Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0206061 (interstitial pneumonia)
 6,105 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fas is expressed in various cells and transduces the cell death signal. p21 is a mediator of p53-dependent G1 arrest associated with deoxyribonucleic acid (DNA) damage. The upregulation of p53 and p21 associated with DNA damage in idiopathic pulmonary fibrosis has been described previously. In this study, p53, p21, and Fas expression and DNA damage were examined in interstitial pneumonia associated with collagen vascular diseases (CVD-IP). DNA damage was assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end-labelling (TUNEL) and p53, p21 and Fas proteins were detected by immunohistochemistry in 13 cases of CVD-IP, 13 of sarcoidosis, seven of hypersensitivity pneumonitis (HP) and eight control patients with normal lung parenchyma. TUNEL-positive signals were found in bronchiolar or alveolar epithelial cells in 11 of 13 (85%) specimens of CVD-IP, but not in sarcoidosis, HP or controls, except for a case of chronic HP with pulmonary fibrosis. p53, p21 and Fas were detected in bronchiolar or alveolar epithelial cells in nine (69%), 10 (77%) and 12 (92%) of 13 specimens of CVD-IP, respectively, but not in sarcoidosis, HP or controls, except for a case of chronic HP. These results suggest that the upregulation of p53, p21 and Fas in bronchiolar and alveolar epithelial cells associated with deoxyribonucleic acid damage may participate in the process of pulmonary fibrosis in interstitial pneumonia associated with collagen vascular diseases and chronic hypersensitivity pneumonitis.
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PMID:Expression of p53, p21 (Waf1/Cip1/Sdi1) and Fas antigen in collagen vascular and granulomatous lung diseases. 981 69

Interleukin 18 (IL-18) was discovered as an interferon-gamma (IFN-gamma)-inducing factor and plays important roles in natural killer (NK) cell activation. IL-18 also induces proinflammatory cytokines; chemokines; helper T-cell 2 (T(H)2) cytokines (eg, IL-4, IL-13); and immunoglobulin E (Ig-E) and IgG1 production. The combination of IL-18 plus IL-2 or IL-12 up-regulates IFN-gamma gene expression and NK cytotoxicity and has synergistic antitumor activity in vivo and in vitro. Here it is reported that daily administration of IL-18 with IL-2, but not of IL-18 or IL-2 alone, induces lethal lung injury in normal mice, but not in IL-18 receptor alpha (IL-1 receptor-related protein)-deficient (IL-18 receptor alpha(-/-)) mice. Marked interstitial infiltration of lymphocytes, composed mainly of NK cells, was found in the lungs of IL-18/IL-2-treated mice. Increased cytokine and chemokine levels were observed in the sera and lungs of IL-18/IL-2-treated mice. Administration of IL-18/IL-2 was also lethal to mice treated with a metalloproteinase inhibitor, which inhibited tumor necrosis factor-alpha and Fas-ligand release. While IFN-gamma(-/-) mice were partially resistant to the treatment, IL-4(-/-), IL-13(-/-), IL-4/IL-13(-/-), and Stat6(-/-) mice were sensitive to IL-18/IL-2, indicating that these genes were not involved in the host response. The lethal effect by IL-18/IL-2 was completely eliminated in severe combined immunodeficient mice pretreated with antiasialo-GM1 antibody and normal mice pretreated with anti-NK1.1 but not with anti-CD4 or anti-CD8, monoclonal antibody. These results suggest that specific cytokines, chemokines, and NK cells are involved in the pathogenesis of interstitial pneumonia. These results suggest that the clinical use of this interleukin may result in unexpected physiological consequences.
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PMID:Interleukin 18 (IL-18) in synergy with IL-2 induces lethal lung injury in mice: a potential role for cytokines, chemokines, and natural killer cells in the pathogenesis of interstitial pneumonia. 1183 Apr 78

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. TUNEL-positive 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.
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PMID:Mitochondria-mediated apoptosis of lung epithelial cells in idiopathic interstitial pneumonias. 1248 Sep 19

Apoptosis is thought to be involved in lung epithelial cell damage in acute respiratory distress syndrome and interstitial pneumonia. Both the role of apoptosis and its underlying molecular mechanisms in human lung tissue remain unclear. To address these issues, we developed an in vitro assay in which a human lung epithelial cell line and a staphylococcal enterotoxin B (SEB)-reactive human CD8(+) CTL line were co-cultured in the presence of SEB. SEB-stimulated CD8(+) CTL induced apoptosis in the lung epithelial cell line primarily through the perforin/granzyme-mediated pathway. In these cells, apoptosis was initially independent of death receptor pathways. We also tested the effect of IFN-gamma on modulation of apoptosis in lung epithelial cells. In IFN-gamma-pretreated lung epithelial cells, CD95 (APO-1/Fas) activation as well as TNF-related apoptosis-inducing ligand (TRAIL) receptor and TNFR activation led to apoptosis. Furthermore, we found that the interaction of SEB-stimulated CD8(+) CTL with lung epithelial cells induced an increase in TNF-alpha secretion. These results suggest an important role for bacterial superantigen-reactive CD8(+) CTL in induction of lung epithelial cell apoptosis and in modulation of inflammatory processes in lung tissue.
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PMID:Activated T killer cells induce apoptosis in lung epithelial cells and the release of pro-inflammatory cytokine TNF-alpha. 1516 47

Pulmonary accumulation of fibroblasts and myofibroblasts in idiopathic pulmonary fibrosis/usual interstitial pneumonia (IFP/UIP) has been linked to (1) increased migration of a circulating pool of fibrocytes, (2) cell proliferation, and (3) resistance to apoptosis. The mechanism of physiologic apoptosis of lung fibroblasts is poorly understood. Using normal and fibrotic human lung fibroblasts and the human lung fibroblast cell line, MRC-5, we examined the regulation of Fas-induced apoptosis by the proinflammatory cytokines TNF-alpha and IFN-gamma. Herein, we show that the basal resistance of lung fibroblasts and myofibroblasts to Fas-induced apoptosis is overcome by sensitization with TNF-alpha. IFN-gamma did not sensitize cells to Fas-induced apoptosis, but exhibited synergistic activity with TNF-alpha. Sensitization by TNF-alpha was observed in MRC-5 cells and in fibroblasts and myofibroblasts from normal and fibrotic human lung, suggesting that this represents a conserved mechanism to engage Fas-induced apoptosis. The mechanism of sensitization was localized at the level of recruitment of the adapter protein, FADD, to the cytoplasmic domain of Fas. Collectively, these findings suggest that fibroblast apoptosis involves two steps, sensitization and induction, and that inadequate pulmonary inflammation in IPF/UIP may favor fibroblast accumulation by reducing sensitization to apoptosis.
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PMID:TNF-alpha sensitizes normal and fibrotic human lung fibroblasts to Fas-induced apoptosis. 1627 60

Epithelial remodeling probably contributes to parenchymal deterioration in usual interstitial pneumonia/idiopathic pulmonary fibrosis (UIP/IPF), but understanding its mechanisms is still a challenge. The aim of our study was to examine apoptosis and the epithelial changes in the histologic pattern of UIP. After immunohistochemical staining we quantified the content of type I cells, type II cells, surfactant-A protein, bcl-2, and Fas-ligand (Fas-L) in control and alveolar collapse, fibroblastic foci, and honeycomb in UIP areas of 23 open lung biopsies. A significant association was found between epithelial changes and parenchymal deterioration (p < 0.05). Type I epithelial cell density was similar between control (1.7 +/- 0.7%) and UIP alveolar collapse areas (1.8 +/- 0.6%) but decreased progressively in fibroblastic foci zones (0.8 +/- 0.4%) and honeycomb changes (0.4 +/- 0.3%). Type II cell density increased from control (25.6 +/- 8.3%) to areas of alveolar collapse (34.5 +/- 11.4%), then decreased toward fibroblastic foci (15.4 +/- 6.0%) and honeycomb change areas (23.1 +/- 8.6%). The surfactant-A protein increased from control (6.7 +/- 3.2%) to areas of alveolar collapse (31.1 +/- 9.5%) and decreased toward fibroblastic foci (14.5 +/- 4.9%) and honeycomb change areas (21.1 +/- 8.9%). Fas-L positive epithelial cell density presented a progressive decline from control (48.5 +/- 9.5%), alveolar collapse (37.9 +/- 12.4%), fibroblastic foci (27.4 +/- 6.8%), and honeycomb change areas (21.9 +/- 6.5%). A similar decline in density was found for bcl-2 positive epithelial cells from control (20.4 +/- 2.7%), alveolar collapse (18.9 +/- 5.1%), and fibroblastic foci areas (13.8 +/-2.9%), then increased honeycomb change areas (16.3 +/- 2.8%). We conclude that loss of the nuclear (bcl-2) and membrane (Fas-L) regulation of normal cell population density and suppression of cell death by apoptosis in UIP may be a determinant of the abnormal epithelial/parenchymal remodeling in UIP.
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PMID:Structural features of epithelial remodeling in usual interstitial pneumonia histologic pattern. 1700 51

Increased apoptosis of alveolar epithelial cells and impaired apoptosis of myofibroblasts have been linked to the pathogenesis of idiopathic pulmonary fibrosis/usual interstitial pneumonia (IPF/UIP). Fas, a death receptor of the TNF-receptor superfamily, has been implicated in apoptosis of both cell types, though the mechanisms are poorly understood. The goals of this study were: (1) to examine the localization of Fas-associated death-domain-like IL-1beta-converting enzyme inhibitory protein (c-FLIP), an NF-kappaB-dependent regulator of Fas-signaling, in lung tissues from IPF/UIP patients and control subjects; and (2) to compare c-FLIP expression with epithelial cell and myofibroblast apoptosis, proliferation, and NF-kappaB activation. c-FLIP expression was restricted to airway epithelial cells in control lung tissues. In contrast, in patients with IPF/UIP, c-FLIP was also expressed by alveolar epithelial cells in areas of injury and fibrosis, but was absent from myofibroblasts in fibroblastic foci and from alveolar epithelial cells in uninvolved areas of lung tissue. Quantification of apoptosis and proliferation revealed an absence of apoptotic or proliferating cells in fibroblastic foci and low levels of apoptosis and proliferation by alveolar epithelial cells. Quantification of NF-kappaB expression and nuclear translocation revealed strong staining and translocation in alveolar epithelial cells and weak staining and minimal nuclear translocation in myofibroblasts. These findings suggest that: (1) c-FLIP expression is induced in the abnormal alveolar epithelium of patients with IPF/UIP, (2) the resistance of myofibroblasts to apoptosis in patients with IPF/UIP occurs independently of c-FLIP expression, and (3) increased NF-kappaB activation and c-FLIP expression by the alveolar epithelium may be linked.
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PMID:Compartmentalized expression of c-FLIP in lung tissues of patients with idiopathic pulmonary fibrosis. 1937 46

Previous studies showed that apoptotic epithelial cells were involved in the pathogenesis of idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia (UIP); however, little is known about apoptosis in chronic hypersensitivity pneumonitis (HP). This study was performed to examine whether apoptosis has a role in chronic HP. We performed immunohistochemical studies for p53, p21, Fas, Fas ligand, and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling methods on surgical lung specimens. The expression of Fas and Fas ligand was up-regulated in UIP-like lesions compared with nonspecific interstitial pneumonia (NSIP)-like lesions. The expression of p53 and p21 on epithelial cells increased significantly in UIP-like lesions compared with fibrotic NSIP-like lesions and in fibrotic NSIP-like lesions compared with normal lung tissues. These results confirm that apoptotic epithelial cells are present in chronic HP as seen in IPF. Augmented epithelial apoptosis may contribute much more to UIP-like lesions than to NSIP-like lesions in chronic HP.
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PMID:The pathogenesis of chronic hypersensitivity pneumonitis in common with idiopathic pulmonary fibrosis: expression of apoptotic markers. 2085 43

Idiopathic interstitial pneumonia (IIP) is a progressive fibrosing interstitial pneumonia of unknown etiology with a poor prognosis. The aim of this study is to prove the occurrence of particle deposition and particle-induced tissue damage in IIP by examining proapoptotic Fas expression with in-air microparticle induced X-ray emission (in-air micro-PIXE) analysis. A total of 21 patients were enrolled. Lung tissues from 12 IIP patients and nontumorous lung tissues from 9 lung cancer patients (as a control) were subjected to in-air micro-PIXE analysis. The distribution of particles in lung tissue was compared with the localization of Fas expression by immunohistochemistry. Silicon (Si) was identified in 58.3% of IIP samples and 44.4% of control samples. Iron (Fe) was identified 25% in IIP samples and 11.1% in control samples. The mean lung tissue content of Si and Fe relative to S did not differ between IIP and control patients. Only two IIP patients showed the co-localization of Si and Fe deposition with Fas expression. Adaptation of this method would contribute to assess the influence of particles on IIP.
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PMID:Influence of tissue particles on Fas expression in idiopathic interstitial pneumonia. 2119 85