Chondroitin sulfate in tissue remodeling: Therapeutic implications for pulmonary fibrosis

Fibrosis is characterized by the deposition of extracellular matrix (ECM) proteins, while idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease characterized by dysregulated tissue repair and remodeling. Anti-inflammatory drugs, such as corticosteroids and immunosuppressants, and antifibrotic drugs, like pirfenidone and nintedanib, are used in IPF therapy. However, their limited effects suggest that single mediators are inadequate to control IPF. Therefore, therapies targeting the multifactorial cascades that regulate tissue remodeling in fibrosis could provide alternate solutions. ECM molecules have been shown to modulate various biological functions beyond tissue structure support and thus, could be developed into novel therapeutic targets for modulating tissue remodeling. Among ECM molecules, glycosaminoglycans (GAG) are linear polysaccharides consisting of repeated disaccharides, which regulate cell-matrix interactions. Chondroitin sulfate (CS), one of the major GAGs, binds to multifactorial mediators in the ECM and reportedly participates in tissue remodeling in various diseases; however, to date, its biological functions have drawn considerably less attention than other GAGs, like heparan sulfate. In the present review, we discuss the involvement and regulation of CS in tissue remodeling and pulmonary fibrotic diseases, its role in pulmonary fibrosis, and the therapeutic approaches targeting CS.     

Predictive factors for the long-term use of pirfenidone in patients with fibrosing interstitial lung disease

BackgroundPirfenidone is an anti-fibrotic agent approved for idiopathic pulmonary fibrosis (IPF), and long-term treatment data and the effect of continuation after disease progression have been reported. The efficacy and safety of pirfenidone in fibrosing interstitial lung disease (ILD) patients without IPF have been recently reported in clinical trials; therefore, the benefits of long-term treatment are also expected. This study aims to analyze the long-term treatment data of pirfenidone and clarify the predictive factors for long-term use of pirfenidone in non-IPF patients.MethodsWe retrospectively reviewed the records of consecutive fibrosing ILD patients who started using pirfenidone between 2008 and 2014.ResultsOf the 266 fibrosing ILD patients, 167 patients had IPF, and 99 had non-IPF. Despite the non-significant differences in body size and pulmonary function between IPF and non-IPF patients, the non-IPF patients had better overall survival than the IPF patients (median 4.06 years vs. 2.09 years, p < 0.0001). In addition, the non-IPF patients had a significantly longer time to treatment discontinuation than the IPF patients (median 2.20 years vs. 1.20 years, p = 0.002). Multivariate logistic regression analysis for ≥2 years of use of pirfenidone showed that the percent predicted forced vital capacity (%FVC) and age were predictive factors common to both IPF and non-IPF patients.ConclusionsOur results indicate that non-IPF patients can continue using pirfenidone for longer durations than IPF patients. Initiation of pirfenidone for fibrosing ILD patients with higher %FVC and younger age would lead to long-term use of pirfenidone.     

Changes in serum KL-6 levels during short-term strict antigen avoidance are associated with the prognosis of patients with fibrotic hypersensitivity pneumonitis caused by avian antigens

BackgroundBird-related hypersensitivity pneumonitis (BRHP) is the most common type of fibrotic hypersensitivity pneumonitis (HP). Antigen avoidance (AA) is a key step in the diagnosis and management of HP, but not all fibrotic HP patients improve through AA. Because of the poor prognosis of fibrotic HP, predictive biomarkers to identify patients showing rapid progression during AA are urgently needed.MethodsFrom a retrospective review of the medical records of 1941 patients with interstitial lung disease, 75 cases of fibrotic BRHP confirmed by a provocation test or surgical lung biopsy were identified. To identify potential prognostic markers obtained at or around diagnosis, physiological and serological variables at diagnosis and the relative changes in those variables during strict AA were evaluated. Cox proportional hazards models with log-rank testing were used to compare the associations between these variables and survival.ResultsUnivariate analyses showed that gender, smoking status, and the relative change in the serum levels of Krebs von den Lungen-6 (KL-6) were associated with prognosis (P = 0.02, 0.04, and 0.02, respectively), but the presence of honeycombing and the forced vital capacity were not associated with survival. The relative change in KL-6 levels (greater than vs. less than a 10% decrease) was significantly associated with survival in a stratified analysis (73.9 vs. 34.9 months; P = 0.04).ConclusionsThe relative change in KL-6 levels is associated with the prognosis of patients with fibrotic BRHP independent of previously identified prognostic biomarkers. This finding could help pulmonologists identify fibrotic BRHP patients that are likely to show rapid progression.     

The prognostic value of the COPD Assessment Test in fibrotic interstitial lung disease

BackgroundThe COPD Assessment Test (CAT) has been studied as a measure of health status in idiopathic pulmonary fibrosis (IPF) and interstitial lung disease associated with connective tissue disease. However, its prognostic value is unknown. The present study explored the association between CAT score and mortality in fibrotic interstitial lung disease (FILD), including IPF and other forms of ILD.MethodsWe retrospectively analyzed 501 consecutive patients with FILD who underwent clinical assessment, including pulmonary function test and CAT. The association between CAT score and 3-year mortality was assessed using Cox proportional hazard analysis, Kaplan–Meier plots, and the log-rank test for trend. To handle missing data, the imputed method was used.ResultsThe patients’ median age was 68 years, and 320 were male (63.9%). Regarding CAT severity, 203 patients had a low impact level (score <10), 195 had a medium level (10–20), 80 had a high level (21–30), and 23 had a very high level (31–40). During the 3-year study period, 118 patients died. After adjusting for age, sex, forced vital capacity, diffusion capacity for carbon monoxide, IPF diagnosis, and usual interstitial pneumonia pattern on high-resolution computed tomography, the CAT score was significantly associated with 3-year mortality (hazard ratio in increments of 10 points: 1.458, 95% confidence interval 1.161–1.830; p < 0.001). In addition, patients with high and very high impact levels had twofold and threefold higher mortality risk than those with low levels, respectively.ConclusionThe CAT has prognostic value in FILD.     

Nintedanib inhibits epithelial-mesenchymal transition in A549 alveolar epithelial cells through regulation of the TGF-β/Smad pathway

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder. Recent studies have suggested that epithelial-mesenchymal transition (EMT) of alveolar epithelial cells influences development of pulmonary fibrosis, which is mediated by transforming growth factor β (TGF-β). Tumor necrosis factor α (TNF-α), an important proinflammatory cytokine in IPF, has been shown to enhance TGF-β-induced EMT. Nintedanib, a multiple tyrosine kinase inhibitor that is currently used to treat IPF, has been shown to suppress EMT in various cancer cell lines. However, the mechanism of EMT inhibition by nintedanib and its effect on TGF-β and TNF-α signaling pathways in alveolar epithelial cells have not been fully elucidated.MethodsA549 alveolar epithelial cells were stimulated with TGF-β2 and TNF-α, and the effects of nintedanib on global gene expression were evaluated using microarray analysis. Furthermore, Smad2/3 phosphorylation was assessed using western blotting.ResultsWe found that in A549 cells, TGF-β2 and TNF-α treatment induces EMT, which was inhibited by nintedanib. Gene ontology analysis showed that nintedanib significantly attenuates the gene expression of EMT-related cellular pathways and the TGF-β signaling pathway, but not in the TNF-α-mediated signaling pathway. Furthermore, hierarchical cluster analysis revealed that EMT-related genes were attenuated in nintedanib-treated cells. Additionally, nintedanib was found to markedly suppress phosphorylation of Smad2/3.ConclusionNintedanib inhibits EMT by mediating EMT-related gene expression and the TGF-β/Smad pathway in A549 alveolar epithelial cells.     

A modified GAP model for East-Asian populations with idiopathic pulmonary fibrosis

BackgroundThe easy-to-calculate gender, age, and lung physiology (GAP) model shows good predictive and discriminative performance in the prognosis of idiopathic pulmonary fibrosis (IPF). However, the GAP model was not effective in predicting the prognosis accurately in previous Japanese and Korean IPF cohort studies. Therefore, we developed a modified GAP model for the East-Asian populations by weighing the GAP variables. The validity of the modified GAP model was subsequently evaluated in East-Asian IPF patients.MethodsThe derivation cohort comprised 326 patients with IPF. Weights of the variables were adjusted on the basis of coefficients derived from Cox regression models. The total points were distributed to the three stages of the disease so that the number of patients included in each stage was appropriate. The validity of the modified model was analyzed in another Japanese cohort of 117 patients with IPF and a nationwide cohort of Korean patients with IPF.ResultsPredicted survival rates differed significantly in the derivation cohort using the modified GAP model for each stage of IPF (log-rank test: stage I vs. stage II, p < 0.001; stage II vs. stage III, p < 0.001). Model performance improved according to Harrell's C-index (at three years: 0.696 in the original GAP model to 0.738 in the modified model). The performance of the modified model was validated in the Japanese validation and Korean national cohorts.ConclusionsOur modification of the original GAP model showed improved performance in East-Asian IPF patient populations.     

Small cell lung cancer; recent advances of its biology and therapeutic perspective

Lung cancer is historically divided into two major categories: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). While the therapeutic efficacy of NSCLC has improved due to the development of molecular targeted therapy and immune checkpoint inhibitors (ICIs) treatment, there has been very slow progress in the therapeutic advances of SCLC. Since SCLC is a deadly disease with rapid progression and early metastasis and comprises approximately 10% of lung cancer cases, more attention should be given to the therapeutic strategy for SCLC. Most SCLC cases respond to cytotoxic drugs, cisplatin, and etoposide. The objective response rate to the standard regimen is reported to be approximately 70% that is sufficient as standard therapy. However, almost all tumors recur and become refractory to chemotherapy which is the most important problem of this deadly disease.Recently, for the first time in several decades, ICIs have changed the standard therapy for SCLC. It must be emphasized that although ICIs paved the new way for SCLC therapy, more precise and effective therapy for SCLC is desired. Unfortunately, precise molecular mechanisms of SCLC are yet to be understood. Recent elaborate studies on the cell biology of SCLC uncovered several important aspects of molecular mechanisms. Gene profiling of cancer cells can be done using modern technology like next-generation sequencing (NGS). In this minireview, we describe the advances of modern technology in SCLC research and consider future therapeutic strategies based on the molecular mechanisms of SCLC.     

Platythorax progresses with lung involvement in pleuroparenchymal fibroelastosis

BackgroundPatients diagnosed with pleuroparenchymal fibroelastosis (PPFE) exhibit unique clinical features, including upper lobe-dominant lung involvement and platythorax (or flattened thoracic cage). Although platythorax have been shown to be a sign of disease progression, the temporal relationship between the progression of platythorax and the extent of lung involvement has not been closely investigated.MethodsWe retrospectively investigated patients diagnosed with PPFE, who did not exhibit fibrotic lesions other than PPFE in the lower lobes. We estimated the fibrosis score, which is a visual score indicating the percentage of lung parenchyma occupied by the disease on computed tomography images selected every 2 cm from the lung apex to the lung base, and the flat chest index (the ratio of the anteroposterior diameter of the thoracic cage to the transverse diameter of the thoracic cage). Additionally, we investigated serial changes in the flat chest index and fibrosis score.ResultsA total of 29 patients were included in this study. The fibrosis score was found to be weakly and inversely correlated with forced vital capacity %predicted at the diagnosis (r = ?0.40, p = 0.038). Furthermore, the annual changes in the flat chest index and fibrosis score was found to be moderately and inversely correlated (r = ?0.663, p = 0.0037).ConclusionsThese results indicate that there is a causal relationship between the progression of fibroelastosis and that of platythorax in patients with PPFE.     

Serial 6-month change in forced vital capacity predicts subsequent decline and mortality in Japanese patients with newly diagnosed idiopathic pulmonary fibrosis

BackgroundThe clinical course of idiopathic pulmonary fibrosis (IPF) is characterized by a progressive decline in lung function; however, predicting changes in lung function is difficult. We sought to determine whether the prior 6-month trend in forced vital capacity (FVC) could predict mortality and the subsequent 6-month trend in FVC.MethodsWe retrospectively analyzed consecutive patients with newly diagnosed IPF who underwent serial pulmonary function tests. The immediate two years after the initial evaluation were divided into four terms of six months each and stratified on the basis of presence or absence of a ≥10% relative decline in FVC at six months (declined and stable groups, respectively).ResultsWe included 107 patients with %predicted FVC of 80.8% and %predicted diffusing capacity of the lung for carbon monoxide of 58.9%. In multivariate analysis, a decline in %predicted FVC in the initial six months was found to be an independent prognostic factor (hazard ratio 4.45, 95% confidence interval 2.62–7.56, p < 0.01). Among the 46 terms in which the FVC declined during the initial 1.5-year study period, a decline in FVC was exhibited in 23 (50.0%) of the subsequent terms. Among 231 terms in which FVC remained stable, a decline was observed in 32 (13.9%) of the subsequent terms (relative risk 3.61, p < 0.01). The frequency of FVC decline in each term was 16–27%. FVC was stable or declined in all four terms in 50.5% and 15.9% of cases, respectively.ConclusionsSix-month decline in FVC predicts subsequent FVC change and mortality in IPF patients in the era of antifibrotic agents.     

Clinical course and prognosis in survivors of acute exacerbations of idiopathic pulmonary fibrosis

BackgroundPatients with idiopathic pulmonary fibrosis (IPF) are at risk of acute exacerbations (AEs) that manifest as respiratory distress. However, the clinical course after AEs of IPF (AE-IPFs) has not been well described. Therefore, we aimed to elucidate the clinical course and prognosis in survivors of AE-IPFs.MethodsConsecutive patients with IPF who presented to our institution with their first AE-IPFs between January 2008 and December 2019 were included in this study. Data were retrospectively collected, and the clinical course, survival, and cause of death were further analyzed.ResultsNinety-seven patients were included in this retrospective study. Among them, 67 (69.1%) were discharged alive, with a median survival time after discharge of 1081 days. AE recurrence and pneumonia were the most common causes of death, each accounting for 22.2% of cases among survivors of AE-IPFs. AEs were the most frequent during the first 3 years after discharge, whereas pneumonia was more common thereafter.ConclusionsSurvivors of AE-IPFs have a relatively favorable long-term prognosis. Among the survivors of first AE-IPFs, AE recurrence and pneumonia were the most common causes of death after discharge. Therefore, preventing AE recurrence and lung infections is crucial for prolonging survival in survivors of AE-IPFs.     

Extent of pulmonary fibrosis on high-resolution computed tomography is a prognostic factor in patients with pleuroparenchymal fibroelastosis

BackgroundSeveral prognostic factors for pleuroparenchymal fibroelastosis (PPFE) have recently been reported. However, detailed high-resolution computed tomography (HRCT) findings have not yet been evaluated as prognostic factors. This study retrospectively investigated whether HRCT findings are prognostic factors in patients with PPFE compared to those with idiopathic pulmonary fibrosis (IPF).MethodsPatients with PPFE and IPF diagnosed at our hospital between January 2008 and December 2016 were enrolled. Clinical and HRCT characteristics were obtained. In addition to our patients, we also analyzed data of PPFE patients whose cause of death had been identified in previous studies.ResultsWe enrolled 15 patients with PPFE and 75 patients with IPF. Consolidation and maximum pleural thickening were significantly higher in patients with PPFE than in those with IPF (both P < .001). Fibrosis score, honeycomb area, and traction bronchiectasis were not significantly different between these patient groups but were significant prognostic factors in patients with PPFE in univariate analysis (P = .021, P = .017, and P = .014, respectively). The proportions of deaths by acute exacerbation or lung cancer were significantly lower in patients with PPFE than in those with IPF (P < .001 and P = .001, respectively), whereas death by respiratory failure was significantly more frequent in PPFE patients (P < .001).ConclusionsHRCT findings, such as fibrosis score, honeycomb area, and traction bronchiectasis, were independent prognostic factors in patients with PPFE. Respiratory failure, but not acute exacerbation and lung cancer, was the main cause of death in patients with PPFE.     

Predictors of acute exacerbation in biopsy-proven idiopathic pulmonary fibrosis

BackgroundAcute exacerbation (AE) is a major cause of death in patients with idiopathic pulmonary fibrosis (IPF). Current evidence on AE-IPF has been largely based on clinical, rather than pathological, analyses.MethodsWe investigated AE incidence and its predictors using clinical, radiological, and pathological data of patients diagnosed with IPF by multi-disciplinary discussion.This study, a secondary analysis of previous research, included 155 patients with IPF who underwent surgical lung biopsy (SLB). Cumulative AE incidence was evaluated by the Kaplan–Meier method. Predictors of AE-IPF were analyzed with a Fine-Gray sub-distribution hazard model. Sub-analysis was performed using propensity score-matching analysis.ResultsIn this cohort, the median age of the patients was 66 years and the median percent-predicted forced vital capacity was 82.8%. The cumulative AE incidence rates at 30 days and one year post SLB were 1.9% and 7.6%, respectively. On multivariable analysis, a lower percent-predicted diffusing capacity of the lung for carbon monoxide (%DL_CO) (hazard ratio 0.98 per 1% increase, P = 0.02) and fibroblastic foci (FF)-present (vs. absent; hazard ratio 3.01, P = 0.04) were independently associated with a higher incidence of AE. The propensity score-matching analysis with adjustment for age, gender, and %DL_CO revealed that the cumulative AE incidence rate was significantly higher in the FF-present subgroup than in the FF-absent subgroup (1-year incidence rate, 10.5% vs. 0%, respectively; P = 0.04 by Gray's test).ConclusionsFF and %DL_CO were independent predictors of AE in patients with biopsy-proven IPF. FF may be associated with the pathogenesis of AE-IPF.     

Serum cytokine changes induced by direct hemoperfusion with polymyxin B-immobilized fiber in patients with acute respiratory failure

BackgroundPolymyxin B-immobilized Fiber therapy (PMX-DHP) may improve the prognosis of patients with rapidly progressive interstitial lung diseases (ILDs). However, the mechanisms by which PMX-DHP ameliorates oxygenation are unclear. The present study aimed to clarify the changes in serum cytokine concentrations during PMX-DHP with steroid pulse therapy.MethodsPatients with acute respiratory failure (ARF) and rapidly progressive ILDs, acute exacerbation of idiopathic pulmonary fibrosis (IPF), or acute respiratory distress syndrome (ARDS), and treated with PMX-DHP were assessed, including patients with IPF. The serum concentrations of 38 cytokines were compared between the ARF and IPF groups before treatment. In the ARF group, cytokine levels were compared before, immediately after PMX-DHP, and the day after termination of steroid pulse therapy.ResultsFourteen ARF and eight IPF patients were enrolled. A comparison of the cytokine levels before treatment initiation revealed that EGF, GRO, IL-10, MDC, IL-12p70, IL-15, sCD40L, IL-7, IP-10, MCP-1, and MIP-1β were significantly different between the two groups. In the ARF group treated with PMX-DHP, the concentrations of MDC, IP-10, and TNF-α continuously decreased during treatment (P < 0.01). Further, the cytokine levels of GRO, IL-10, IL-1Ra, IL-5, IL-6, and MCP-1 decreased after the entire treatment period, with no change observed during the steroid-only period (P < 0.01, except GRO and MCP-1). Although PMX-DHP significantly reduced eotaxin and GM-CSF serum levels (P < 0.01 and P < 0.05), these levels did not change after treatment.ConclusionsPMX-DHP combined with steroid pulse therapy might reduce GRO, IL-10, IL-1Ra, IL-5, IL-6, and MCP-1 levels in ARF, contributing to better oxygenation in the disorder.     

Takayasu Arteritis: JACC Focus Seminar 3/4

Takayasu arteritis is a rare idiopathic large-vessel vasculitis that typically affects young women. An early "prepulseless" stage is often missed, associated with nonspecific constitutional symptoms (fever, malaise, and weight loss) and elevated inflammatory markers. Unchecked disease progression leads to the "pulseless" stage, manifest clinically by missing pulses, vascular tenderness, and ischemic symptoms (limb claudication, dizziness, angina, and renovascular hypertension), and is characterized pathologically by arterial wall thickening and stenotic/occlusive lesions or aneurysm formation. Vascular complications (stroke, blindness, heart failure, and aneurysm rupture) could follow unless disease progression is halted by immunosuppressive therapy and critical lesions are palliated by timely endovascular therapy or open surgery. Early diagnosis, effective therapy, and lifelong surveillance for disease activity relapses and vascular disease progression are critical to successful long-term outcomes. The outlook for patients has improved significantly in recent years with the establishment of diagnostic and classification criteria, better investigational modalities, and more effective medical and invasive therapy.     

Incidence and changes in treatment of acute exacerbation of idiopathic pulmonary fibrosis in Japan: A claims-based retrospective study

BackgroundAcute exacerbation is an essential prognostic factor in idiopathic pulmonary fibrosis (IPF) and is the leading cause of death in Japanese patients with IPF. Its epidemiology, treatment status, and effect on IPF progression have been insufficiently investigated. We examined the incidence of acute exacerbation and treatment status before and after the onset of acute exacerbation in Japanese patients with IPF to provide basic information for treatment strategies.MethodsA Japanese claims database (April 2008–March 2019) from acute-care hospitals was analyzed. Incidence of acute exacerbation, time to the next event, and percentages of patients who received each treatment by the year before and after the onset of acute exacerbation were examined in patients diagnosed with IPF at least once. Acute exacerbation was defined according to the use of steroid pulse therapy.ResultsWe identified 9961 patients with IPF and 2629 acute exacerbations (average age at the time of acute exacerbation: 74.8 years, percentage of men: 79%). The annual incidence of acute exacerbation was approximately 10% between 2010 and 2018. The time to the next acute exacerbation shortened with increasing number of these events. The percentage of patients receiving antifibrotic drugs remained constant (30%–40%) throughout the period. The percentages of patients receiving steroid therapy, immunosuppressive drugs, and oxygen therapy increased after the onset of acute exacerbation compared with before the onset.ConclusionsThe annual incidence of acute exacerbation was approximately 10% in recent years. It is suggested that acute exacerbation worsens respiratory function in patients with IPF.     

Role of serum surfactant protein-D as a prognostic predictor in fibrotic hypersensitivity pneumonitis

BackgroundSerum Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) are candidate diagnostic and activity markers for fibrotic hypersensitivity pneumonitis (HP), although their correlation with prognosis remains unclear. We aimed to evaluate the prognostic usefulness of serum KL-6 and SP-D in patients with fibrotic HP.MethodsThis was a retrospective medical record review of 185 patients with fibrotic HP at a single center from 2005 to 2019. The baseline and minimum serum KL-6 and SP-D levels over two years were recorded. The contribution of KL-6 and SP-D levels to the incidence of progressive fibrosing interstitial lung disease (PF-ILD) and mortality were evaluated using multivariate analysis.ResultsThe respective baseline and minimum levels were 1441 and 808 U/ml for KL-6 and 254 and 132 ng/mL for SP-D. A high minimum SP-D level was significantly associated with a high incidence of PF-ILD by logistic regression, independent of baseline forced vital capacity and honeycombing. Similarly, a high minimum SP-D level was significantly associated with high mortality by Cox proportional hazard model analysis. The stratified minimum SP-D levels of <100, 100–200, and >200 revealed significantly distinct groups in the entire cohort, with PF-ILD incidence rates of 28%, 48%, and 74% and median survival times of 120, 74, and 45 months, respectively.ConclusionsHigh minimum SP-D levels over two years were correlated with an unfavorable prognosis in our cohort. Patient with consistently high SP-D levels during the clinical course may have a poor prognosis and be a candidate for early treatment intensification.     

Mechanistic Biomarkers Informative of Both Cancer and Cardiovascular Disease: JACC State-of-the-Art Review

Cardiovascular disease (CVD) and cancer are leading causes of morbidity and mortality worldwide. Although conventionally managed as separate disease processes, recent research has lent insight into compelling commonalities between CVD and cancer, including shared mechanisms for disease development and progression. In this review, the authors discuss several pathophysiological processes common to both CVD and cancer, such as inflammation, resistance to cell death, cellular proliferation, neurohormonal stress, angiogenesis, and genomic instability, in an effort to understand common mechanisms of both disease states. In particular, the authors highlight key circulating and genomic biomarkers associated with each of these processes, as well as their associations with risk and prognosis in both cancer and CVD. The purpose of this state-of-the-art review is to further our understanding of the potential mechanisms underlying cancer and CVD by contextualizing pathways and biomarkers common to both diseases.