结缔组织生长因子在特发性肺纤维化患者肺组织的表达及意义

目的:研究结缔组织生长因子(CTGF)在特发性肺纤维化(IPF)患者肺组织的表达及意义。方法:IPF组的肺组织标本来自35例IPF患者,对照组的正常肺组织标本来自30例肺叶切除术。用原位杂交结合免疫组化方法检测CTGFmRNA及其蛋白的表达,用免疫组化方法检测纤维连接蛋白(Fn)的表达。结果:IPF组CTGFm-RNA及其蛋白以及Fn的阳性面积百分比均高于对照组(P均<0.001);IPF组CTGFmRNA及其蛋白在增生的Ⅱ型肺泡上皮细胞、肺泡巨嗜细胞和肺间质成纤维细胞中的表达强度均高于对照组(P均<0.001),在细支气管上皮细胞中的表达无差异(P>0.05);IPF组CTGFmRNA及其蛋白的阳性面积百分比与Fn阳性面积百分比之间呈正相关。结论:IPF患者肺组织CTGFmRNA及其蛋白表达增高,并主要定位于Ⅱ型肺泡上皮细胞、肺泡巨嗜细胞和间质成纤维细胞,CTGF可能通过促进Fn的合成而在IPF中发挥作用。     

特发性肺纤维化患者支气管/肺泡上皮细胞凋亡和Fas/FasL基因表达

目的：检测细胞凋亡、Fas/FasL mRNA及其蛋白在特发性肺纤维化患者肺泡/支气管上皮细胞的表达,探讨细胞凋亡和促凋亡信号在此疾病中的意义。方法：应用末端原位杂交（TUNEL）、原位杂交、免疫组化技术,对12例特发性肺纤维化患者的肺活检组织（IPF组）及10例正常肺组织（对照组）检测了细胞凋亡、Fas/FasL mRNA及其蛋白表达的变化。结果：特发性肺纤维化组肺泡/支气管上皮细胞凋亡指数上调,明显高于对照组（P〈0.01）;IPF组肺泡/支气管上皮细胞中Fas/FasL mRNA及其蛋白表达上调,高于对照组（P〈0.01）;IPF组肺泡/支气管上皮细胞凋亡指数与其Fas/FasL mRNA及蛋白表达之间均无明显相关（P〉0.05）。结论：肺纤维化时肺泡/支气管上皮细胞凋亡上调,Fas/FasL mRNA及其蛋白表达增强,在肺纤维化发生、发展中起重要作用。     

特发性肺纤维化7例报告

特发性肺纤维化７例报告广州市第一人民医院（５１０１８０）刘朝晖钟维农曾军黄玉宇中山医科大学病理学教研室李扬特发性肺纤维化（ＩＰＦ）临床表现复杂，预后不良，发病率有逐年上升趋势，我院１９８８年～１９９４年经纤支镜肺活检、经皮肺活检及支气管肺泡灌洗共诊断...     

经纤支镜肺活检在特发性肺纤维化诊断中的价值

62例临床诊断为特发性肺纤维化（IPF）的病人,经纤支镜肺活检检查,病理结果显示：37例明确诊断为IPF,9例虽组织较小但符合IPF的诊断,9例为非特异性病理改变或因取材不满意未能明确诊断7例排除了IPF的诊断并被确诊为其它疾病,病理诊断符合率达74．2％,提示经纤支镜肺活检对IPF的诊断和鉴别诊断具有重要的价值。     

支气管肺泡灌洗法诊断肺部疾病20例

对于肺部疾病,我们通常的检查手段是查痰、X线胸片、肺CT及纤维支气管镜(简称纤支镜)下活检、刷检。而对于一些通过上述方法仍不能确诊的肺部疾病,我们还可行经皮肺活检、开胸肺活检等。我们采用纤支镜下支气管肺泡灌洗(BAL)法诊断了     

肺结节病的临床研究——附21例报告

目的：提高对结节病的认识。方法：回顾分析经病理确诊为结节病21例患者的临床资料。结果：胸部结节病多数有双侧肺门阴影对称性增大（71％）。63％的患者支气管肺泡灌洗液中CD4／CD8比值超过3.5。90％的患者结核菌素纯蛋白衍生物试验（PPD）为阴性。纤维支气管镜（纤支镜）支气管黏膜和肺活检及胸部小切口开胸肺活检病理确诊阳性率分别为80％和100％。结论：胸部X线、PPD及支气管肺泡灌洗液CD4／CD8检查有助于诊断结节病。经纤支镜支气管黏膜和肺活检和胸部小切口开胸肺活检是简便易行，创伤小，阳性率高的方法，特别是后者，对疑难病例的确诊有重要的临床价值。     

PDGF,TGF-β1与肝纤维化关系的研究

目的探讨血小板衍生生长因子BB（PDGF—BB）和转化生长因子β1（TGF—β1）与肝纤维化的关系。方法45例慢性丙型肝炎患者，根据PCⅢ分为对照组及实验组，检测聚乙二醇化干扰素治疗后o，12，24W时PDGF—BB、TGF—β1及PCⅢ水平。结果实验组PCⅢ，PDGF—BB及TGF—β1含量在治疗的12，24W与0W相比有显著性下降，PDGF—BB及TGF—β1随PCⅢ的下降而减低；实验组PDGF—BB，TGF—β1与PCⅢ具有相关性。结论PDGF—BB，TGF—β1是肝纤维化标志物，在肝纤维化检测中有重要作用。     

转化生长因子β与肺泡巨噬细胞在肺纤维化中的作用研究进展

肺纤维化（pulmonary fibrosis,PF）是较为严重的呼吸系统疾病。转化生长因子β（TGF—β）在肺纤维化过程中扮演着重要的角色,是最关键的致纤维化细胞因子。肺泡巨噬细胞（alveolar macrophage,AM）是主要的炎症细胞,能合成和释放TGF-β以及其它炎症介质,在炎症损伤及修复过程中都发挥了重要作用。本文对TGF-β以及AM在肺纤维化中的作用作一综述。     

细支气管肺泡癌31例临床病理分析

[目的]总结经病理证实的31例细支气管肺泡癌的临床、影像学特征及诊断方法.[方法]对本院1997年1月至2006年12月收治的31例细支气管肺泡癌进行回顾性分析.[结果]本组病例占同期住院肺癌患者的5.2%(31/596),患者临床症状、影像学表现形式多样,胸部CT表现:孤立结节型14例,多发结节型5例,弥漫型12例,CT引导经皮肺穿刺阳性率66.7%(16/24),纤支镜活检、肺活检阳性率25%(7/28),8例经手术病理诊断.[结论]细支气管肺泡癌虽属肺腺癌的一个亚型,但具有特殊生物学特征,高分辨CT有助于诊断,纤支镜和CT引导经皮肺穿刺是其确诊的重要方法.     

特发性肺间质纤维化护理体会

临床上将一组原因不明的弥漫性肺间质纤维化疾病称为特发性肺间质纤维化（IPF）。今年6月，我科收治1例经纤支镜肺活检、支气管肺泡灌洗、胸片、胸部CT片确诊的IPF患者，在诊疗过程中护理工作发挥了重要作用。同时作为全部护理工作的参与者，我们也在实际工作中产生了深刻的体会，总结如下。     

Platelet-derived growth factor in idiopathic pulmonary fibrosis.

Fibrosis is a complex process involving an inflammatory reaction, fibroblast proliferation, and abnormal accumulation of interstitial collagens. Mononuclear cells are usually present in lung fibrosis. Activated monocytes and macrophages in culture have been shown to produce several growth factors including platelet-derived growth factor (PDGF). PDGF is a potent mitogen and chemoattractant for fibroblasts and smooth muscle cells and a stimulator of collagen synthesis. We have studied the expression of c-sis/PDGF-2 mRNA in lung tissues derived from five patients with idiopathic pulmonary fibrosis (IPF) and from four control individuals without IPF. Northern blot analysis of specimens obtained from four patients with IPF revealed the expression of the c-sis/PDGF-2 protooncogene. A control lung tissue without IPF did not express the c-sis protooncogene. In situ hybridization extended these studies demonstrating the expression of the c-sis mRNA in the five specimens with IPF but not in the four control specimens without IPF. The expression of c-sis mRNA was localized primarily in the epithelial cells. Invading alveolar macrophages also expressed c-sis mRNA. The expression of c-sis mRNA was accompanied by the expression of PDGF-like proteins in lung specimens with IPF but not in control lung specimens. These findings demonstrate the in vivo expression of the c-sis/PDGF-2 protooncogene and the production of PDGF-like proteins in the epithelial cells and macrophages of the fibrotic tissue. This localized and sustained production of PDGF-like mitogen may constitute an important contributing factor in the abnormal fibroblast proliferation and collagen production, events associated with pulmonary fibrosis.     

Comparison of cell profiles of bronchial and bronchoalveolar lavage fluids between normal subjects and patients with idiopathic pulmonary fibrosis

The cell profiles of bronchial and bronchoalveolar lavage fluids (BLF and BALF) of patients with idiopathic pulmonary fibrosis (IPF) were compared with those of normal volunteers (NV) and age-matched control patients (CP), to characterize the cell profiles of the bronchoalveolar region in normals and patients with IPF. In BALF of nonsmokers from both control groups (NV and CP), alveolar macrophages (AM) were predominant and the percentage of neutrophil leukocytes and that of eosinophil leukocytes below 1% of the total cells. The percentage of neutrophils and that of bronchial epithelial cells were higher in BLF than in BALF of both control groups. Of the immune and inflammatory cells in BLF, the mean percentage of neutrophils was 12% in NV group and 42% in CP group. The percentage of neutrophils and that of eosinophils in BALF were higher in IPF group than in CP group, but the percentage of neutrophils in BLF of IPF group was comparable to that of CP group. In the IPF group, the percentage of neutrophils in BALF was lower than that in BLF. These results indicated that even in healthy subjects, a considerable number of neutrophils are present in the bronchial region and that the cell profile of the lavage fluid of the bronchoalveolar tree changes depending on the method of lavage. Presumably the higher percentage of neutrophils in BALF of patients with IPF is partly due to derangements of the alveolar structure, because the amount of saline infused into this region is limited.     

Blockade of the Wnt/β-catenin pathway attenuates bleomycin-induced pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease and characterized by abnormal growth of fibroblasts and lung scarring. While the pathogenesis of IPF is not clearly understood, activation of transforming growth factor-β (TGF-β) and disruption of alveolar basement membrane seem to play important roles in leading to excess disruption of the matrix, which is associated with activated matrix metalloproteinase (MMP) and aberrant proliferation of myofibroblasts. The Wnt/β-catenin pathway is an important regulator of cellular proliferation and differentiation and abnormal activation of Wnt/β-catenin signal was observed in IPF. We examined whether inhibition of the Wnt/β-catenin pathway could attenuate pulmonary fibrosis in a bleomycin-induced murine model of pulmonary fibrosis. Pulmonary fibrosis was induced in C57BL/6N mice by intratracheal instillation of bleomycin. To inhibit the Wnt/β-catenin pathway, small interfering RNA (siRNA) for β-catenin was administered into trachea 2 h before bleomycin instillation and every 48 h afterward until sacrifice on day 14. The level of β-catenin expression was increased in the epithelial cells of bleomycin-administered mice. Intratracheal treatment with β-catenin siRNA significantly reduced β-catenin expression, pulmonary fibrosis and collagen synthesis in bleomycin-administered mice compared with controls, with no significant effect on the inflammatory response. The β-catenin-targeted siRNA also significantly decreased the levels of MMP-2 (P<0.01) and TGF-β (P<0.01) expression in the lung tissue. Blockade of the Wnt/β-catenin pathway by β-catenin siRNA decreased bleomycin-induced pulmonary fibrosis in the murine model. These findings suggest that targeting Wnt/β-catenin signaling may be an effective therapeutic approach in the treatment of IPF.     

Oxidant-mediated epithelial cell injury in idiopathic pulmonary fibrosis.

Lung inflammatory cells of patients with idiopathic pulmonary fibrosis (IPF) were evaluated for their ability to injure 51Cr-labeled AKD alveolar epithelial cells in the presence and absence of IPF alveolar epithelial lining fluid (ELF). The IPF cells were spontaneously releasing exaggerated amounts of superoxide (O.2) and hydrogen peroxide (H2O2) compared with normal (P less than 0.02). Cytotoxicity of the AKD cells was markedly increased when the IPF inflammatory cells were incubated with autologous ELF (P less than 0.02). The majority of IPF patients had ELF myeloperoxidase levels above normal (P less than 0.002). Incubation of IPF ELF with AKD cells in the presence of H2O2 caused increased cellular injury (P less than 0.01 compared with control), which was suppressed by methionine, a myeloperoxidase system scavenger. IPF patients with high concentrations of ELF myeloperoxidase deteriorated more rapidly than those with low ELF myeloperoxidase (P less than 0.05). Thus, IPF is characterized by an increased spontaneous production of oxidants by lung inflammatory cells, the presence of high concentrations of myeloperoxidase in the ELF of the lower respiratory tract, and a synergistic cytotoxic effect of alveolar inflammatory cells and ELF on lung epithelial cells, suggesting oxidants may play a role in causing the epithelial cell injury of this disorder.     

WNT1-inducible signaling protein–1 mediates pulmonary fibrosis in mice and is upregulated in humans with idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is characterized by distorted lung architecture and loss of respiratory function. Enhanced (myo)fibroblast activation, ECM deposition, and alveolar epithelial type II (ATII) cell dysfunction contribute to IPF pathogenesis. However, the molecular pathways linking ATII cell dysfunction with the development of fibrosis are poorly understood. Here, we demonstrate, in a mouse model of pulmonary fibrosis, increased proliferation and altered expression of components of the WNT/β-catenin signaling pathway in ATII cells. Further analysis revealed that expression of WNT1-inducible signaling protein–1 (WISP1), which is encoded by a WNT target gene, was increased in ATII cells in both a mouse model of pulmonary fibrosis and patients with IPF. Treatment of mouse primary ATII cells with recombinant WISP1 led to increased proliferation and epithelial-mesenchymal transition (EMT), while treatment of mouse and human lung fibroblasts with recombinant WISP1 enhanced deposition of ECM components. In the mouse model of pulmonary fibrosis, neutralizing mAbs specific for WISP1 reduced the expression of genes characteristic of fibrosis and reversed the expression of genes associated with EMT. More importantly, these changes in gene expression were associated with marked attenuation of lung fibrosis, including decreased collagen deposition and improved lung function and survival. Our study thus identifies WISP1 as a key regulator of ATII cell hyperplasia and plasticity as well as a potential therapeutic target for attenuation of pulmonary fibrosis.     

PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis

Although aging is a known risk factor for idiopathic pulmonary fibrosis (IPF), the pathogenic mechanisms that underlie the effects of advancing age remain largely unexplained. Some age-related neurodegenerative diseases have an etiology that is related to mitochondrial dysfunction. Here, we found that alveolar type II cells (AECIIs) in the lungs of IPF patients exhibit marked accumulation of dysmorphic and dysfunctional mitochondria. These mitochondrial abnormalities in AECIIs of IPF lungs were associated with upregulation of ER stress markers and were recapitulated in normal mice with advancing age in response to stimulation of ER stress. We found that impaired mitochondria in IPF and aging lungs were associated with low expression of PTEN-induced putative kinase 1 (PINK1). Knockdown of PINK1 expression in lung epithelial cells resulted in mitochondria depolarization and expression of profibrotic factors. Moreover, young PINK1-deficient mice developed similarly dysmorphic, dysfunctional mitochondria in the AECIIs and were vulnerable to apoptosis and development of lung fibrosis. Our data indicate that PINK1 deficiency results in swollen, dysfunctional mitochondria and defective mitophagy, and promotes fibrosis in the aging lung.