BMC Pulm Med. 2022 Oct 26;22(1):387. doi: 10.1186/s12890-022-02197-3.

ABSTRACT

BACKGROUND: Acute exacerbation (AE) of systemic autoimmune disease-related interstitial lung diseases (SAID-ILD) is less common than AE of idiopathic pulmonary fibrosis (IPF) and the details of AE-SAID-ILD have not been elucidated, but the prognosis is similarly devastating. This study was undertaken to determine the incidences of AE-ILD in each SAID and to elucidate the proportion of progressive fibrosing (PF)-ILD in AE-SAID-ILD.

METHODS: We retrospectively analysed data for patients with SAID-ILD who were diagnosed and observed at our hospital between 1999 and 2020.

RESULTS: Two hundred and thirty-two patients with SAID-ILD were enrolled, with a mean observation period of 100.2 months. AE-SAID-ILD was found in 25 patients (10.78%), mainly in patients with RA (17 patients, 68%) and elderly male patients with a smoking history. The overall incidence of AE-SAID-ILD was 1.29%/person-year, and the incidence for each SAID was as follows: RA 2.193, microscopic polyarteritis (MPA) 3.203, systemic sclerosis (SSc) 2.277, primary Sjögren syndrome 0.426, and polymyositis/dermatomyositis 0.222. The incidence of AE of RA/MPA/SSc-ILD was significantly higher than that of other AE-SAID-ILD (p < 0.001). Five of 25 patients (20%) fulfilled the criteria for PF-ILD. The 90-day survival rate was 48.0%, and a higher neutrophil count at AE (HR 13.27, 95%CI 2.447-246, p = 0.001) and early commencement of long-duration direct haemoperfusion with a polymyxin B-immobilised fibre column (HR 0.105, 95%CI 0.005-0.858, p = 0.035) were significant prognostic factors.

CONCLUSIONS: The incidence of AE-SAID-ILD was significantly higher in patients with RA, MPA, or SSc than in patients with other SAID. Furthermore, even in patients with AE-SAID-ILD, the proportion of PF-ILD just before AE was not high (20%).

PMID:36289542 | DOI:10.1186/s12890-022-02197-3

Respir Res. 2022 Oct 26;23(1):291. doi: 10.1186/s12931-022-02195-3.

ABSTRACT

BACKGROUND: Although corticosteroid therapy with dose tapering is the most commonly used treatment for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), there is no consensus on the tapering regimen. This study aimed to investigate the association between early corticosteroid dose tapering and in-hospital mortality in patients with AE-IPF.

METHODS: In this retrospective cohort study, we analyzed the data of a cohort from eight Japanese tertiary care hospitals and routinely collected administrative data from a cohort from 185 Japanese hospitals. Patients with AE-IPF were classified into the early and non-early tapering groups depending on whether the maintenance dose of corticosteroids was reduced within two weeks of admission. Propensity score analysis with inverse probability weighting (IPW) was performed to estimate the effect of early corticosteroid dose tapering.

RESULTS: The multi-center cohort included 153 eligible patients, of whom 47 (31%) died, whereas the administrative cohort included 229 patients, of whom 51 (22%) died. Patients with early tapering tended to have a better prognosis than those without it (unadjusted hazard ratio [95% confidence interval] 0.41 [0.22-0.76] and 0.65 [0.36-1.18] in the multi-center and administrative cohorts, respectively). After IPW, the early tapering group had a better prognosis than the non-early tapering group (IPW-adjusted hazard ratio [95% confidence interval] 0.37 [0.14-0.99] and 0.27 [0.094-0.83] in the multi-center and administrative cohorts, respectively).

CONCLUSION: Early corticosteroid dose tapering was associated with a favorable prognosis in patients with AE-IPF. Further studies are warranted to confirm the effects of early corticosteroid dose tapering in patients with AE-IPF.

PMID:36289512 | DOI:10.1186/s12931-022-02195-3

Ter Arkh. 2022 Mar 15;94(3):409-412. doi: 10.26442/00403660.2022.03.201407.

ABSTRACT

INTRODUCTION: The widespread use of artificial intelligence (AI) programs during the COVID-19 pandemic to assess the exact volume of lung tissue damage has allowed them to train a large number of radiologists. The simplicity of the program for determining the volume of the affected lung tissue in acute interstitial pneumonia, which has density indicators in the range from -200 HU to -730 HU, which includes the density indicators of "ground glass" and reticulation (the main radiation patterns in COVID-19) allows you to accurately determine the degree of prevalence process. The characteristics of chronic interstitial pneumonia, which are progressive in nature, fit into the same density framework. Аim. To аssess AI's ability to assess the progression of fibrosing lung disease using lung volume counting programs used for COVID-19 and chronic obstructive pulmonary disease.

RESULTS: Retrospective analysis of computed tomography data during follow-up of 75 patients with progressive fibrosing lung disease made it possible to assess the prevalence and growth of interstitial lesions.

CONCLUSION: Using the experience of using AI programs to assess acute interstitial pneumonia in COVID-19 can be applied to chronic interstitial pneumonia.

PMID:36286906 | DOI:10.26442/00403660.2022.03.201407

Eur J Health Econ. 2022 Oct 27. doi: 10.1007/s10198-022-01538-7. Online ahead of print.

ABSTRACT

PURPOSE: Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease found mostly in elderly persons, characterized by a high symptom burden and frequent encounters with health services. This study aimed to quantify the economic burden of IPF in Australia with a focus on resource utilization and associated direct costs.

METHODS: Participants were recruited from the Australian IPF Registry (AIPFR) between August 2018 and December 2019. Data on resource utilization and costs were collected via cost diaries and linked administrative data. Clinical data were collected from the AIPFR. A "bottom up" costing methodology was utilized, and the costing was performed from a partial societal perspective focusing primarily on direct medical and non-medical costs. Costs were standardized to 2021 Australian dollars ($).

RESULTS: The average annual total direct costs per person with IPF was $31,655 (95% confidence interval (95% CI): $27,723-$35,757). Extrapolating costs based on prevalence estimates, the total annual costs in Australia are projected to be $299 million (95% CI: $262 million-$338 million). Costs were mainly driven by antifibrotic medication, hospital admissions and medications for comorbidities. Disease severity, comorbidities and antifibrotic medication all had varying impacts on resource utilization and costs.

CONCLUSION: This cost-of-illness study provides the first comprehensive assessment of IPF-related direct costs in Australia, identifies the key cost drivers and provides a framework for future health economic analyses. Additionally, it provided insight into the major cost drivers which include antifibrotic medication, hospital admissions and medications related to comorbidities. Our findings emphasize the importance of the appropriate management of comorbidities in the care of people with IPF as this was one of the main reasons for hospitalizations.

PMID:36289130 | DOI:10.1007/s10198-022-01538-7

Tomography. 2022 Oct 13;8(5):2574-2587. doi: 10.3390/tomography8050215.

ABSTRACT

3D Single-breath Chemical Shift Imaging (3D-SBCSI) is a hybrid MR-spectroscopic imaging modality that uses hyperpolarized xenon-129 gas (Xe-129) to differentiate lung diseases by probing functional characteristics. This study tests the efficacy of 3D-SBCSI in differentiating physiology among pulmonary diseases. A total of 45 subjects-16 healthy, 11 idiopathic pulmonary fibrosis (IPF), 13 cystic fibrosis (CF), and 5 chronic obstructive pulmonary disease (COPD)-were given 1/3 forced vital capacity (FVC) of hyperpolarized Xe-129, inhaled for a ~7 s MRI acquisition. Proton, Xe-129 ventilation, and 3D-SBCSI images were acquired with separate breath-holds using a radiofrequency chest coil tuned to Xe-129. The Xe-129 spectrum was analyzed in each lung voxel for ratios of spectroscopic peaks, chemical shifts, and T2* relaxation. CF and COPD subjects had significantly more ventilation defects than IPF and healthy subjects, which correlated with FEV1 predicted (R = -0.74). FEV1 predicted correlated well with RBC/Gas ratio (R = 0.67). COPD and IPF had significantly higher Tissue/RBC ratios than other subjects, longer RBC T2* relaxation times, and greater RBC chemical shifts. CF subjects had more ventilation defects than healthy subjects, elevated Tissue/RBC ratio, shorter Tissue T2* relaxation, and greater RBC chemical shift. 3D-SBCSI may be helpful in the detection and characterization of pulmonary disease, following treatment efficacy, and predicting disease outcomes.

PMID:36287814 | DOI:10.3390/tomography8050215

Adv Respir Med. 2022 Oct 4;90(5):425-450. doi: 10.3390/arm90050052.

ABSTRACT

The recommendations were developed as answers to previously formulated questions concerning everyday diagnostic and therapeutic challenges. They were developed based on a review of the current literature using the GRADE methodology. The experts suggest that PF-ILD be diagnosed based on a combination of different criteria, such as the aggravation of symptoms, progression of radiological lesions, and worsening of lung function test parameters. The experts recommend a precise diagnosis of an underlying disease, with serological testing for an autoimmune disease always being included. The final diagnosis should be worked out by a multidisciplinary team (MDT). Patients with an interstitial lung disease other than IPF who do not meet the criteria for the progressive fibrosis phenotype should be monitored for progression, and those with systemic autoimmune diseases should be regularly monitored for signs of interstitial lung disease. In managing patients with interstitial lung disease associated with autoimmune diseases, an opinion of an MDT should be considered. Nintedanib rather than pirfenidon should be introduced in the event of the ineffectiveness of the therapy recommended for the treatment of the underlying disease, but in some instances, it is possible to start antifibrotic treatment without earlier immunomodulatory therapy. It is also admissible to use immunomodulatory and antifibrotic drugs simultaneously. No recommendations were made for or against termination of anti-fibrotic therapy in the case of noted progression during treatment of a PF-ILD other than IPF. The experts recommend that the same principles of non-pharmacological and palliative treatment and eligibility for lung transplantation should be applied to patients with an interstitial lung disease other than IPF with progressive fibrosis as in patients with IPF.

PMID:36285980 | DOI:10.3390/arm90050052

Am J Physiol Lung Cell Mol Physiol. 2022 Oct 25. doi: 10.1152/ajplung.00428.2021. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis is a progressive lung disease with limited survival. The specific roles of Janus Kinases - tyrosine kinases that transduce cytokine-mediated signals - in lung fibrosis are not well defined. In this study, the interactions between JAK1/STAT3 signaling and TGF-β induced fibroblast responses were investigated using both pharmacological and siRNA approaches in human normal and IPF-derived lung fibroblasts. We found that JAK1 directly interacts with the TGF-β receptor I (TβRI), and silencing JAK1 promotes myofibroblast trans-differentiation. However, the suppression of JAK1 signaling in vitro and in vivo using an inhibitor (Upadacitinib) did not alter lung fibroblast activation or fibrosis development. STAT3 was constitutively active in cultured primary lung fibroblasts: this STAT3 activation was JAK1 dependent and repressed myofibroblast trans-differentiation. Loss of phosphorylated STAT3 following transcriptional JAK1 silencing promoted myofibroblast trans-differentiation. In contrast, transcriptional silencing of unphosphorylated STAT3 suppressed TGF-β signaling, decreased SMAD3 activation, and reduced myofibroblast trans-differentiation and ECM production. Taken together, these observations support a role for JAK1/STAT3 as a direct regulator of TGF-β signaling in lung fibroblasts. Modulation of JAK1/STAT3 signaling in lung fibroblasts represents a non-canonical approach to regulate TGF-β induced fibrosis and suggests the potential for a novel approach to treat pulmonary fibrosis.

PMID:36283961 | DOI:10.1152/ajplung.00428.2021

Respir Med Res. 2022 Oct 18;82:100965. doi: 10.1016/j.resmer.2022.100965. Online ahead of print.

ABSTRACT

BACKGROUND: Sarcopenia, defined using abdominal computed tomography (CT), has been used as a prognostic marker for patients with idiopathic pulmonary fibrosis (IPF). However, no consensus on the impact of sarcopenia as defined using chest CT exists. Therefore, this study aimed to investigate the impact of sarcopenia, defined using CT at the carina-level, on the long-term prognosis of patients with IPF.

METHODS: This single-center retrospective cohort study included 117 patients with IPF. Sarcopenia was defined as skeletal muscle mass measured at the carina-level on chest CT images. All-cause mortality was analyzed using the Kaplan-Meier method, and the log-rank test was used to evaluate the differences between sarcopenia and non-sarcopenia groups. A Cox proportional hazards regression model was used to analyze the impact of sarcopenia on all-cause mortality in model 1 with adjustment for body mass index and gender-age-physiology stage as a confounding factor and in model 2 with sex, age, and% forced vital capacity (FVC).

RESULTS: The median follow-up period was 956 days, and 57 deaths were recorded. The sarcopenia group had a significantly lower survival rate than the non-sarcopenia group. The multivariate Cox proportional hazards analysis revealed that sarcopenia was a significant predictor of all-cause mortality in models 1 and 2. In patients with no diffusing capacity for carbon monoxide (DLCO) measurement, sarcopenia was a significant prognostic predictor of all-cause mortality independent of%FVC.

CONCLUSION: Sarcopenia, defined at the carina level, is a risk factor for all-cause mortality in patients with IPF. Assessment of sarcopenia by CT imaging is useful and less burdensome in patients with IPF.

PMID:36283327 | DOI:10.1016/j.resmer.2022.100965

Radiology. 2022 Oct 25:220292. doi: 10.1148/radiol.220292. Online ahead of print.

ABSTRACT

Background Total lung capacity (TLC) has been estimated with use of chest radiographs based on time-consuming methods, such as planimetric techniques and manual measurements. Purpose To develop a deep learning-based, multidimensional model capable of estimating TLC from chest radiographs and demographic variables and validate its technical performance and clinical utility with use of multicenter retrospective data sets. Materials and Methods A deep learning model was pretrained with use of 50 000 consecutive chest CT scans performed between January 2015 and June 2017. The model was fine-tuned on 3523 pairs of posteroanterior chest radiographs and plethysmographic TLC measurements from consecutive patients who underwent pulmonary function testing on the same day. The model was tested with multicenter retrospective data sets from two tertiary care centers and one community hospital, including (a) an external test set 1 (n = 207) and external test set 2 (n = 216) for technical performance and (b) patients with idiopathic pulmonary fibrosis (n = 217) for clinical utility. Technical performance was evaluated with use of various agreement measures, and clinical utility was assessed in terms of the prognostic value for overall survival with use of multivariable Cox regression. Results The mean absolute difference and within-subject SD between observed and estimated TLC were 0.69 L and 0.73 L, respectively, in the external test set 1 (161 men; median age, 70 years [IQR: 61-76 years]) and 0.52 L and 0.53 L in the external test set 2 (113 men; median age, 63 years [IQR: 51-70 years]). In patients with idiopathic pulmonary fibrosis (145 men; median age, 67 years [IQR: 61-73 years]), greater estimated TLC percentage was associated with lower mortality risk (adjusted hazard ratio, 0.97 per percent; 95% CI: 0.95, 0.98; P < .001). Conclusion A fully automatic, deep learning-based model estimated total lung capacity from chest radiographs, and the model predicted survival in idiopathic pulmonary fibrosis. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Sorkness in this issue.

PMID:36283113 | DOI:10.1148/radiol.220292

J Korean Med Sci. 2022 Oct 24;37(41):e294. doi: 10.3346/jkms.2022.37.e294.

ABSTRACT

BACKGROUND: The demand for lung transplants continues to increase in Korea, and donor shortages and waitlist mortality are critical issues. This study aimed to evaluate the factors that affect waitlist outcomes from the time of registration for lung transplantation in Korea.

METHODS: Data were obtained from the Korean Network for Organ Sharing for lung-only registrations between September 7, 2009, and December 31, 2020. Post-registration outcomes were evaluated according to the lung disease category, blood group, and age.

RESULTS: Among the 1,671 registered patients, 49.1% had idiopathic pulmonary fibrosis (group C), 37.0% had acute respiratory distress syndrome and other interstitial lung diseases (group D), 7.2% had chronic obstructive pulmonary disease (group A), and 6.6% had primary pulmonary hypertension (group B). Approximately half of the patients (46.1%) were transplanted within 1 year of registration, while 31.8% died without receiving a lung transplant within 1 year of registration. Data from 1,611 patients were used to analyze 1-year post-registration outcomes, which were classified as transplanted (46.1%, n = 743), still awaiting (21.1%, n = 340), removed (0.9%, n = 15), and death on waitlist (31.8%, n = 513). No significant difference was found in the transplantation rate according to the year of registration. However, significant differences occurred between the waitlist mortality rates (P = 0.008) and the still awaiting rates (P = 0.009). The chance of transplantation after listing varies depending on the disease category, blood type, age, and urgency status. Waitlist mortality within 1 year was significantly associated with non-group A disease (hazard ratio [HR], 2.76, P < 0.001), age ≥ 65 years (HR, 1.48, P < 0.001), and status 0 at registration (HR, 2.10, P < 0.001).

CONCLUSION: Waitlist mortality is still higher in Korea than in other countries. Future revisions to the lung allocation system should take into consideration the high waitlist mortality and donor shortages.

PMID:36281485 | DOI:10.3346/jkms.2022.37.e294

Int J Tuberc Lung Dis. 2022 Nov 1;26(11):1001-1005. doi: 10.5588/ijtld.22.0212.

ABSTRACT

Interstitial lung diseases (ILDs) include a large variety of fibrotic lung conditions caused by genetic and environmental factors. Occupational exposures might also play a significant role, but the real health burden is currently unknown. Here, we aim to evaluate the role of work-related exposures in ILDs, focussing on idiopathic pulmonary fibrosis (IPF) and hypersensitivity pneumonitis (HP). We performed a focused review of the literature on work-related HP and IPF over the past 5 years. Using a meta-analytic approach, we quantified the occupational burden of IPF and HP, and estimated that occupational exposures to metal, silica and environmental tobacco smoke increased IPF risk with a pooled odds ratio of 1.7 (95% CI 1.42-2.03). The proportion of HP cases related to workplace exposure was 17% (95% CI 7-28). Our review supports the hypothesis that occupational exposures are a significant risk factor in the aetiopathogenesis of IPF and HP. We recommend that further research be performed to identify the underlying occupational factors and the maximum permitted exposure to reduce the associated IPF and HP burden.

PMID:36281049 | DOI:10.5588/ijtld.22.0212

Dtsch Med Wochenschr. 2022 Oct;147(21):1383-1390. doi: 10.1055/a-1825-4967. Epub 2022 Oct 24.

ABSTRACT

The interstitial lung diseases ILDs are a heterogeneous group of diseases that often lead to progressive fibrosis of the lungs with corresponding functional impairment. With nintedanib, a tyrosinkinase inhibitor and angiokinase inhibitor, as well as pirfenidone, which unfolds its effect among other things by inhibiting the transforming growth factor β, there are currently 2 approved antifibrotic drugs. In the rapidly progressing idiopathic pulmonary fibrosis IPF, the antifibrotic drugs nintedanib and pirfenidone have been established and approved in therapy for several years. The initiation of antifibrotic therapy should be carried out early after diagnosis by multidisciplinary discussion (MDD). In systemic scleroderma with lung involvement nintedanib should be used in the case of relevant fibrosis in addition to immunosuppressive therapy. Recently, nintedanib has also become a new option for the treatment of progressive fibrosing ILDs (PF-ILDs). This describes the course of various disease entities such as connective tissue disease associated ILDs (CTD-ILDs), fibrosing hypersensitivity pneumonitis or fibrosing courses of non-IPF idiopathic interstitial pneumonitis (non-IPF IIPs) that have a corresponding fibrose-related worsening of respiratory symptoms, a deterioration of lung-functioning parameters or a disease progression in CT. Although pirfenidone also shows positive signals for this group of patients in some selected studies, its use in PF-ILD is not yet recommended. In particular, gastrointestinal side effects can occur under therapy with antifibrotic drugs and require a long-term close interdisciplinary connection of patients.

PMID:36279864 | DOI:10.1055/a-1825-4967

Exp Biol Med (Maywood). 2022 Oct 22:15353702221128564. doi: 10.1177/15353702221128564. Online ahead of print.

ABSTRACT

In recent years, with the increase of air pollution, smoking, aging, and respiratory infection, the incidence rate and mortality of lung diseases are increasing annually, which has become a major hazard to human health. N6-methyladenosine (m6A) RNA methylation is the most abundant modifications in eukaryotes, and such modified RNA can be specifically recognized and combined by m6A recognition proteins and then mediate RNA splicing, maturation, enucleation, degradation, and translation. More and more studies have revealed that the m6A modification is involved in the pathogenesis and development of some diseases; however, the mechanisms of m6A in lung diseases are poorly understood. In this review, we summarize the latest progress in the biological function of m6A modifications in lung diseases and discuss the potential therapeutic and prognostic strategies. The dysregulation of global m6A levels and m6A regulators may affect the occurrence and development of asthma, chronic obstructive pulmonary disease, lung cancer, and other lung diseases through inflammation and immune function. In lung cancer, this modification has an important impact on malignant cell proliferation, migration, invasion, and drug resistance. In addition, abnormally changed m6A-modified proteins in lung cancer tissue samples and circulating tumor cells (CTCs) may be used as diagnostic and prognostic markers of lung cancer. Models composed of multiple m6A regulators can be used to evaluate the risk prediction or prognosis of asthma and pulmonary fibrosis. In general, the in-depth study of m6A modifications is a frontier direction in disease research. It provides novel insights for understanding of the molecular mechanisms underlying disease occurrence, development, and drug resistance, as well as for the development of effective novel therapeutics.

PMID:36278325 | DOI:10.1177/15353702221128564

Front Physiol. 2022 Oct 6;13:980942. doi: 10.3389/fphys.2022.980942. eCollection 2022.

ABSTRACT

Background: Chronic lung allograft dysfunction (CLAD) is the major cause of death beyond 2 years after lung transplantation and develops in 50% of all patients by 5 years post-transplant. CLAD is diagnosed on the basis of a sustained drop of 20% for at least 3 months in the forced expiratory volume (FEV1), compared to the best baseline value achieved post-transplant. CLAD presents as two main phenotypes: bronchiolitis obliterans syndrome (BOS) is more common and has better prognosis than restrictive allograft syndrome (RAS). Respiratory oscillometry is a different modality of lung function testing that is highly sensitive to lung mechanics. The current study investigated whether spectral and intrabreath oscillometry can differentiate between CLAD-free, BOS- and RAS-CLAD at CLAD onset, i.e., at the time of the initial 20% drop in the FEV1. Methods: A retrospective, cross-sectional analysis of 263 double lung transplant recipients who underwent paired testing with oscillometry and spirometry at the Toronto General Pulmonary Function Laboratory from 2017 to 2022 was conducted. All pulmonary function testing and CLAD diagnostics were performed following international guidelines. Statistical analysis was conducted using multiple comparisons. Findings: The RAS (n = 6) spectral oscillometry pattern differs from CLAD-free (n = 225) by right-ward shift of reactance curve similar to idiopathic pulmonary fibrosis whereas BOS (n = 32) has a pattern similar to obstructive lung disease. Significant differences were found in most spectral and intrabreath parameters between BOS, RAS, and time-matched CLAD-free patients. Post-hoc analysis revealed these differences were primarily driven by BOS instead of RAS. While no differences were found between CLAD-free and RAS patients with regards to spectral oscillometry, the intrabreath metric of reactance at end-inspiration (XeI) was significantly different (p < 0.05). BOS and RAS were differentiated by spectral oscillometry measure R5, and intrabreath resistance at end expiration, ReE (p < 0.05 for both). Conclusion: Both spectral and intrabreath oscillometry can differentiate BOS-CLAD from CLAD-free states while intrabreath oscillometry, specifically XeI, can uniquely distinguish RAS-CLAD from CLAD-free. Spectral and intrabreath oscillometry offer complementary information regarding lung mechanics in CLAD patients to help distinguish the two phenotypes and could prove useful in prognostication.

PMID:36277208 | PMC:PMC9582781 | DOI:10.3389/fphys.2022.980942

Oxid Med Cell Longev. 2022 Oct 12;2022:7686956. doi: 10.1155/2022/7686956. eCollection 2022.

ABSTRACT

Ferroptosis is a type of programmed cell death characterized by iron overload, oxidative stress, imbalance in lipid repair, and mitochondria-specific pathological manifestations. Growing number of molecular mechanisms and signaling pathways have been found to be involved in ferroptosis progression, including iron metabolism, amino acid metabolism, lipid metabolism, and energy metabolism. It is worth noting that ferroptosis is involved in the progression of fibrotic diseases such as liver cirrhosis, cardiomyopathy, and idiopathic pulmonary fibrosis, and inhibition of ferroptosis has acquired beneficial outcomes in rodent models, while studies on ferroptosis and renal fibrosis remains limited. Recent studies have revealed that targeting ferroptosis can effectively mitigate chronic kidney injury and renal fibrosis. Moreover, myofibroblasts suffer from ferroptosis during fiber and extracellular matrix deposition in the fibrotic cascade reaction and pharmacological modulation of ferroptosis shows great therapeutic effect on renal fibrosis. Here, we summarize the latest molecular mechanisms of ferroptosis from high-quality studies and review its therapeutic potential in renal fibrosis.

PMID:36275899 | PMC:PMC9581688 | DOI:10.1155/2022/7686956

Allergy Asthma Clin Immunol. 2022 Oct 21;18(1):93. doi: 10.1186/s13223-022-00734-7.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease with limited treatment options. Plumbagin (PL) is an herbal extract with diverse pharmacological effects that have been recently used to treat various types of cancer. This study aims to explore the anti-fibrotic effect of PL and possible underlying mechanisms in IPF.

METHODS: We used a bleomycin-induced experimental mouse model of lung fibrosis to assess the potential anti-fibrotic effect of PL. Histological analysis of lung tissue samples by H&E and Masson's trichrome staining and hydroxyproline assay was performed to evaluate the fibrotic alterations. ELISA and real-time quantitative PCR were conducted to determine the amount of tumor necrosis factor-alpha (TNFα), tumor growth factor-beta (TGF-β), connective tissue growth factor (CTGF), and endothelin-1 (ET-1).

RESULTS: Bleomycin exposure induced lung fibrosis, which was indicated by inflammation, collagen deposition, and structural damage. PL remarkably prevented bleomycin-induced lung fibrosis. Furthermore, PL significantly inhibited TNF-α and TGF-β production. PL also diminished the upregulated expression of CTGF and ET-1 induced by bleomycin.

CONCLUSION: Overall, our findings suggest PL as an anti-fibrotic agent acting via down-regulation of TGF-β/CTGF or ET-1 axis, as well as TNF-α, to improve lung fibrosis.

PMID:36271442 | DOI:10.1186/s13223-022-00734-7

Monaldi Arch Chest Dis. 2022 Oct 21. doi: 10.4081/monaldi.2022.2363. Online ahead of print.

ABSTRACT

Pleuroparenchymal fibroelastosis (PPFE) is a rare lung disease with unprecedented features characterized by fibroelastotic changes in the subpleural lung parenchyma affecting the upper lobes. PPFE is usually idiopathic, but it can be caused by infection, autoimmunity, bone marrow or lung transplantation, or a genetic predisposition. Histopathologic examination of lung biopsy samples reveals homogenous subpleural fibrosis and abundant elastic fibers, allowing for a definitive diagnosis. As PPFE mimics many interstitial lung diseases, clinicians face significant difficulties in making a definitive final diagnosis. Since most disease-related comorbid conditions manifest at an advanced stage, invasive tissue sampling for histopathologic evaluation is consistently impossible. Such a patient presentation highlights the importance of an analysis based solely on clinical findings, which would provide a definitive diagnosis without the need for a biopsy. Because of its exceptional and inconceivable presentation, PPFE creates a diagnostic dilemma. In light of our two cases and the literature data, we present a diagnostic assessment score assay that relies solely on clinical manifestations without histopathological tissue verification to shed light on the diagnosis of PPFE. This review focuses on PPFE identification through the use of a diagnostic assessment analysis to improve early disease recognition without the use of invasive diagnostic interventions to obtain biopsy samples for histopathologic evaluation. This analytic approach, while not diagnostic in and of itself, may provide a useful pathway for differential diagnosis and may preclude redundant initiatives.

PMID:36269206 | DOI:10.4081/monaldi.2022.2363

Ann Transl Med. 2022 Sep;10(18):992. doi: 10.21037/atm-22-4042.

ABSTRACT

BACKGROUND: Elevated expression of human epididymis protein 4 (HE4) was previously described in connective tissue disease-associated interstitial lung diseases (CTD-ILDs) and cystic fibrosis (CF), but the clinical significance of HE4 has remained unknown in idiopathic pulmonary fibrosis (IPF), which is a progressive fibrosing ILD with a heterogeneous course that is in urgent need of reliable biomarkers in its clinical practice.

METHODS: A total of 27 IPF patients with acute exacerbation status (AE-IPF), 32 IPF patients with stable status (S-IPF), and 29 sex-age matched healthy controls were retrospectively included. The levels of serum HE4 and Krebs von den Lungen-6 (KL-6) of the 3 cohorts were measured. In addition, the pulmonary expression of HE4 was evaluated in lung transplant specimens of IPF using immunohistochemistry and Western blot, and noncancerous lung tissue resected from early-stage lung cancer patients as controls. The endpoint of follow-up was March 1st, 2022, and the Cox regression model was used to analyze the prognostic value of HE4.

RESULTS: The levels of HE4 and KL-6 were obviously elevated in AE-IPF patients compared to S-IPF (296.4 vs. 178.1 pmol/L for HE4, P<0.001; 2,007.0 vs. 990.5 IU/mL for KL-6, P<0.001) or healthy controls (296.4 vs. 51.8 pmol/L for HE4, P<0.001; 2,007.0 vs. 181.0 IU/mL for KL-6, P<0.001). Significant correlations were observed between serum HE4 levels and percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (r=-0.526, P<0.001), percent predicted forced vital capacity (FVC%) (r=-0.344, P=0.024), gender-age-physiology (GAP) index (r=0.535, P<0.001), and oxygenation index (r=-0.550, P<0.001) in IPF patients. In histological analysis, overexpression of HE4 in mucosal epithelium of dilated bronchi was observed in IPF patients compared with controls. Multivariate cox regression revealed that serum levels of HE4 [hazard ratio (HR) =1.004, P=0.042] and GAP index (HR =1.374, P=0.010) were associated with worse survival in IPF patients.

CONCLUSIONS: The expression of serum HE4 was obviously elevated in IPF patients, especially in AE-IPF patients. In addition, serum HE4 could be utilized as a biomarker of disease severity and poor prognosis of IPF patients. These findings warrant further validation in larger, multi-center, and longitudinal cohorts.

PMID:36267722 | PMC:PMC9577718 | DOI:10.21037/atm-22-4042

Front Physiol. 2022 Oct 4;13:867473. doi: 10.3389/fphys.2022.867473. eCollection 2022.

ABSTRACT

We applied quantitative CT image matching to assess the degree of motion in the idiopathic ILD such as usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP). Twenty-one normal subjects and 42 idiopathic ILD (31 UIP and 11 NSIP) patients were retrospectively included. Inspiratory and expiratory CT images, reviewed by two experienced radiologists, were used to compute displacement vectors at local lung regions matched by image registration. Normalized three-dimensional and two-dimensional (dorsal-basal) displacements were computed at a sub-acinar scale. Displacements, volume changes, and tissue fractions in the whole lung and the lobes were compared between normal, UIP, and NSIP subjects. The dorsal-basal displacement in lower lobes was smaller in UIP patients than in NSIP or normal subjects (p = 0.03, p = 0.04). UIP and NSIP were not differentiated by volume changes in the whole lung or upper and lower lobes (p = 0.53, p = 0.12, p = 0.97), whereas the lower lobe air volume change was smaller in both UIP and NSIP than normal subjects (p = 0.02, p = 0.001). Regional expiratory tissue fractions and displacements showed positive correlations in normal and UIP subjects but not in NSIP subjects. In summary, lung motionography quantified by image registration-based lower lobe dorsal-basal displacement may be used to assess the degree of motion, reflecting limited motion due to fibrosis in the ILD such as UIP and NSIP.

PMID:36267579 | PMC:PMC9577177 | DOI:10.3389/fphys.2022.867473

Front Endocrinol (Lausanne). 2022 Oct 4;13:1001563. doi: 10.3389/fendo.2022.1001563. eCollection 2022.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive condition with an unfavorable prognosis. A recent study has demonstrated that IPF patients exhibit characteristic alterations in the fatty acid metabolism in their lungs, suggesting an association with IPF pathogenesis. Therefore, in this study, we have explored whether the gene signature associated with fatty acid metabolism could be used as a reliable biological marker for predicting the survival of IPF patients.

METHODS: Data on the fatty acid metabolism-related genes (FAMRGs) were extracted from databases like Kyoto Encyclopedia of Genes and Genomes (KEGG), Hallmark, and Reactome pathway. The GSE70866 dataset with information on IPF patients was retrieved from the Gene Expression Omnibus (GEO). Next, the consensus clustering method was used to identify novel molecular subgroups. Gene Set Enrichment Analysis (GSEA) was performed to understand the mechanisms involved. The Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) algorithm was used to evaluate the level of immune cell infiltration in the identified subgroups based on gene expression signatures of immune cells. Finally, the Least Absolute Shrinkage and Selection Operator (LASSO) regression and multivariate Cox regression analysis were performed to develop a prognostic risk model.

RESULTS: The gene expression signature associated with fatty acid metabolism was used to create two subgroups with significantly different prognoses. GSEA reveals that immune-related pathways were significantly altered between the two subgroups, and the two subgroups had different metabolic characteristics. High infiltration of immune cells, mainly activated NK cells, monocytes, and activated mast cells, was observed in the subgroup with a poor prognosis. A risk model based on FAMRGs had an excellent ability to predict the prognosis of IPF. The nomogram constructed using the clinical features and the risk model could accurately predict the prognosis of IPF patients.

CONCLUSION: The fatty acid metabolism-related gene expression signature could be used as a potential biological marker for predicting clinical outcomes and the level of infiltration of immune cells. This could eventually enhance the accuracy of the treatment of IPF patients.

PMID:36267568 | PMC:PMC9576944 | DOI:10.3389/fendo.2022.1001563