Upregulation of Fas-signalling molecules in lung epithelial cells from patients with idiopathic pulmonary fibrosis

Maeyama, Takashige; Kuwano, Kazuyoshi; Kawasaki, Masayuki; Kunitake, Ritsuko; Hagimoto, Naoki; Matsuba, Tokuji; Yoshimi, Michihiro; Inoshima, Ichiro; Yoshida, Koichiro; Hara, Nobuyuki

doi:10.1183/09031936.01.17201800

Cited by 60 publications

(53 citation statements)

References 21 publications

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“…Positive signals for caspase-3 and -8 were predominantly detected in bronchiolar and alveolar epithelial cells in lung tissues from patients with usual interstitial pneumonia (UIP) and nonspecific interstitial pneumonia (NSIP) as we previously demonstrated (Maeyama et al, 2001). Positive signals for caspase-9 were predominantly detected in bronchiolar and alveolar epithelial cells in UIP and NSIP (Fig.…”

Section: Immunohistochemistrymentioning

confidence: 82%

“…Although there are various initiating factors or causes, the terminal stages are characterized by proliferation and progressive accumulation of connective tissue replacing normal functional parenchyma. We previously demonstrated that the Fas-Fas ligand (FasL) pathway was up-regulated in IIP and may be associated with the damage and apoptosis of lung epithelial cells through FADD and caspase-8 activation (Kuwano et al, 1999;Maeyama et al, 2001). We also demonstrated that there was DNA damage or apoptosis accompanied by an up-regulation of p53 in lung epithelial cells from patients with IIP (Kuwano et al, 1996).…”

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confidence: 99%

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Mitochondria-Mediated Apoptosis of Lung Epithelial Cells in Idiopathic Interstitial Pneumonias

Kuwano

Hagimoto

Maeyama

et al. 2002

Laboratory Investigation

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SUMMARY:We previously demonstrated that the up-regulation of p53, Fas, and DNA damage are present in lung epithelial cells from patients with idiopathic interstitial pneumonias (IIP). Fas ligation induces apoptosis of lung epithelial cells predominantly through the direct activation of the caspase cascade via caspase-8 activation, whereas the up-regulation of p53 and other cellular stresses can induce mitochondria-mediated apoptosis. In this study, we investigated the incidence of mitochondria-mediated apoptosis of epithelial cells in IIP. We performed TUNEL staining to detect apoptotic cells and western blot analysis and immunohistochemistry to assess the expression and activation of caspases and the cytochrome c release from mitochondria in lung tissues from eight patients with usual interstitial pneumonia, five patients with nonspecific interstitial pneumonia, and eight patients with normal lung parenchyma. The expressions of pro-and cleaved caspase-8, 9, 3, and cytochrome c release from the mitochondria were all significantly increased in the lung tissues of IIP compared with normal lung parenchyma. The positive signals for caspases in epithelial cells were increased in IIP compared with normal lung parenchyma by immunohistochemistry. The results of TUNEL and electron microscopy suggested that apoptotic cells were predominantly epithelial cells. TUNELpositive cells in % of epithelial cells were significantly increased in IIP compared with normal lung parenchyma, and significantly correlated with cytochrome c release from the mitochondria and with the expression of cleaved caspase-3 in epithelial cells. We conclude that mitochondria-mediated apoptosis may be involved in the pathophysiology of IIP. (Lab Invest 2002, 82:1695-1706.

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Section: Immunohistochemistrymentioning

confidence: 82%

mentioning

confidence: 99%

Mitochondria-Mediated Apoptosis of Lung Epithelial Cells in Idiopathic Interstitial Pneumonias

Kuwano

Hagimoto

Maeyama

et al. 2002

Laboratory Investigation

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“…The IL-1␤-converting enzyme (ICE; also called caspase 1) is able to process IL-1␤ and is also involved in apoptosis (33,36,46). Hogquist et al (20,21) had shown that IL-1␤ release is correlated with cell injury and that the processing of the precursor protein only occurs efficiently in cells that are undergoing apoptosis.…”

Section: Discussionmentioning

confidence: 99%

Regulation of Proinflammatory Cytokines in Human Lung Epithelial Cells Infected withMycoplasma pneumoniae

et al. 2002

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Mycoplasma pneumoniae is a small bacterium without a cell wall that causes tracheobronchitis and atypical pneumonia in humans. It has also been associated with chronic conditions, such as arthritis, and extrapulmonary complications, such as encephalitis. Although the interaction of mycoplasmas with respiratory epithelial cells is a critical early phase of pathogenesis, little is known about the cascade of events initiated by infection of respiratory epithelial cells by mycoplasmas. Previous studies have shown that M. pneumoniae can induce proinflammatory cytokines in several different study systems including cultured murine and human monocytes. In this study, we demonstrate that M. pneumoniae infection also induces proinflammatory cytokine expression in A549 human lung carcinoma cells. Infection of A549 cells resulted in increased levels of interleukin-8 (IL-8) and tumor necrosis factor alpha mRNA, and both proteins were secreted into culture medium. IL-1␤ mRNA also increased after infection and IL-1␤ protein was synthesized, but it remained intracellular. In contrast, levels of IL-6 and gamma interferon mRNA and protein remained unchanged or undetectable. Using protease digestion and antibody blocking methods, we found that M. pneumoniae cytadherence is important for the induction of cytokines. On the other hand, while M. pneumoniae protein synthesis and DNA synthesis do not appear to be prerequisites for the induction of cytokine gene expression, A549 cellular de novo protein synthesis is responsible for the increased cytokine protein levels. These results suggest a novel role for lung epithelial cells in the pathogenesis of M. pneumoniae infection and provide a better understanding of M. pneumoniae pathology at the cellular level.

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“…DNA damage and apoptosis in lung epithelial cells have also been reported for acute lung injury and diffuse alveolar damage [47,48]. Increased expression of proapoptotic proteins and decreased expression of antiapoptotic proteins have also been observed in IPF [49,50]. One of the intracellular events required for apoptotic cell death in several systems, including the Fas-FasL pathway, is the activation of caspases.…”

Section: Epithelial Cell Apoptosis Is Involved In Lung Fibrosismentioning

confidence: 99%

The Alveolar Epithelium and Pulmonary Fibrosis

Li¹

2009

JEBP

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Idiopathic interstitial pneumonias (IIPs) are a heterogeneous group of diffuse pulmonary parenchymal diseases that are comprised of seven distinct clinical and pathological entities. Idiopathic pulmonary fibrosis (IPF) and cryptogenic organizing pneumonia (COP) represent two of the most prevalent members of the disease group with major differences in their pathogenesis, clinical course and prognosis. IPF is a refractory and lethal IIP characterized by fibroblast proliferation, deposition of extracellular matrix (ECM) and progressive lung scarring. The incidence of IPF is estimated at 15 to 40 cases per 100,000 per year, and the mean survival from the time of diagnosis is 3 to 5 years regardless of treatment. While its pathogenesis is incompletely understood, the currently accepted paradigm proposes that injury of the alveolar epithelium is followed by a burst of pro-inflammatory and fibroproliferative mediators that invoke responses associated with dysregulated repair of the damaged alveolar epithelium. Recently, there have been studies suggesting that the activation of the alveolar epithelial cells (AECs) may play an active role in the pathogenesis of pulmonary fibrosis. Here, we review the advances in recent studies on the role of the alveolar epithelium in pulmonary fibrosis. AECS: A BRIEF OVERVIEW OF STRUCTURE AND PHYSIOLOGICAL FUNCTIONSTwo types of AECs populate the alveolar epithelium in normal adult lungs, alveolar epithelial type I (AT I) and alveolar epithelial type II (AT II) cells. AT I pneumocytes comprise 40% of the AECs and cover 90% of the internal surface area of the lung. AT I cells are highly attenuated and form an interface with pulmonary capillaries that are intimately involved in gas exchange. These cells also take part in peptide and amino acid transportation across the lung by pinocytosis and transporter-mediated transport [1]. Recently, AT I cells have been shown to be also important in the transportation of water and sodium across the lung [2,3].AT II cells, on the other hand, AT II cells make up 16% of the parenchymal cells in the lung and account for only 5% of the alveolar surface. These cells are cuboidal cells that are situated between AT I cells and they contain characteristic lamellar bodies and apical microvilli. AT II cells synthesize, store and secrete the pulmonary surfactant (PS), which consists of lipids and their associated proteins and whose function is to reduce the surface tension of the lung alveolus and prevent it from collapse or overdistension with respiration. AT II cells also regulate alveolar fluid balance in normal lungs and during the resolution of pulmonary edema [4] and the pathogenesis of acute lung injury with pulmonary edema is associated with an insufficient number of AT II cells and transportation of water into the lung alveolus. Recently, AT II cells have been shown to synthesize and secrete immunomodulatory proteins important for host defense, including surfactant proteins A (SP-A) and D (SP-D) [5]. SP-A can combine with lipid A in the lipopol...

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Upregulation of Fas-signalling molecules in lung epithelial cells from patients with idiopathic pulmonary fibrosis

Cited by 60 publications

References 21 publications

Mitochondria-Mediated Apoptosis of Lung Epithelial Cells in Idiopathic Interstitial Pneumonias

Mitochondria-Mediated Apoptosis of Lung Epithelial Cells in Idiopathic Interstitial Pneumonias

Regulation of Proinflammatory Cytokines in Human Lung Epithelial Cells Infected withMycoplasma pneumoniae

The Alveolar Epithelium and Pulmonary Fibrosis

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