Clinical Utility of YKL-40 in Polymyositis/dermatomyositis-associated Interstitial Lung Disease

2017 ◽  
Vol 44 (9) ◽  
pp. 1394-1401 ◽  
Author(s):  
Hironao Hozumi ◽  
Tomoyuki Fujisawa ◽  
Noriyuki Enomoto ◽  
Ran Nakashima ◽  
Yasunori Enomoto ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Vital Capacity ◽  
Biological Activities ◽  
Hazard Analysis ◽  
Alveolar Epithelial Cells ◽  
Arterial Oxygen ◽  
Healthy Controls ◽  
Alveolar Epithelial ◽  
Disease Prognosis

Objective.Interstitial lung disease (ILD) is involved in polymyositis/dermatomyositis (PM/DM), a disease associated with poor prognoses. Chitinase-3-like-1 protein (YKL-40) has pleiotropic biological activities involved in inflammation, cell proliferation, and tissue remodeling; however, the clinical application of YKL-40 remains limited. We investigated the clinical significance of YKL-40 in PM/DM–ILD.Methods.Sixty-nine consecutive patients with PM/DM–ILD and 34 healthy controls were analyzed. We measured baseline and followup serum YKL-40 using an ELISA, evaluated the association of YKL-40 with clinical variables and survival, and examined YKL-40 expression in lung specimens from patients with PM/DM–ILD using immunohistochemistry.Results.Serum YKL-40 levels were significantly greater in patients with PM/DM–ILD compared with healthy controls (p < 0.0001). Serum YKL-40 was correlated with arterial oxygen pressure (r = –0.40, p < 0.001) and percent-predicted DLCO (r = –0.41, p = 0.01) in patients with PM/DM–ILD. Multivariate Cox hazard analysis demonstrated that higher serum YKL-40 and lower percent-predicted forced vital capacity were independently associated with a poor prognosis. Immunohistochemistry analysis demonstrated that YKL-40 expression was enhanced in aggregated intraalveolar macrophages and hyperproliferative alveolar epithelial cells in patients with PM/DM–ILD.Conclusion.YKL-40 is a promising biomarker for evaluating PM/DM–ILD activity/severity and predicting disease prognosis. Insights into YKL-40 might help elucidate the pathogenesis of PM/DM–ILD.

scholarly journals Blocking TGFβvia Inhibition of theαvβ6 Integrin: A Possible Therapy for Systemic Sclerosis Interstitial Lung Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-7 ◽  
Author(s):  
Tamiko R. Katsumoto ◽  
Shelia M. Violette ◽  
Dean Sheppard
Keyword(s):  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Significant Proportion ◽  
Alveolar Epithelial Cells ◽  
Lung Epithelium ◽  
Alveolar Epithelial ◽  
Low Levels ◽  
Fibrotic Lung Diseases

Interstitial lung disease (ILD) is a commonly encountered complication of systemic sclerosis (SSc) and accounts for a significant proportion of SSc-associated morbidity and mortality. Its pathogenesis remains poorly understood, and therapies that treat SSc ILD are suboptimal, at best. SSc ILD pathogenesis may share some common mechanisms with other fibrotic lung diseases, in which dysregulation of lung epithelium can contribute to pathologic fibrosis via recruitment or in situ generation and activation of fibroblasts. TGFβ, a master regulator of fibrosis, is tightly regulated in the lung by the integrinαvβ6, which is expressed at low levels on healthy alveolar epithelial cells but is highly induced in the setting of lung injury or fibrosis. Here we discuss the biology ofαvβ6 and present this integrin as a potentially attractive target for inhibition in the setting of SSc ILD.

scholarly journals Clinical Significance of Serum Chitotriosidase Level in Anti-MDA5 Antibody–positive Dermatomyositis-associated Interstitial Lung Disease

2019 ◽  
Vol 46 (8) ◽  
pp. 935-942 ◽  
Author(s):  
Tomoyuki Fujisawa ◽  
Hironao Hozumi ◽  
Hideki Yasui ◽  
Yuzo Suzuki ◽  
Masato Karayama ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Poor Prognosis ◽  
Hazard Analysis ◽  
Characteristic Curve ◽  
Trna Synthetase ◽  
Healthy Controls ◽  
Laboratory Findings ◽  
Median Serum ◽  
Potential Biomarker

Objective.To assess prognostic factors of antimelanoma differentiation-associated gene 5 antibody (anti-MDA5)–positive dermatomyositis/clinically amyopathic DM–associated interstitial lung disease (DM/CADM-ILD) and evaluate the use of serum chitotriosidase, a marker for macrophage activation, as a potential biomarker in anti-MDA5-positive DM/CADM-ILD.Methods.This retrospective study included 30 patients with anti-MDA5–positive DM/CADM-ILD. The clinical characteristics and laboratory findings at the time of diagnosis were analyzed. Serum chitotriosidase levels were measured in the 30 patients, in 21 healthy controls, and in 25 patients with anti-aminoacyl-tRNA synthetase antibody–positive (anti-ARS)-polymyositis (PM)/DM/CADM-ILD, and the potential of serum chitotriosidase as a prognostic biomarker in anti-MDA5–positive DM/CADM-ILD was assessed.Results.The median serum chitotriosidase level in patients with anti-MDA5–positive DM/CADM-ILD was 17.3 ng/ml, which was higher than that in healthy controls and anti-ARS–PM/DM/CADM-ILD (2.0 and 8.9 ng/ml, respectively). Of the 30 patients, 10 died of respiratory failure associated with DM/CADM-ILD deterioration. Cox hazard analysis demonstrated that higher serum chitotriosidase level and lower PaO2 value were significant predictors of a poor outcome. Using optimal cutoff levels according to receiver-operating characteristic curve analyses, chitotriosidase ≥ 23.5 ng/ml, ferritin ≥ 800 ng/ml, and Krebs von den Lungen–6 ≥ 720 U/ml were significantly associated with a poor prognosis. Serum chitotriosidase levels were negatively correlated with PaO2 and percentage predicted forced vital capacity. The survival rate was significantly poorer in patients with high chitotriosidase levels (≥ 23.5 ng/ml) than in those with low chitotriosidase levels (< 23.5 ng/ml).Conclusion.Serum chitotriosidase may be a potential biomarker for predicting a poor prognosis in patients with anti-MDA5–positive DM/CADM-ILD.

scholarly journals Intrapulmonary Autoantibodies to HSP72 Are Associated with Improved Outcomes in IPF

2019 ◽  
Vol 2019 ◽  
pp. 1-11
Author(s):  
Ross Mills ◽  
Abhinav Mathur ◽  
Lisa M. Nicol ◽  
Jeremy J. Walker ◽  
Alexander A. Przybylski ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Alveolar Epithelial Cells ◽  
Adaptive Responses ◽  
Disease Pathogenesis ◽  
Alveolar Epithelial ◽  
Improved Outcomes ◽  
Shock Proteins ◽  
The Relationship

Rationale. Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic interstitial lung disease, with high mortality. Currently, the aetiology and the pathology of IPF are poorly understood, with both innate and adaptive responses previously being implicated in the disease pathogenesis. Heat shock proteins (Hsp) and antibodies to Hsp in patients with IPF have been suggested as therapeutic targets and prognostic biomarkers, respectively. We aimed to study the relationship between the expression of Hsp72 and anti-Hsp72 antibodies in the BAL fluid and serum Aw disease progression in patients with IPF.Methods. A novel indirect ELISA to measure anti-Hsp72 IgG was developed and together with commercially available ELISAs used to detect Hsp72 IgG, Hsp72 IgGAM, and Hsp72 antigen, in the serum and BALf of a cohort of IPF (n=107) and other interstitial lung disease (ILD) patients (n=66). Immunohistochemistry was used to detect Hsp72 in lung tissue. The cytokine expression from monocyte-derived macrophages was measured by ELISA.Results. Anti-Hsp72 IgG was detectable in the serum and BALf of IPF (n=107) and other ILDs (n=66). Total immunoglobulin concentrations in the BALf showed an excessive adaptive response in IPF compared to other ILDs and healthy controls (p=0.026). Immunohistochemistry detection of C4d and Hsp72 showed that these antibodies may be targeting high expressing Hsp72 type II alveolar epithelial cells. However, detection of anti-Hsp72 antibodies in the BALf revealed that increasing concentrations were associated with improved patient survival (adjusted HR 0.62, 95% CI 0.45-0.85;p=0.003).In vitroexperiments demonstrate that anti-Hsp72 complexes stimulate macrophages to secrete CXCL8 and CCL18.Conclusion. Our results indicate that intrapulmonary anti-Hsp72 antibodies are associated with improved outcomes in IPF. These may represent natural autoantibodies, and anti-Hsp72 IgM and IgA may provide a beneficial role in disease pathogenesis, though the mechanism of action for this has yet to be determined.

Chest wall muscle atrophy as a contributory factor for forced vital capacity decline in systemic sclerosis-associated interstitial lung disease

Rheumatology ◽  
2020 ◽  
Vol 60 (1) ◽  
pp. 250-255
Author(s):  
Takashi Nawata ◽  
Yuichiro Shirai ◽  
Mikito Suzuki ◽  
Masataka Kuwana
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Chest Wall ◽  
Muscle Atrophy ◽  
Forced Vital Capacity ◽  
Vital Capacity ◽  
Pulmonary Function Tests ◽  
Potential Contribution ◽  
Muscle Area ◽  
Chest Wall Muscle

Abstract Objective To investigate the potential contribution of accessory respiratory muscle atrophy to the decline of forced vital capacity (FVC) in patients with SSc-associated interstitial lung disease (ILD). Methods This single-centre, retrospective study enrolled 36 patients with SSc-ILD who underwent serial pulmonary function tests and chest high-resolution CT (HRCT) simultaneously at an interval of 1–3 years. The total extent of ILD and chest wall muscle area at the level of the ninth thoracic vertebra on CT images were evaluated by two independent evaluators blinded to the patient information. Changes in the FVC, ILD extent, and chest wall muscle area between the two measurements were assessed in terms of their correlations. Multiple regression analysis was conducted to identify the independent contributors to FVC decline. Results Interval changes in FVC and total ILD extent were variable among patients, whereas chest wall muscle area decreased significantly with time (P=0.0008). The FVC change was negatively correlated with the change in ILD extent (r=−0.48, P=0.003) and was positively correlated with the change in the chest wall muscle area (r = 0.53, P=0.001). Multivariate analysis revealed that changes in total ILD extent and chest wall muscle area were independent contributors to FVC decline. Conclusion In patients with SSc-ILD, FVC decline is attributable not only to the progression of ILD but also to the atrophy of accessory respiratory muscles. Our findings call attention to the interpretation of FVC changes in patients with SSc-ILD.

scholarly journals Patient-specific iPSCs carrying an SFTPC mutation reveal the intrinsic alveolar epithelial dysfunction at the inception of interstitial lung disease

2020 ◽  
Author(s):  
Konstantinos-Dionysios Alysandratos ◽  
Scott J. Russo ◽  
Anton Petcherski ◽  
Evan P. Taddeo ◽  
Rebeca Acín-Pérez ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Disease Onset ◽  
Metabolic Reprogramming ◽  
Patient Specific ◽  
Autophagic Flux ◽  
Alveolar Epithelial ◽  
Epithelial Dysfunction

SummaryThe incompletely understood pathogenesis of pulmonary fibrosis (PF) and lack of reliable preclinical disease models have limited development of effective therapies. An emerging literature now implicates alveolar epithelial type 2 cell (AEC2) dysfunction as an initiating pathogenic event in the onset of a variety of PF syndromes, including adult idiopathic pulmonary fibrosis (IPF) and childhood interstitial lung disease (chILD). However, inability to access primary AEC2s from patients, particularly at early disease stages, has impeded identification of disease-initiating mechanisms. Here we present an in vitro reductionist model system that permits investigation of epithelial-intrinsic events that lead to AEC2 dysfunction over time using patient-derived cells that carry a disease-associated variant, SFTPCI73T, known to be expressed solely in AEC2s. After generating patient-specific induced pluripotent stem cells (iPSCs) and engineering their gene-edited (corrected) counterparts, we employ directed differentiation to produce pure populations of syngeneic corrected and mutant AEC2s, which we expand >1015 fold in vitro, providing a renewable source of cells for modeling disease onset. We find that mutant iPSC-derived AEC2s (iAEC2s) accumulate large amounts of misprocessed pro-SFTPC protein which mistrafficks to the plasma membrane, similar to changes observed in vivo in the donor patient’s AEC2s. These changes result in marked reduction in AEC2 progenitor capacity and several downstream perturbations in AEC2 proteostatic and bioenergetic programs, including a late block in autophagic flux, accumulation of dysfunctional mitochondria with consequent time-dependent metabolic reprograming from oxidative phosphorylation to glycolysis, and activation of an NF-κB dependent inflammatory response. Treatment of SFTPCI73T expressing iAEC2s with hydroxychloroquine, a medication commonly prescribed to these patients, results in aggravation of autophagy perturbations and metabolic reprogramming. Thus, iAEC2s provide a patientspecific preclinical platform for modeling the intrinsic epithelial dysfunction associated with the inception of interstitial lung disease.

scholarly journals Increased levels of VCAM-1 in sera and VLA-4 expression on neutrophils in dermatomyositis with interstitial lung disease

2020 ◽  
Author(s):  
Meiyi Lin ◽  
Xudong Liu ◽  
Chunshu Yang ◽  
Shan Zhao ◽  
Bailing Tian ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Diffuse Alveolar Damage ◽  
Total Serum ◽  
Enzyme Linked Immunosorbent Assay ◽  
Healthy Controls ◽  
High Resolution Computed Tomography ◽  
Peripheral Blood Neutrophil ◽  
Late Antigen ◽  
And Gender

Abstract Background: Vascular cell adhesion molecule-1(VCAM-1) and its ligand very late antigen (VLA-4) play important roles in many autoimmune diseases. Our study aimed to investigate serum VCAM-1 level and VLA-4 expression on peripheral blood neutrophil surface in patients with dermatomyositis (DM), especially focusing on patients with interstitial lung disease(ILD). Methods: Blood specimens of 30 patients with DM and 30 healthy controls matched for age and gender were recruited. Total serum VCAM-1 level was measured using commercial enzyme-linked immunosorbent assay (ELISA) and the percentages of VLA-4 expression on the surface of neutrophils were analyzed by flow cytometry. We divided patients into subgroups according to whether they had ILD and whether they exhibited diffuse alveolar damage (DAD) via high-resolution computed tomography (HRCT).Results: Serum VCAM-1 levels were increased in DM patients compared with healthy controls (p<0.001). Patients with DM-ILD had higher serum VCAM-1 levels than those with none-ILD (p=0.015). The VCAM-1 levels were significantly increased in the DM-DAD group compared to the none-DAD group (p=0.002). The percentages of VLA-4 expression on neutrophils surface in DM patients were significantly elevated than that in healthy controls (p<0.001). The percentage of VLA-4 expression on neutrophils in DM patients with ILD were higher than none-ILD group(p=0.013). In the patients with ILD, DAD group had higher percentage of VLA-4 expression on neutrophils than none-DAD group (p=0.008).Conclusions: Our findings indicated that serum VCAM-1 level could be used as a potential serological biomarker for DM-ILD.

scholarly journals Diagnosis and management of interstitial lung disease of systemic sclerosis in challenging health conditions

2019 ◽  
pp. 18-20
Author(s):  
Daniel Rivas-Vargas
Keyword(s):  
Systemic Sclerosis ◽  
Interstitial Lung Disease ◽  
Lung Disease ◽  
Vital Capacity ◽  
Screening Method ◽  
Skin Fibrosis ◽  
Number Of Patients ◽  
History Of ◽  
Salt And Pepper

A 51-year-old woman presented with swelling in both hands and a 3-months history of triphasic Raynaud phenomenon. She denied cough and dyspnea. The physical examination was notable for swollen hands, facial telangiectasia and salt and pepper lesions. She had no skin fibrosis. The determination of antinuclear antibodies and antitopoisomerase were positive. A spirometry demonstrated a forced vital capacity of 86% of the predicted. High resolution chest computed tomography revealed bilateral, basal and subpleural ground glass opacities. These findings were consistent with the diagnosis of Scleroderma-Related Interstitial Lung Disease. Moreover, due to the absence of skin fibrosis, a diagnosis of systemic sclerosis sine scleroderma was made. Infusions of endovenous cyclophosphamide were indicated at 4-week intervals, followed by oral azathioprine. This case showed that using PFT as the single screening method for SSc-ILD may cause clinicians to miss a significant number of patients and that the absence of pulmonary symptoms does not exclude lung disease in patients with normal FVC.

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