Decreased VEGF concentration in lung tissue and vascular injury during ARDS.

Endothelial injury is an important prognostic factor in acute respiratory distress syndrome (ARDS). Decreased production of vascular endothelial growth factor (VEGF) in ARDS may favour vascular lesions, since VEGF promotes endothelial survival by inhibiting apoptosis. This study sought to document low VEGF levels in lung tissue from ARDS patients, to determine whether the cause was injury to alveolar type II cells (the main pulmonary source of VEGF) and to evaluate the vascular consequences. Lung specimens were obtained by open biopsy or autopsy from 29 patients with severe ARDS (two survivors) and five controls. As compared with controls, homogenates of lung tissue from ARDS patients contained less VEGF (median (interquartile range) ARDS 8.2 (4.7-12.2) versus controls 28.4 (9.9-47.1) ng x g(-1) protein). Increased immunostaining with surfactant protein B was seen in ARDS lungs. Extensive cellular apoptosis (terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labelling staining), including endothelial and alveolar type II cells, was demonstrated, and vascular bed density (CD31 immunostaining) decreased in ARDS lungs as compared with controls. VEGF levels were negatively correlated to apoptotic endothelial cell counts. In conclusion, decreased vascular endothelial growth factor levels in lung tissue may participate in the decrease in lung perfusion in acute respiratory distress syndrome.     

慢性阻塞性肺疾病肺血管内皮细胞和肺泡上皮细胞凋亡的实验研究

目的 研究COPD患者及烟雾暴露COPD大鼠肺血管内皮细胞和肺泡上皮细胞凋亡的相互关系及其与肺功能和肺气肿的相关性.方法 采用烟雾暴露法建立COPD大鼠模型.分别采集COPD患者(13例)和对照患者(12例)及烟雾暴露80 d大鼠(11只)和对照大鼠(12只)的肺组织标本,用HE染色评估肺部病理改变,用平均内衬间隔(MLI)与平均肺泡数(MAN)评估大鼠肺气肿程度;用原位末端标记法对肺血管内皮细胞和肺泡上皮细胞凋亡进行定量检测,分析这两种细胞凋亡的相关性,及其与肺功能和肺气肿指标的相关性.正态分布的计量资料以x±s表示,采用两独立样本的t检验进行分析;非正态分布的计量资料以中位数(四分位间距)表示,采用两个独立样本比较的Wilcoxon秩和检验;采用Spearman秩相关进行相关分析.结果 COPD患者和大鼠均出现明显肺气肿病理改变.COPD患者肺血管内皮细胞和肺泡上皮细胞凋亡指数[(13.2±2.6)%和(28.9±3.1)%]明显高于对照患者[(5.6±1.5)%和(5.8±1.2)%].COPD患者肺泡上皮细胞凋亡指数[(28.9±3.1)%]明显高于肺血管内皮细胞凋亡指数[(13.2±2.6)%],二者间呈正相关(r=0.60,P<0.05);COPD患者肺血管内皮细胞和肺泡上皮细胞的凋亡指数与FEV.占预计值%呈负相关(r值分别为-0.83和-0.69,均P<0.05),与FEV1/FVC呈负相关(r值分别为-0.95和-0.71,均P<0.05),与残气容积/肺总量呈正相关(r值分别为0.93和0.70,均P<0.05).COPD大鼠肺血管内皮细胞和肺泡上皮细胞凋亡指数[(4.1±0.4)%和(10.0±1.0)%]明显高于对照大鼠[(0.2±0.1)%和(2.1±0.4)%],COPD大鼠肺组织MLI与肺泡上皮细胞凋亡指数呈正相关(r=0.59,P<0.05),MAN与肺泡上皮细胞凋亡指数呈负相关(r=-0.81,P<0.05).结论 COPD患者和大鼠肺内存在异常的细胞凋亡现象,其肺泡上皮细胞凋亡较肺血管内皮细胞凋亡更为明显,且二者呈正相关;COPD患者和大鼠肺血管内皮细胞和肺泡上皮细胞的凋亡与其肺功能及肺气肿的改变明显相关,推测肺血管内皮细胞和肺泡上皮细胞凋亡可能参与COPD的发病过程.     

Oral N-acetylcysteine attenuates pulmonary emphysema and alveolar septal cell apoptosis in smoking-induced COPD in rats

Background and objective:   The role of apoptosis in lung destruction in emphysema/COPD is increasingly being recognized. The relationship between anti-oxidants and alveolar septal cell apoptosis in COPD lungs remains to be elucidated. The aim of this study was to investigate the effects of the anti-oxidant, N -acetylcysteine (NAC), on the development of emphysema and alveolar septal cell apoptosis in smoking-induced COPD in rats.
Methods:   Sprague–Dawley rats ( n  = 48) were randomly assigned to normal, COPD, sham and NAC groups. The effects of treatment were assessed by measuring the levels of vascular endothelial growth factor (VEGF) in BAL fluid by ELISA, VEGF and VEGF receptor-2 (VEGFR2) protein expression by western blotting, and the apoptotic index (AI) of alveolar septal cells by terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay. Histopathological evaluations (mean linear intercept (MLI), destructive index (DI)) and lung function measurements were performed.
Results:   FEV_0.3/FVC and PEF were lower in the COPD group than in the normal group. MLI and DI were lower in the NAC-treated group than in the COPD or sham-treated groups. As confirmed by western blotting, the levels of VEGF in BAL fluid were higher in the NAC-treated group than in the COPD group. VEGFR2 protein expression was higher in the NAC-treated group than in the COPD group. The AI was significantly lower in the NAC-treated group than in the COPD group. There was an inverse correlation between levels of VEGF in BAL fluid and the AI of alveolar septal cells.
Conclusions:   NAC attenuates lung damage, pulmonary emphysema and alveolar septal cell apoptosis by partly reversing the decrease in VEGF secretion and VEGFR2 protein expression in smoking-induced COPD in rats.     

Azithromycin increases phagocytosis of apoptotic bronchial epithelial cells by alveolar macrophages.

Chronic obstructive pulmonary disease (COPD) is associated with increased apoptosis and defective phagocytosis in the airway. As uncleared cells can undergo secondary necrosis and perpetuate inflammation, strategies to improve clearance would have therapeutic significance. There is evidence that the 15-member macrolide antibiotic azithromycin has anti-inflammatory properties. Its effects may be increased in the lung due to its ability to reach high concentrations in alveolar macrophages (AMs). The present study investigated the effects of low-dose (500 ng x mL(-1)) azithromycin on the phagocytosis of apoptotic bronchial epithelial cells and neutrophils by AMs. Flow cytometry was applied to measure phagocytosis and receptors involved in AM recognition of apoptotic cells. Cytokines were investigated using cytometric bead array. Baseline phagocytosis was reduced in COPD subjects compared with controls. Azithromycin significantly improved the phagocytosis of epithelial cells or neutrophils by AMs from COPD subjects by 68 and 38%, respectively, often up to levels comparable with controls. The increase in phagocytosis was partially inhibited by phosphatidylserine, implicating the phosphatidylserine pathway in the pro-phagocytic effects of azithromycin. Azithromycin had no effect on other recognition molecules (granulocyte-macrophage colony-stimulating factor, CD44, CD31, CD36, CD91, alphavbeta3 integrin). At higher doses, azithromycin decreased levels of pro-inflammatory cytokines. Thus, low-dose azithromycin therapy could provide an adjunct therapeutic option in chronic obstructive pulmonary disease.     

Expression of adhesion molecules during apoptosis of circulating neutrophils in COPD

STUDY OBJECTIVES: Neutrophil accumulation occurs in the lungs of patients with COPD. This can be due to increased recruitment and/or delayed tissue clearance. Previous studies have described alterations in circulating neutrophils in these patients that can facilitate the former. Dysregulation of neutrophil apoptosis may contribute to the latter. This study investigated the potential abnormalities of the apoptotic process in COPD patients. DESIGN: Prospective study. SETTINGS: Outpatient clinic in a urban, tertiary hospital. PATIENTS: Fourteen stable patients with COPD, 8 smokers with normal lung function, and 8 healthy nonsmoking subjects. MEASUREMENTS AND RESULTS: We cultured circulating neutrophils that had been harvested from the study subjects at 2, 6, and 24 h. Apoptosis was assessed using flow cytometry by annexin binding and CD16 expression. The surface expression of the adhesion molecules Mac-1 (CD11b) and L-selectin (CD62L) also was determined by flow cytometry. The percentage of apoptotic neutrophils increased with time similarly in all groups. However, the surface expression of Mac-1 (CD11b) was higher, and that of L-selectin (CD62L) was lower, during apoptosis in the neutrophils of patients with COPD. CONCLUSIONS: These results show that, quantitatively, in vitro neutrophil apoptosis in COPD patients occurred at a rate similar to that found in healthy individuals and smokers with normal lung function. Qualitatively, however, the increased surface expression of Mac-1 (CD11b) and the decreased surface expression of L-selectin (CD62L) observed in the apoptotic neutrophils of COPD patients indicate increased activation during the apoptotic process. This may be relevant for the pathogenesis of COPD.     

Functional significance of apoptosis in chronic obstructive pulmonary disease

Chronic obstructive pulmonary disease (COPD) is a highly prevalent airway disease characterized by an abnormal inflammatory response of the lungs to noxious particles and gases. Cigarette smoking remains a major risk factor in COPD development. Accumulating evidence suggests that apoptosis, a regulated form of cell death, may play an important role in COPD pathogenesis. Increased numbers of apoptotic cells can be detected in lung tissue and airways of human subjects with COPD, relative to normal lungs or those from smokers without COPD. Alveolar wall destruction associated with emphysema development, may involve increased apoptosis of alveolar structural cells. Several intervention-induced apoptotic models (e.g., cigarette smoke, vascular-endothelial growth factor inhibition, and interferon-gamma) cause emphysematous changes in vitro and in vivo. Increased apoptosis in COPD can also imply defects in the normal physiological clearance of apoptotic cells. Additional factors that relate to perpetuation of the pathogenesis of COPD, including protease/antiprotease imbalance, inflammation and oxidative stress, may mutually promote apoptosis or contribute to impaired clearance of apoptotic cells. Given that cigarette smoking is the most common cause of COPD, identification of the pathways of cigarette smoke-induced apoptosis may further the understanding of COPD pathogenesis. However, apoptosis rate is not diminished after cessation of cigarette smoking, indicating that other mechanisms perpetuate apoptosis in COPD. Therefore, understanding functional relationships between apoptosis and protease/antiprotease imbalance, inflammation, oxidative stress and other factors potentially involved in COPD pathogenesis may uncover crucial therapeutic targets.     

急性呼吸窘迫综合征患者肺组织细胞凋亡及Fas／FasL表达？…

目的 探讨细胞凋亡在急性呼吸窘迫综合征（ＡＲＤＳ）发病中的作用机制。方法 ＡＲＤＳ组９例,对照组５例,采用ＴＵＮＥＬ法以及免疫组织化学技术观察ＡＢＤＳ患肺组织细胞凋亡及Ｆａｓ／ＦａｓＬ系统表达的变化,结果 ＡＲＤＳ急性期患肺组织细胞凋亡率明显高于对照组,且主要表现为肺泡上皮和肺血管内皮细胞凋亡增加;Ｆａｓ抗原,ＦａｓＬ在ＡＲＤＳ急性期患肺组织中的表达与对照组比较明显下调,并且与肺组织细胞凋亡     

Role of angiogenesis and vascular remodeling in chronic obstructive pulmonary disease

Recently, angiogenesis and pulmonary vascular remodeling in COPD has been investigated. It has been hypothesized that endothelial dysfunction might be an initiating event that promotes vessel remodeling in COPD.Inflammatory tissue- a pivotal pathological feature of COPD- often hypoxic, can induce angiogenesis through upregulation of factors such as VEGF or FGF and regulators of angiogenesis such as chemokines (CXC family), acting either as angiogenic or angiostatic. Angiopoietins are distinct molecules that act in association with VEGF at different stages of angiogenic process. The regulation of angiogenesis is determined by a dual, yet opposing balance of angiogenic and angiostatic factors that promote or inhibit neovascularization, respectively, not yet elucidated in detail in COPD.Recent studies suggested an increased expression of VEGF in pulmonary muscular arteries of patients with moderate COPD and also in smokers with normal lung function. This was also associated with enlargement of the arterial wall. However, in patients with severe emphysema, the expression of VEGF tended to be low, despite intense vascular remodelling. Furthermore, it has been suggested that VEGF might be involved in the pathogenesis of emphysema through apoptotic mechanisms. Experimental studies showed that the lung microvascular endothelial cells (including the alveolar septal capillary cells) are particularly vulnerable and dependent on VEGF for their survival. Apoptosis of endothelial, leading to the loss of capillaries may well be a central mechanism in patients with emphysema and muscle wasting.This review article summarizes the current knowledge regarding the contribution of vascular remodeling, as well as the pathogenetic and therapeutic implications of pivotal angiogenic mediators, in COPD.     

室间隔缺损并肺动脉高压患者肺字疐Fas/FasL表达与细胞凋亡的研究

目的探讨细胞凋亡在室间隔缺损并肺动脉高压(VSD-PH)发病中的作用及基因调控机制,为本病防治提供理论依据.方法采用TUNEL法及免疫组化技术观察了30例VSD-PH患者(观察组)及10例室间隔缺损不伴肺动脉高压患者(对照组)肺组织细胞凋亡及Fas/FasL系统表达的变化.结果观察组肺泡上皮和肺血管内皮细胞凋亡率明显低于对照组;Fas、FasL在肺组织中的表达与对照组比较明显下调.结论肺血管内皮和肺泡上皮细胞凋亡不足可能参与肺动脉高压的形成.     

Increased airway granzyme b and perforin in current and ex-smoking COPD subjects

Increased bronchial epithelial cell apoptosis and CD8+ T-cell numbers in the blood and airways have been reported in COPD. These cells can induce apoptosis via the granzyme-b/perforin-mediated pathway. We hypothesized that increased levels of granzyme-b/perforin would be detected in COPD, contributing to apoptosis and tissue damage. Intracellular granzyme-b/perforin were measured in blood-derived T-cells and natural killer (NK) cells from COPD subjects (30 current and 30 ex-smokers), 20 asymptomatic current-smokers and 30 never-smokers, and bronchoalveolar lavage (BAL)-derived T-cells from a cohort of these subjects using flow cytometry. Soluble granzyme-b was determined by ELISA. In blood, there was an increased percentage of T-cells expressing intracellular granzyme-b/perforin for both COPD groups but not asymptomatic smokers (versus never-smokers). Soluble granzyme-b was undetectable. In BAL, soluble granzyme-b levels and the percentage of T-cells expressing intracellular granzyme-b/perforin were increased in both COPD groups and asymptomatic smokers. There was a significant correlation between granzyme-b expression in BAL and apoptosis of bronchial epithelial cells. Most circulating NK cells expressed granzyme-b/perforin, with the median fluorescence intensity of staining increased in both COPD groups and asymptomatic smokers. Granzyme-mediated apoptosis may thus be one mechanism of lung injury in COPD. The changes that persist despite smoking cessation in COPD likely reflect pathophysiological changes in COPD as opposed to the effects of smoking per se.     

The roles of apoptosis in lung injury]

Apoptosis serves important roles in organ development, cell differentiation, and the maintenance of homeostasis. Lung injury studies have underlined the role of fibroblast and endothelial cell apoptosis during lung repair from acute lung injuries, and demonstrated apoptosis of alveolar epithelial cells in association with diffuse alveolar damage. Pulmonary fibrosis is characterized by the loss of lung epithelial cells and the proliferation of fibroblasts. It is possible that Fas, Fas ligand, p 53, p 21, and other apoptosis-regulating proteins may play important roles in the pathophysiology of lung injury and fibrosis.     

Cell death, remodeling, and repair in chronic obstructive pulmonary disease?

Apoptotic cells can be detected in the parenchyma and airways of patients with chronic obstructive pulmonary disease (COPD) in greater numbers than seen in normal lungs or those from smokers without COPD. Implications include more apoptosis and/or decreased clearance of apoptotic cells. Both epithelial and endothelial cells become apoptotic. What role does the apoptosis play in the emphysema or small airway alterations seen in COPD? In simple terms, loss of cells by apoptosis would be expected to accompany, or perhaps initiate, the overall tissue destruction normally believed responsible. Indeed, direct induction of apoptosis in pulmonary endothelial or epithelial cells in rodents is accompanied by emphysematous changes. On the other hand, apoptotic cells are normally removed from tissues rapidly with minimal tissue response, to be followed by cell replacement to maintain homeostasis. The presence of detectable apoptotic cells, therefore, may imply defects in these clearance mechanisms, and, in keeping with this hypothesis, there is increasing evidence for such defects in patients with COPD. Mice with abnormalities in apoptotic cell removal also tend to develop spontaneous "emphysema." A reconciling hypothesis is that recognition of apoptotic cells not only leads to removal but also, normally, to signals for cell replacement. If this latter response is lacking in COPD-susceptible smokers, defects in normal alveolar or small airway repair could significantly contribute to the structural disruption. The concept puts emphasis on defective repair as well as initial injury (i.e., persistent alteration of dynamic tissue homeostasis, as a key contributor to COPD), with, it is hoped, additional approaches for mitigation.     

Apoptosis and proliferation in lungs of ventilated and oxygen-treated preterm infants.

Apoptosis and proliferation and the effect of exogenous surfactant on these processes were investigated in the lungs of mechanically ventilated/oxygen-treated preterm infants with respiratory distress syndrome and stillborn foetuses. Apoptotic and proliferation indices were determined in lung tissue sections from 27 ventilated/oxygen-treated preterm infants and 29 stillborn foetuses. The effect of exogenous surfactant on apoptosis and proliferation was studied in 16 ventilated preterm infants; 11 untreated infants served as control. Apoptotic and proliferating cells were identified by double labelling combining terminal deoxynucleotidyltransferase-mediated deoxyuridine triphosphate nick end-labelling or Ki-67 with cell marker proteins. Pathways to cell death were explored by immunolabelling of cleaved caspases-3, -8 and -9. In the lungs of ventilated/oxygen-treated preterm infants, the numbers of apoptotic and proliferating cells increased significantly compared to the respective numbers in the lungs of stillborn foetuses. Apoptosis was detected in alveolar epithelial cells, whereas epithelial, endothelial and smooth muscle cells proliferated. Surfactant treatment reduced apoptosis induced by ventilation/oxygen-treatment; however, the decrease was not significant. Caspases-8 and -9 do not contribute to ventilation-induced apoptosis, whereas caspase-3 is involved. In conclusion, ventilation/oxygen-treatment induces epithelial cell apoptosis and proliferation of epithelial, endothelial and smooth muscle cells in the lungs of preterm infants.     

4-Hydroxy-2-nonenal,a specific lipid peroxidation product,is elevated in lungs of patients with chronic obstructive pulmonary disease

Cigarette smoking results in oxidative stress and inflammation in the lungs, which are involved in the pathogenesis of chronic obstructive pulmonary disease (COPD). 4-Hydroxy-2-nonenal (4-HNE), a highly reactive diffusible product of lipid peroxidation, is a key mediator of oxidant-induced cell signaling and apoptosis. 4-HNE has a high affinity toward cysteine, histidine, and lysine groups and forms direct protein adducts. We investigated the presence of 4-HNE-modified proteins in lung tissue obtained from subjects with and without COPD. We studied 23 current or ex-smokers with similar smoking histories with COPD (n = 11; FEV(1) < 70% predicted) or without COPD (n = 12; FEV(1) > 84% predicted) who had undergone lung resection. As 4-HNE and transforming growth factor-beta(1) (TGF-beta(1)) can modulate gamma-glutamylcysteine synthetase (gamma-GCS) mRNA levels in lung cells, we assessed the relations between 4-HNE-modified protein levels, FEV(1), gamma-GCS, and TGF-beta(1). 4-HNE-modified protein levels were elevated in airway and alveolar epithelial cells, endothelial cells, and neutrophils in subjects with COPD, compared with the levels in subjects without COPD (p < 0.01). We also observed a significant inverse correlation between the levels of 4-HNE adducts in alveolar epithelium, airway endothelium, and neutrophils and FEV(1) (p < 0.05) and a positive correlation between 4-HNE adducts and TGF-beta(1) protein and mRNA as well as gamma-GCS mRNA levels in airway and alveolar epithelium (p < 0.01). The elevated levels of 4-HNE may play a role in the signaling events in lung inflammation leading to the imbalance of the expression of both proinflammatory mediators and protective antioxidant genes in COPD.     

Lymphocyte population and apoptosis in the lungs of smokers and their relation to emphysema.

Previously, it had been shown that T-lymphocytes are the predominant inflammatory cells found in the alveolar wall of smokers and their numbers correlated with the extent of emphysema. However, the phenotype of these cells was not defined. The aim of this study was to describe the different T-cell phenotypes and investigate the possible presence of apoptosis in the lung parenchyma of smokers. Samples from lungs were obtained at surgery from 15 patients who smoked and six who had never smoked. Samples were frozen and prepared for histological and immunocytochemical examination. Slides were stained for CD3+, CD4+, CD8+, gammadelta T-cells, CD56 natural killers ((NK) cells), and elastase (neutrophils). Anti-CD95 monoclonal antibodies and in situ end-labelling techniques were used to detect Fas expression and apoptosis. Positive staining cells were expressed as cells-mm alveolar wall-, percentage of total cells, and Fas/APO and apoptosis index. Emphysema was identified macroscopically, microscopically and reported as present or absent. All subjects had pulmonary function tests before surgery. Neutrophils were the predominant cell in the lung parenchyma of nonsmokers and smokers without emphysema. In smokers with emphysema, the CD3+ and CD8+ were the predominant cells (p<0.05) in the alveolar wall. gammadelta cells were increased in all smokers and no increased numbers of NK cells was found. The T-cell numbers x mm alveolar wall(-1) showed a bilinear relationship with the amount smoked increasing at an inflection point of 30 packs yr(-1) (R2= 0.345; p < 0.01). Apoptosis in smokers showed a bilinear relationship with the amount smoked increasing sharply in smokers with emphysema (R2=0.3613; p < 0.009). It is concluded that the pathogenesis of emphysema might be mediated by T-lymphocytes, mainly CD8+ cytolytic T-cells, and that apoptosis might be one of the mechanisms of lung destruction leading to the development of emphysema. If this is the case, it could be speculated that T-cell inflammation is a response to antigenic stimuli originating in the lung and induced by cigarette smoking.     

Hepatocyte growth factor and lung fibrosis

Idiopathic pulmonary fibrosis is currently believed to be driven by alveolar epithelial cells, with abnormally activated alveolar epithelial cells accumulating in an attempt to repair injured alveolar epithelium (1). Thus, targeting the alveolar epithelium to prevent or inhibit the development of pulmonary fibrosis might be an interesting therapeutic option in this disease. Hepatocyte growth factor (HGF) is a growth factor for epithelial and endothelial cells, which is secreted by different cell types, especially fibroblasts and neutrophils. HGF has mitogenic, motogenic, and morphogenic properties and exerts an antiapoptotic action on epithelial and endothelial cells. HGF has also proangiogenic effect. In vitro, HGF inhibits epithelial-to-mesenchymal cell transition and promotes myofibroblast apoptosis. In vivo, HGF has antifibrotic properties demonstrated in experimental models of lung, kidney, heart, skin, and liver fibrosis. Hence, the modulation of HGF may be an attractive target for the treatment of lung fibrosis.     

中性粒细胞活化和上皮细胞凋亡在急性肺损伤发生中的作用

致病因子一方面诱导肺泡巨噬细胞和上皮细胞产生多种细胞因子和趋化因子,激活中性粒细胞并使其向损伤部位聚集,从而产生炎症因子的瀑布式反应;另一方面激活死亡受体通路Fas-FasL等诱发肺上二皮细胞凋亡,从而引起肺组织损伤.另外,Fas活化后可通过介导肺内炎症介质释放和中性粒细胞聚集进一步加重肺损伤.中性粒细胞活化和上皮细胞凋亡在急性肺损伤的发生过程中起重要作用.     

An animal model of autoimmune emphysema

Although cigarette smoking is implicated in the pathogenesis of emphysema, the precise mechanisms of chronic progressive alveolar septal destruction are not well understood. We show, in a novel animal model, that immunocompetent, but not athymic, nude rats injected intraperitoneally with xenogeneic endothelial cells (ECs) produce antibodies against ECs and develop emphysema. Immunization with ECs also leads to alveolar septal cell apoptosis and activation of matrix metalloproteases MMP-9 and MMP-2. Anti-EC antibodies cause EC apoptosis in vitro and emphysema in passively immunized mice. Moreover, immunization also causes accumulation of CD4+ T cells in the lung. Adoptive transfer of pathogenic, spleen-derived CD4+ cells into naive immunocompetent animal also results in emphysema. This study shows for the first time that humoral- and CD4+ cell-dependent mechanisms are sufficient to trigger the development of emphysema, suggesting that alveolar septal cell destruction might result from immune mechanisms.     

Up-regulated membrane and nuclear leukotriene B4 receptors in COPD

STUDY OBJECTIVES: We investigated the role of two leukotriene B4 (LTB4) receptors, BLT1 and peroxisome proliferator-activated receptor (PPAR)-alpha, in conferring the susceptibility to develop COPD in smokers. Proinflammatory LTB4 activities are mediated by BLT1, while the inactivation of LTB4 is promoted by PPARalpha. PATIENTS AND METHODS: BLT1 and PPARalpha proteins were quantified by immunohistochemistry in specimens obtained during lung surgery from 19 smokers with or without COPD and from 7 nonsmoking subjects. RESULTS: We have shown that the percentages of PPARalpha-positive alveolar macrophages and PPARalpha-positive cells in the alveolar wall were increased in COPD patients compared with control subjects. Moreover, the patients with COPD exhibited a significant increase of BLT1-positive alveolar macrophages compared with nonsmokers and an increased number of BLT1-positive cells in the alveolar walls compared with non-COPD smokers. In contrast, BLT1 and PPARalpha immunoreactivity did not differ significantly between nonsmokers and non-COPD smokers. Most of BLT1-positive cells in the alveolar walls were neutrophils and CD8 cells. While the number of neutrophils infiltrating the lung parenchyma was similar among the three groups, the number of CD8 T cells was increased in COPD patients, but there was no evidence that BLT1 was up-regulated specifically on these cells in COPD patients. CONCLUSION: The results demonstrated that BLT1 and PPARalpha are detectable in alveolar macrophages and CD8 T cells in human lung tissue, and suggest that the dual LTB4 receptor system is up-regulated in the peripheral lungs of smokers who are susceptible to the development of COPD. This system might represent a novel target for therapeutic intervention in COPD patients.