liquid has a good therapeutic effect on idiopathic pulmonary fibrosis in rats via regulation of inflammation, extracellular matrix and cytokines.
PMID:35576111 | DOI:10.3724/zdxbyxb-2021-0203
Meta-Analysis of Effect of Nintedanib on Reducing FVC Decline Across Interstitial Lung Diseases
Adv Ther. 2022 May 14. doi: 10.1007/s12325-022-02145-x. Online ahead of print.
ABSTRACT
INTRODUCTION: The effect of nintedanib on slowing the rate of decline in forced vital capacity (FVC) has been investigated in randomized placebo-controlled trials in subjects with idiopathic pulmonary fibrosis (IPF), other progressive fibrosing interstitial lung diseases (ILDs), and ILD associated with systemic sclerosis (SSc-ILD). We assessed the consistency of the effect of nintedanib on the rate of decline in FVC over 52 weeks across four placebo-controlled phase III trials.
METHODS: We used data on FVC decline from the INPULSIS-1 and INPULSIS-2 trials in subjects with IPF, the INBUILD trial in subjects with progressing fibrosing ILDs other than IPF, and the SENSCIS trial in subjects with SSc-ILD. In each trial, the primary endpoint was the annual rate of decline in FVC (mL/year) assessed over 52 weeks. We performed fixed effect and random effects meta-analyses based on the relative treatment effect of nintedanib versus placebo on the rate of decline in FVC (mL/year) over 52 weeks. Heterogeneity of the relative treatment effect of nintedanib across populations was assessed using the I2 statistic, τ2 and corresponding p value from a Q test for heterogeneity.
RESULTS: The combined analysis comprised 1257 subjects treated with nintedanib and 1042 subjects who received placebo. Nintedanib reduced the rate of decline in FVC (mL/year) over 52 weeks by 51.0% (95% CI 39.1, 63.0) compared with placebo. The relative effect (95% CI) was the same using the fixed effect and random effects models. There was no evidence of heterogeneity in the relative treatment effect of nintedanib across the populations studied (I2 = 0%, τ2 = 0, p = 0.93).
CONCLUSIONS: A meta-analysis of data from four placebo-controlled trials demonstrated that nintedanib approximately halved the rate of decline in FVC over 52 weeks across subjects with different forms of pulmonary fibrosis, with no evidence of heterogeneity in its relative treatment effect across patient populations.
PMID:35576048 | DOI:10.1007/s12325-022-02145-x
Oxygenated right ventricular assist device with a percutaneous dual-lumen cannula as a bridge to lung transplantation
J Thorac Dis. 2022 Apr;14(4):832-840. doi: 10.21037/jtd-21-1199.
ABSTRACT
BACKGROUND: Oxygenated right ventricular assist device (oxyRVAD) placement has become more streamlined with the introduction of the dual-lumen pulmonary artery cannula. Peripherally cannulated oxyRVAD may provide oxygenation support with right heart support as an alternative to venoarterial extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplantation.
METHODS: A single-institution, retrospective analysis was performed on patients placed on oxyRVAD with a dual-lumen pulmonary artery cannula with the intention of bridging to lung transplantation in 2019.
RESULTS: Four patients with idiopathic pulmonary fibrosis were placed on oxyRVAD as a bridge to transplantation. Two patients were extubated and ambulated while waiting for a lung offer, and two patients required conversion to venoarteriovenous ECMO (VAV ECMO) from oxyRVAD. The median waiting time for extracorporeal life support (ECLS) was 42 h. All patients underwent double lung transplantation. Two patients stayed on oxyRVAD, and one patient was placed on venovenous ECMO (VV ECMO) after transplantation. Primary graft dysfunction score at 72 h after transplantation was grade 1 in three patients and grade 3 in one patient.
CONCLUSIONS: Peripherally cannulated oxyRVAD with percutaneous dual-lumen venous cannula could be an ambulatory bridge for lung transplantation. It is unknown whether oxyRVAD is feasible as a long-term bridge to lung transplantation.
PMID:35572883 | PMC:PMC9096291 | DOI:10.21037/jtd-21-1199
Prognostic Role of NLR, PLR and MHR in Patients With Idiopathic Pulmonary Fibrosis
Front Immunol. 2022 Apr 28;13:882217. doi: 10.3389/fimmu.2022.882217. eCollection 2022.
ABSTRACT
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease with low survival time. Since the pathophysiological progression of IPF is closely associated with immunological and inflammatory responses, immune biomarkers, including neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), and monocyte-high density lipoprotein ratio (MHR), have the potential to predict overall survival in IPF patients.
METHODS: A total of 278 patients with IPF were finally enrolled. The demographic and clinical characteristics of the patients at baseline were recorded. Multivariable Cox regression analysis was used to evaluate the association between the three biomarkers and overall survival in both the total cohort and acute exacerbation subgroup.
RESULTS: The median follow-up was 5.84 months. After adjusting for confounders, we found that only elevated NLR was associated with worse overall survival (OR = 1.019, 95% CI 1.001-1.037, P =0.041) by using multivariable Cox regression analysis. In 116 acute exacerbation IPF patients, the results of the Cox multiple regression model also indicated that the NLR was a significant prognostic factor (OR= 1.022, 95% CI 1.001-1.044, P =0.036). The NLR before death was also significantly higher than that at admission in nonsurvival acute exacerbation IPF patients (P=0.014). No significant differences were found in PLR (P=0.739) or MHR changes (P=0.478).
CONCLUSIONS: Our results indicated that elevated NLR expression is associated with shorter overall survival in IPF patients, which is independent of other prognostic factors. The NLR may be regarded as a reliable prognostic biomarker for IPF patients.
PMID:35572564 | PMC:PMC9096781 | DOI:10.3389/fimmu.2022.882217
Heterogeneous microenvironment analysis to explore the potential regulatory role of endothelial-mesenchymal transition in idiopathic pulmonary fibrosis
Ann Transl Med. 2022 Apr;10(8):486. doi: 10.21037/atm-22-1438.
ABSTRACT
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive interstitial lung disease mainly caused by excessive proliferation of fibroblasts and activation of myofibroblasts. The cellular microenvironment is mainly composed of different types of cellular components and extracellular matrix (ECM), whose changes directly affect cellular heterogeneity, resulting in immensely complex cellular interactions. However, microenvironment study is mainly focused on the pathological process of tumors, and the microenvironment changes during IPF development remain unclear.
METHODS: The current study intends to employ IPF-related single-cell sequencing and gene expression profile data to analyze the scores of different cell clusters in the IPF microenvironment, and exploit the underlying interaction between cells to illustrate the fundamental mechanism causing IPF.
RESULTS: Our analysis revealed that the amount of endothelial cells was obviously decreased, and the amount of fibroblasts and myofibroblasts was increased during the development of IPF, suggesting a possible endothelial-mesenchymal transition (EndMT) process. Furthermore, we found that the hub genes obtained through IPF-related gene expression profile analysis may play a regulative role in the number and function of endothelial cells and fibroblasts/myofibroblasts during IPF.
CONCLUSIONS: Our research represents a valuable analysis of the cellular microenvironment, and provides a novel mechanistic insight into the pathobiology of not only EndMT in IPF, but also other traumatic fibrotic disease disorders.
PMID:35571445 | PMC:PMC9096361 | DOI:10.21037/atm-22-1438
Pirfenidone ameliorates chronic pancreatitis in mouse models through immune and cytokine modulation
Pancreatology. 2022 May 7:S1424-3903(22)00169-7. doi: 10.1016/j.pan.2022.05.002. Online ahead of print.
ABSTRACT
Chronic pancreatitis (CP) is an irreversible fibro-inflammatory disease of the pancreas with no current targeted therapy. Pirfenidone, an anti-fibrotic and anti-inflammatory drug, is FDA approved for treatment of Idiopathic Pulmonary Fibrosis (IPF). Its efficacy in ameliorating CP has never been evaluated before. We recently reported that pirfenidone improves acute pancreatitis in mouse models. The aim of the current study was to evaluate the therapeutic efficacy of pirfenidone in mouse models of CP. We used caerulein and L-arginine models of CP and administered pirfenidone with ongoing injury, or in well-established disease. We evaluated for fibrosis by Sirius-red staining for collagen, immunohistochemistry, western blotting, and qPCR for fibrosis markers to show the salutary effects of pirfenidone in CP. Our results suggest that treatment with pirfenidone ameliorated CP related changes in the pancreas (i.e., atrophy, acinar cell loss, fibrosis, and inflammation) not only when administered with ongoing injury, but also in well-established models of caerulein as well as L-arginine induced CP. It reduces the pro-fibrotic phenotype of macrophages (in-vivo and in-vitro), reduces macrophage infiltration into the pancreas and alters the intra-pancreatic cytokine milieu preceding changes in histology. The therapeutic effect of pirfenidone is abrogated in absence of macrophages. Furthermore, it reduces collagen secretion, cytokine levels and fibrosis markers in pancreatic stellate cells in-vitro. As it is FDA approved, our findings in mouse models simulating clinical presentation of patients to the clinic, can be used as the basis of a clinical trial evaluating the efficacy of this drug as a therapeutic agent for CP.
PMID:35570091 | DOI:10.1016/j.pan.2022.05.002
Mechanical forces: The missing link between idiopathic pulmonary fibrosis and lung cancer
Eur J Cell Biol. 2022 May 10;101(3):151234. doi: 10.1016/j.ejcb.2022.151234. Online ahead of print.
ABSTRACT
Patients with idiopathic pulmonary fibrosis (IPF) have a high risk of developing lung cancer compared with the general population. The morbidity of lung cancer in IPF patient ranges from 3% to 22%, and in some cases exceeds 50%, and these patients have a reduced survival time. However, the mechanisms through which IPF increases the morbidity and mortality in lung cancer remain unclear. By carefully analyzing the pathological features of these two diseases, we uncovered that, first, similar to IPF, lung carcinomas are more frequently found in the peripheral area of the lungs and, second, lung cancers tend to develop from the honeycomb areas in IPF. In accordance with the above pathological features, due to the spatial location, the peripheral areas of the lung experience a high stretch force because the average distance between adjacent alveolar cells in this area tends to be larger than that at the central lung when inflated; furthermore, the honeycomb areas, comprised of condensed fibrous tissue, are characterized by increased stiffness. Both of these pathological features of lung cancer and IPF are coincidentally related to abnormal mechanical forces (stretch and tissue stiffness). Therefore, we believe that the aberrant mechanical forces that are generated in the lung with IPF may contribute to the onset and progression of lung cancer. In this review, we discuss the possible effects of mechanical forces that are generated in IPF on the initiation and progression of lung cancer from the perspective of the hallmarks of cancer, including proliferation, metastasis, angiogenesis, cancer stem cells, immunology, epigenetics, and metabolism, so as to advance our understanding of the pathogenesis of IPF-related lung cancer and to harness these concepts for lung cancer mechanotherapies.
PMID:35569385 | DOI:10.1016/j.ejcb.2022.151234
Trial of a Preferential Phosphodiesterase 4B Inhibitor for Idiopathic Pulmonary Fibrosis
N Engl J Med. 2022 May 15. doi: 10.1056/NEJMoa2201737. Online ahead of print.
ABSTRACT
BACKGROUND: Phosphodiesterase 4 (PDE4) inhibition is associated with antiinflammatory and antifibrotic effects that may be beneficial in patients with idiopathic pulmonary fibrosis.
METHODS: In this phase 2, double-blind, placebo-controlled trial, we investigated the efficacy and safety of BI 1015550, an oral preferential inhibitor of the PDE4B subtype, in patients with idiopathic pulmonary fibrosis. Patients were randomly assigned in a 2:1 ratio to receive BI 1015550 at a dose of 18 mg twice daily or placebo. The primary end point was the change from baseline in the forced vital capacity (FVC) at 12 weeks, which we analyzed with a Bayesian approach separately according to background nonuse or use of an antifibrotic agent.
RESULTS: A total of 147 patients were randomly assigned to receive BI 1015550 or placebo. Among patients without background antifibrotic use, the median change in the FVC was 5.7 ml (95% credible interval, -39.1 to 50.5) in the BI 1015550 group and -81.7 ml (95% credible interval, -133.5 to -44.8) in the placebo group (median difference, 88.4 ml; 95% credible interval, 29.5 to 154.2; probability that BI 1015550 was superior to placebo, 0.998). Among patients with background antifibrotic use, the median change in the FVC was 2.7 ml (95% credible interval, -32.8 to 38.2) in the BI 1015550 group and -59.2 ml (95% credible interval, -111.8 to -17.9) in the placebo group (median difference, 62.4 ml; 95% credible interval, 6.3 to 125.5; probability that BI 1015550 was superior to placebo, 0.986). A mixed model with repeated measures analysis provided results that were consistent with those of the Bayesian analysis. The most frequent adverse event was diarrhea. A total of 13 patients discontinued BI 1015550 treatment owing to adverse events. The percentages of patients with serious adverse events or severe adverse events were similar in the two trial groups.
CONCLUSIONS: In this placebo-controlled trial, treatment with BI 1015550, either alone or with background use of an antifibrotic agent, prevented a decrease in lung function in patients with idiopathic pulmonary fibrosis. (Funded by Boehringer Ingelheim; 1305-0013 ClinicalTrials.gov number, NCT04419506.).
PMID:35569036 | DOI:10.1056/NEJMoa2201737
Behavioural and psychological patterns of patients with idiopathic pulmonary fibrosis: a prospective study
Respir Res. 2022 May 14;23(1):124. doi: 10.1186/s12931-022-02041-6.
ABSTRACT
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung condition. Currently, care models predominantly focus on acute medical and pharmacological needs. As a step towards holistic care, the aim of this prospective study was to investigate the psychological and behavioural needs of IPF patients treated with pirfenidone from diagnosis until two years of follow-up.
METHODS: The following variables were selected from the literature on patients' needs and the COM-B model, a theoretical model explaining behaviour: medication adherence, barriers to adherence, importance and intentions of medication adherence, anxiety, depression, health literacy, knowledge, reported side effects, adherence to sun protection recommendations, alcohol use, physical activity, quality of life and health status. Linear and generalised linear models for longitudinal data were used to evaluate the evolution since treatment initiation.
RESULTS: We included 66 outpatients: 72.7% men, mean age of 70.3 years (range 50-87), predicted mean forced vital capacity of 85.8% (SD 17.4) and predicted mean diffusing capacity for monoxide of 56.9% (SD 15.7). The participants placed considerable importance on following the treatment recommendations. We noticed difficulties regarding health literacy, alcohol use, pirfenidone adherence (decline over time) and adherence to sun protection recommendations (early in follow-up care). There were low levels of physical activity (no effect of time), high body mass indices (decline over time) and moderate levels of depression and anxiety.
CONCLUSION: When providing care to IPF patients, behavioural issues, health literacy and psychological well-being should be taken into consideration. There is a need to further explore interventions and care models to tackle these difficulties. Trial registration This study was registered in the ClinicalTrials.gov database (identifier NCT03567785) on May 9th, 2018.
PMID:35568881 | DOI:10.1186/s12931-022-02041-6
SIRT1 prevents cigarette smoking-induced lung fibroblasts activation by regulating mitochondrial oxidative stress and lipid metabolism
J Transl Med. 2022 May 14;20(1):222. doi: 10.1186/s12967-022-03408-5.
ABSTRACT
BACKGROUND: Cigarette smoking (CS) is a strong risk factor for idiopathic pulmonary fibrosis (IPF). It can activate lung fibroblasts (LF) by inducing redox imbalance. We previously showed that clearing mitochondrial reactive oxygen species (mtROS) protects against CS-induced pulmonary fibrosis. However, the precise mechanisms of mtROS in LF need further investigation. Here we focused on mtROS to elucidate how it was regulated by CS in LF and how it contributed to LF activation.
METHODS: We treated cells with 1% cigarette smoking extract (CSE) and examined mtROS level by MitoSOX™ indicator. And the effect of CSE on expression of SIRT1, SOD2, mitochondrial NOX4 (mtNOX4), fatty acid oxidation (FAO)-related protein PPARα and CPT1a and LF activation marker Collagen I and α-SMA were detected. Nile Red staining was performed to show cellular lipid content. Then, lipid droplets, autophagosome and lysosome were marked by Bodipy 493/503, LC3 and LAMP1, respectively. And lipophagy was evaluated by the colocalization of lipid droplets with LC3 and LAMP1. The role of autophagy on lipid metabolism and LF activation were explored. Additionally, the effect of mitochondria-targeted ROS scavenger mitoquinone and SIRT1 activator SRT1720 on mitochondrial oxidative stress, autophagy flux, lipid metabolism and LF activation were investigated in vitro and in vivo.
RESULTS: We found that CS promoted mtROS production by increasing mtNOX4 and decreasing SOD2. Next, we proved mtROS inhibited the expression of PPARα and CPT1a. It also reduced lipophagy and upregulated cellular lipid content, suggesting lipid metabolism was disturbed by CS. In addition, we showed both insufficient FAO and lipophagy resulted from blocked autophagy flux caused by mtROS. Moreover, we uncovered decreased SIRT1 was responsible for mitochondrial redox imbalance. Furthermore, we proved that both SRT1720 and mitoquinone counteracted the effect of CS on NOX4, SOD2, PPARα and CPT1a in vivo.
CONCLUSIONS: We demonstrated that CS decreased SIRT1 to activate LF through dysregulating lipid metabolism, which was due to increased mtROS and impaired autophagy flux. These events may serve as therapeutic targets for IPF patients.
PMID:35568871 | DOI:10.1186/s12967-022-03408-5
Changes in Oxygenation and Serological Markers in Acute Exacerbation of Interstitial Lung Disease Treated with Polymyxin B Hemoperfusion
J Clin Med. 2022 Apr 28;11(9):2485. doi: 10.3390/jcm11092485.
ABSTRACT
BACKGROUND: Polymyxin B direct hemoperfusion (PMX-DHP) has been tried in acute exacerbation of interstitial lung disease (AE-ILD) patients and has shown clinical benefit. In this study, we tried to investigate the change in oxygenation and serologic markers after PMX-DHP treatment in AE-ILD patients in Korea.
METHODS: We reviewed the medical records of twenty-two patients who were admitted for AE-ILD and underwent PMX-DHP treatment. Changes in vital signs and laboratory findings before and after treatment were compared and factors related to 90-day mortality were analyzed using the Cox regression model.
RESULTS: Of the 22 included patients, 11 (50%) patients were diagnosed with idiopathic pulmonary fibrosis. In AE-ILD patients treated with PMX-DHP, the 28-day mortality rate was 45.5% and the 90-day mortality rate was 72.7%. The P/F ratio before and after PMX-DHP treatment significantly improved in patients from baseline to 24 h (median (IQR), 116.3 (88.5-134.3) mmHg vs. 168.6 (115.5-226.8) mmHg, p = 0.001), and 48 h (116.3 (88.5-134.3) mmHg vs. 181.6 (108.9-232.0) mmHg, p = 0.003). Also, white blood cells (WBCs) and C-reactive protein (CRP) were decreased after PMX-DHP treatment. High acute physiology and chronic health evaluation II scores were associated with 90-day mortality.
CONCLUSIONS: In patients with AE-ILD, PMX-DHP treatment was associated with an improved P/F ratio and lower WBC and CRP levels.
PMID:35566611 | DOI:10.3390/jcm11092485