Syndecan-4 is a transmembrane heparan sulfate proteoglycan expressed in a variety of cells, and its heparan sulfate glycosaminoglycan side chains bind to several proteins exhibiting various biological roles. The authors have previously demonstrated syndecan-4′s critical roles in pulmonary inflammation. In the current study, however, its role in pulmonary fibrosis was evaluated. Wild-type and syndecan-4-deficient mice were injected with bleomycin, and several parameters of inflammation and fibrosis were analyzed. The mRNA expression of collagen and α-smooth muscle action (α-SMA) in lung tissues, as well as the histopathological lung fibrosis score and collagen content in lung tissues, were significantly higher in the syndecan-4-deficient mice. However, the total cell count and cell differentiation in bronchoalveolar lavage fluid were equivalent between the wild-type and syndecan-4-deficient mice. Although there was no difference in the TGF-β expression in lung tissues between the wild-type and syndecan-4-deficient mice, significantly more activation of Smad3 in lung tissues was observed in the syndecan-4-deficient mice compared to the wild-type mice. Furthermore, in the in vitro experiments using lung fibroblasts, the co-incubation of syndecan-4 significantly inhibited TGF-β-induced Smad3 activation, collagen and α-SMA upregulation. Moreover, syndecan-4 knock-down by siRNA increased TGF-β-induced Smad3 activation and upregulated collagen and α-SMA expression. These findings showed that syndecan-4 inhibits the development of pulmonary fibrosis, at least in part, through attenuating TGF-β signaling.
Midkine is a low‐molecular‐weight heparin‐binding protein that is strongly expressed mainly in the midgestation period and has various physiological activities such as in development and cell migration. Midkine has been reported to be strongly expressed in cancer cells and in inflammation and repair processes, and to be involved in the pathogenesis of various diseases. However, its role in the lung is poorly understood. In this study, we analyzed the clinical characteristics of idiopathic pulmonary fibrosis patients in relation to midkine expression and used a mouse bleomycin‐induced pulmonary fibrosis model to investigate the role of midkine in pulmonary fibrosis. In the idiopathic pulmonary fibrosis patients, the serum midkine level was significantly higher than in healthy subjects, and midkine levels in the serum and bronchoalveolar lavage (BAL) fluid correlated positively with the percentage of inflammatory cells in the BAL fluid. In wild‐type mice, intratracheal bleomycin administration increased midkine expression in lung tissue. Additionally, compared with wild‐type mice, midkine‐deficient mice showed low expression of both collagen and α‐smooth muscle actin, as well as a low value for the pathological lung fibrosis score after bleomycin administration. Furthermore, the total cell count and lymphocyte percentage in the BAL fluid, as well as TNF‐α and transforming growth factor‐β expression in lung tissue, were significantly lower in the midkine‐deficient mice compared with wild‐type mice. These results suggest that midkine is involved in the development of pulmonary fibrosis by regulating inflammatory cell migration into the lung, and TNF‐α and transforming growth factor‐β expression.
Background: Decorin is a small leucine-rich repeat proteoglycan that plays a critical role in collagen fibrillogenesis, and regulates inflammation, wound healing and angiogenesis. In idiopathic pulmonary fibrosis (IPF), decorin is expressed in fibrotic lesions; furthermore, intratracheal gene transfer of decorin has been demonstrated to inhibit bleomycin-induced pulmonary fibrosis. Although these results suggest the critical role of decorin in pulmonary fibrosis, the role of decorin in the acute exacerbation of idiopathic interstitial pneumonia (AE-IIP) has not been clarified in detail. Thus, the goal of this study was to determine the role of decorin in AE-IIP. Methods: We retrospectively analyzed AE-IIP patients who had been admitted to our hospital. First, serum decorin levels were compared among patients with AE-IIP, patients with stable idiopathic interstitial pneumonia (SD-IIP), and healthy subjects. Next, the relationship between serum decorin levels and clinical parameters was analyzed in AE-IIP patients. Finally, the association between serum decorin levels and prognosis was evaluated in AE-IIP patients. IIP was divided into IPF and non-IPF, according to the published guidelines. Results: The serum decorin levels of AE-IIP patients were significantly lower than those of both healthy subjects and SD-IIP patients. Serum decorin levels were not related with the clinical parameters and prognosis, when all IIP patients were analyzed. In IPF patients, serum decorin levels had a significant correlation with oxygenation, and IPF patients with low serum decorin levels had a significantly higher survival rate than those with high serum decorin levels. Conclusions: Serum decorin levels are a potential prognostic biomarker in AE-IPF.
BackgroundPatients with idiopathic interstitial pneumonia can experience acute respiratory worsening, also known as acute exacerbation, with a large deterioration on prognosis. The precise mechanism remains unclear; however, syndecan-4 may be involved. Syndecan-4, a transmembrane heparan sulfate proteoglycan expressed in a variety of cells (e.g., epithelial cells, macrophages, fibroblasts, etc.), performs various biological roles by binding to several proteins through its heparan sulfate glycosaminoglycan side chains. The goal of this study was to clarify the role of syndecan-4 in acute exacerbation of idiopathic interstitial pneumonia.MethodsPatients with idiopathic interstitial pneumonia who had been sequentially admitted to our hospital due to acute exacerbation were retrospectively analyzed. First, serum syndecan-4 levels in the acute exacerbation and clinically stable phases were compared. Second, the relationship between serum syndecan-4 levels and clinical parameters was analyzed. Third, the relationship between serum syndecan-4 levels and prognosis was evaluated.ResultsSerum syndecan-4 levels were significantly lower in patients with acute exacerbation of idiopathic interstitial pneumonia than in patients in the clinically stable phase. Serum syndecan-4 levels also showed a significant positive correlation with white blood cell count and a weak positive tendency with KL-6 and baseline %VC. Prognosis was significantly worse in patients with idiopathic interstitial pneumonia with high baseline serum syndecan-4 levels than with low baseline levels. Multiple logistic analysis indicated baseline serum syndecan-4 level as the only prognostic predictor following acute exacerbation.ConclusionsBaseline serum syndecan-4 is a possible prognostic biomarker after the onset of acute exacerbation of idiopathic interstitial pneumonia.
BackgroundIdiopathic interstitial pneumonia (IIP) is characterized by an increased rate of extracellular matrix (ECM) remodeling resulting in fibrosis. Acute exacerbations of IIP represent periods of increased disease activity, thus we hypothesized that ECM remodeling was altered during acute exacerbations and investigated this by serological neo-epitope biomarkers.MethodsPatients who were sequentially admitted to the hospital with acute exacerbations of IIP were retrospectively analyzed for ECM remodeling at time of exacerbation (AE-IIP) and at clinical stability (S-IIP). Biomarkers released by matrix metalloproteinase-mediated degradation of collagen type I (C1M), III (C3M), IV (C4M), and VI (C6M), elastin (ELM7), versican (VCANM), biglycan (BGM), and C-reactive protein (CRPM) were assessed in serum by competitive ELISAs utilizing neo-epitope specific monoclonal antibodies.ResultsSixty-eight patients at AE-IIP and 29 at S-IIP were included in this retrospective analysis. Of these, 28 and 11 patients, respectively, had idiopathic pulmonary fibrosis. At AE-IIP, serum levels of C4M (p = 0.002) and C6M (p = 0.024) were increased as compared with S-IIP, while ELM7 (p = 0.024) and VCANM (p < 0.0001) were decreased. Lower VCANM levels at AE-IIP were associated with increased risk of mortality (HR 0.64 [95% CI 0.43–0.94], p = 0.022).ConclusionsThe ECM remodeling profile was significantly altered during acute exacerbations of IIP, and a biomarker of versican degradation was related to mortality outcome. These results indicate that biomarkers of ECM remodeling may be useful in the non-invasive evaluation of acute exacerbations of IIP. Especially versican degradation, as measured serologically by VCANM, may have prognostic potential and help guide treatment for acute exacerbations.
Since COPD is a heterogeneous disease, a specific anti-inflammatory therapy for this disease has not been established yet. Oxidative stress is recognized as a major predisposing factor to COPD related inflammatory responses, resulting in pathological features of small airway fibrosis and emphysema. However, little is known about effects of oxidative stress on airway smooth muscle. Cigarette smoke increases intracellular Ca2+ concentration and enhances response to muscarinic agonists in human airway smooth muscle. Cigarette smoke also enhances proliferation of these cells with altered mitochondrial protein. Hydrogen peroxide and 8-isoprostans are increased in the exhaled breath condensate in COPD. These endogenous oxidants cause contraction of tracheal smooth muscle with Ca2+ dynamics through Ca2+ channels and with Ca2+ sensitization through Rho-kinase. TNF-α and growth factors potentiate proliferation of these cells by synthesis of ROS. Oxidative stress can alter the function of airway smooth muscle through Ca2+ signaling. These phenotype changes are associated with manifestations (dyspnea, wheezing) and pathophysiology (airflow limitation, airway remodeling, airway hyperresponsiveness). Therefore, airway smooth muscle is a therapeutic target against COPD; oxidative stress should be included in treatable traits for COPD to advance precision medicine. Research into Ca2+ signaling related to ROS may contribute to the development of a novel agent for COPD.
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