Expression of alveolar macrophage adhesion molecules in pulmonary sarcoidosis.

Beta-2-integrins belong to a family of leukocyte surface glycoproteins that are essential for immune functions of bronchoalveolar cells. The expression of three alpha chains designed as CD11a, CD11b, CD11c, a common beta chain CD18, and of a ligand for several integrins CD54 (ICAM-1) was studied on alveolar macrophages of patients with active and inactive sarcoidosis and in control subjects. The percentage of macrophages expressing CD11b (CR3) was significantly increased in patients with active sarcoidosis compared with patients who had inactive disease and control subjects. The adhesion molecule CD54 (ICAM-1) was detected on a higher percentage of alveolar macrophages in patients with active rather than inactive sarcoidosis and in control subjects. Since integrin-mediated adhesion seems to be important in macrophage-lymphocyte interactions during the immune response, higher expression of both CD11b and CD54 on sarcoid alveolar macrophages may be related to several immune abnormalities reported in pulmonary sarcoidosis.     

Inflammatory cytokine levels in induced sputum and bronchoalveolar lavage fluid in pulmonary sarcoidosis

BACKGROUND: The immune inflammatory process in patients with sarcoidosis is not only compartmentalized within the alveolar walls, but also involves the bronchial airways. Analysis of induced sputum has been used as a non-invasive tool for investigating the airways and may reflect the endobronchial and parenchymal inflammation in patients with sarcoidosis. This present study was designed to measure the soluble pro-inflammatory cytokine levels interleukin-1 (IL-1), interleukin-6 (IL-6), tumuor necrosis factor-alpha (TNF-alpha) and percentage of macrophages expressing these cytokines in induced sputum and bronchoalveolar lavage (BAL) fluid in patients with pulmonary sarcoidosis. METHODS: Sputum induction and BAL was carried out in 27 patients with newly diagnosed sarcoidosis. Control group consisted of six patients with a normal chest radiograph (three patients with carcinoma esophagus and three patients with doubtful history of hemoptysis). Induced sputum was also obtained from 10 non-smoking, non-atopic healthy controls. RESULTS: Percentage of macrophages expressing pro-inflammatory cytokines and soluble cytokine levels in induced sputum were higher in patients with sarcoidosis compared to both groups of controls. There was good correlation between IL-6 and TNF-alpha levels (r = 0.49, 0.58 p < 0.05) and percentage of macrophages expressing all three cytokines (r = 0.56-0.71, p < 0.01) between induced sputum and BAL fluid. Mild positive correlation between cytokine levels in sputum and age was also noted (r = 0.33-0.38, p < 0.05). CONCLUSIONS: Induced sputum may reflect changes in cytokine milieu in BAL in sarcoidosis.     

Induced sputum in patients with newly diagnosed sarcoidosis: comparison with bronchial wash and BAL.

OBJECTIVES: Sarcoidosis is characterized by a diffuse alveolar inflammatory process, although bronchial airways are often involved. This study compares the cellular profiles of induced sputum (IS), bronchial washing (BW), and BAL in newly diagnosed sarcoidosis patients to those in control subjects, and examines whether inflammatory cell counts from IS are correlated with inflammatory cell counts from BW and BAL in sarcoidosis patients. PATIENTS AND MEASUREMENTS: We recruited 15 untreated patients with stage I and II pulmonary sarcoidosis and 12 healthy volunteers. Sputum was induced with hypertonic saline solution in all individuals. Bronchoscopy was performed on a different occasion in all patients and in five control subjects. RESULTS: Mean lymphocyte counts in IS, BW, and BAL fluid from sarcoidosis patients were significantly higher than in control subjects (9.4% vs 3.8%, p < 0.05; 12.6% vs 3.9%, p < 0.05; 24.1% vs 2.6%, p < 0.05, respectively). Moreover, total cell count and percentage of epithelial cells in IS were significantly higher in sarcoidosis patients than in control subjects (p < 0.01 and p < 0.05, respectively). In sarcoidosis patients, comparison between different samples showed significantly higher percentages of macrophages in BW and BAL than in IS (p < 0.05 and p < 0.01, respectively), whereas the percentage of neutrophils was higher in IS compared with BW and BAL (p < 0.01 and p < 0.001, respectively). Finally, the percentage of lymphocytes in IS was significantly lower than that in BAL (p < 0.05) but not that in BW. CONCLUSIONS: We demonstrated that, compared with IS in healthy control subjects, IS in untreated pulmonary sarcoidosis patients contains more total cells, lymphocytes, and epithelial cells. Although the relative proportion of inflammatory cells in the three samples differed, lymphocyte counts in IS were high. This finding suggests that IS could be used as a valuable alternative to more conventional invasive techniques in clinical assessment of pulmonary sarcoidosis patients.     

Markers of inflammation in sarcoidosis: blood, urine, BAL, sputum, and exhaled gas

Sarcoidosis is characterized by intense inflammation at the different sites of localization. Many different mediators, such as cytokines, chemokines, and other proteins with various functions, that participate in its complex pathogenesis have been proposed as markers of inflammation. This article examines the principal literature on these different markers analyzed in serum, bronchoalveolar lavage, expired breath, and urine. After many years of research, no single marker sufficiently sensitive and specific for diagnosis of sarcoidosis has yet been found. Greater correlation with clinical parameters is needed and proper validation.     

Angiogenic cytokines in induced sputum of patients with sarcoidosis

Background and objective:   Sarcoidosis is a systemic granulomatous disorder of unknown aetiology involving multiple organs and often associated with non-granulomatous microangiopathic lesions in various organs. Increased angiogenesis-inducing ability of activated alveolar macrophages was found in bronchoalveolar specimens from patients with pulmonary sarcoidosis and from patients with extrapulmonary involvement. In contrast, decreased levels of vascular endothelial growth factor (VEGF) were found in BAL fluid recovered from sarcoid-associated pulmonary fibrosis. This study evaluated whether sarcoidosis is associated with abnormalities of VEGF and IL-8 in induced sputum (IS) samples.
Methods:   Twenty-three sarcoid patients and 13 controls performed IS. CD4/CD8 T-cell subsets were measured, as were pulmonary function tests and VEGF and IL-8.
Results:   Sarcoid patients showed significantly higher mean %lymphocytes ( P  = 0.04), significantly higher mean CD4/CD8 ratio ( P  = 0.0001) and significantly lower VEGF levels ( P  = 0.03) than controls. Patients with stages III–IV sarcoidosis showed a lower level of VEGF compared with those with stages I–II sarcoidosis ( P  = 0.048). IL-8 was detected in 10/35 samples and positively correlated with % neutrophils ( P  = 0.054) and eosinophils ( P  = 0.045). VEGF immunohistochemical staining showed a mixed pattern of expression in the same tissue samples and was low in fibrotic tissue areas.
Conclusion:   VEGF in IS samples may reflect impairment in angiogenesis associated with the extent of sarcoid fibrosis and functional disorders.     

Increased endothelin-1 levels of BAL fluid in patients with pulmonary sarcoidosis

OBJECTIVE AND BACKGROUND: Pulmonary fibrosis in sarcoidosis is a significant cause of morbidity and mortality. Various factors have been intensely studied to define the pathogenesis of lung fibrosis in sarcoidosis. Endothelin (ET) consists of three isoforms and is known for its potent vasoconstrictor properties. ET plays an important role in the fibroproliferative process of interstitial lung diseases. METHODS: To investigate the role of ET in the progression of pulmonary fibrosis in sarcoidosis, ET-1 and ET-3 concentrations were measured in BAL fluid (BALF) in 22 non-smoking patients with sarcoidosis and in control subjects (n = 12). Immunoreactivity of ET-1 was also evaluated in alveolar macrophages (AMs) from sarcoidosis patients. To assess the effects of ET in BALF on fibroblast proliferation, human foetal lung fibroblasts were cultured with sarcoidosis or control BALFs in the presence or absence of the ET-receptor antagonist TAK-044. RESULTS: ET-1 levels in sarcoidosis BALF were significantly higher than those in control, whereas ET-3 levels were not different between sarcoidosis and control. ET-1 levels were correlated with the number of AMs in BALF. ET-1-immunoreactivity was found mainly in AM of sarcoidosis BALF. Sarcoidosis BALF significantly stimulated fibroblast proliferation, compared with control BALF, and the fibroblast proliferation induced by sarcoidosis BALF was inhibited by TAK-044. CONCLUSIONS: Increased levels of ET-1 in AM could enhance fibrogenesis in pulmonary sarcoidosis.     

Cellular profiles of induced sputum in children with stable cystic fibrosis: comparison with BAL.

Neutrophil-dominated endobronchial inflammation is a major characteristic of cystic fibrosis (CF) and there is increasing demand for easy-to-perform noninvasive monitoring for prediction and intervention. Fourteen stable paediatric CF patients (8-17 yrs; mean forced expiratory volume in one second 86.7% of the predicted value) were investigated once by fractional bronchoalveolar lavage (BAL) and by sputum induction on three occasions, 2-6 weeks apart. Sputum was induced by consecutive 10-min inhalations of 3, 4 and 5% saline. CF sputum cellular profiles were compared with BAL fluid cell counts and samples from age-matched healthy children, and between different time points to assess reproducibility. Adequate sputum was recovered on >95% of occasions. In all sputum fractions, CF patients showed higher neutrophil counts than healthy children. Neutrophil percentages were highest in the first BAL fraction (median 92%), followed by sputum, in which the percentages decreased in consecutive fractions (72, 66 and 64%), whereas counts were lowest in the pooled BAL fraction (53%). Increasing percentages of macrophages mirrored the decreases in neutrophil percentage. Results of sputum induction at different time points in the CF patients showed good reproducibility and nonoverlap with counts from healthy children. In conclusion, the results of sputum induction in children with mild stable cystic fibrosis adequately describe airway inflammation by providing cellular profiles with lower relative neutrophil counts than in the first ("bronchial") bronchoalveolar lavage fraction and higher relative neutrophil counts than in subsequent pooled ("more peripheral") bronchoalveolar lavage fractions.     

负性共刺激分子介导免疫下调与免疫逃逸的关系

T细胞充分活化需要识别双信号系统,即主要组织相容性复合体-抗原肽提供的第一信号和共刺激分子提供的第二信号.共刺激分子在调节T细胞的免疫应答中起关键作用,其中负性共刺激分子介导的免疫下调在病毒、细菌、肿瘤细胞等的免疫逃逸中发挥重要作用,也可能与寄生虫慢性感染的免疫逃逸有关.该文就负性共刺激分子介导免疫下调与免疫逃逸关系的研究进展作一综述.     

负性共刺激分子介导免疫下调与免疫逃逸的关系

T细胞充分活化需要识别双信号系统,即主要组织相容性复合体-抗原肽提供的第一信号和共刺激分子提供的第二信号.共刺激分子在调节T细胞的免疫应答中起关键作用,其中负性共刺激分子介导的免疫下调在病毒、细菌、肿瘤细胞等的免疫逃逸中发挥重要作用,也可能与寄生虫慢性感染的免疫逃逸有关.该文就负性共刺激分子介导免疫下调与免疫逃逸关系的...     

Immune reconstitution inflammatory syndrome associated with pulmonary sarcoidosis in an HIV-infected patient: an immunohistochemical study

Sarcoidosis has been rarely described in literature as a cause of interstitial pulmonary disease associated with AIDS. This study reports a case of immune reconstitution inflammatory syndrome associated with pulmonary sarcoidosis in a patient with a history of previous pulmonary tuberculosis concomitant with HIV infection. Results of the immunohistochemical study of samples from the resected right lower lobe are described. Pathological findings suggest a role of Th1, Th2 and Th17 response in IRIS associated sarcoidosis.     

Clinical,radiologic, and induced sputum features of chronic obstructive pulmonary disease in nonsmokers: a descriptive study

Epidemiologic studies show that 5-12% of subjects with chronic obstructive pulmonary disease (COPD) are nonsmokers. Little is known about the pathophysiology of the fixed airflow obstruction in these subjects. We have prospectively identified 25 patients with COPD who had never smoked or had a less than 5 pack years smoking history and present the clinical, radiologic, and induced sputum features. Our population represented 5.7% of total referrals with fixed airflow obstruction over 2 years. Patients had a mean age of 70 years, were predominantly female (86%), and had a mean duration of respiratory symptoms of 7 years. The mean FEV(1) was 58%, and the FEV(1)/FVC was 55%. Features on high-resolution computed tomographic scanning were nonspecific and were considered typical of a wider population with COPD. An induced sputum differential inflammatory cell count suggested the presence of two distinct groups. Nine had significant sputum eosinophilia (mean, 8.1%; normal, less than 1.9%), and the remaining 13 had a normal sputum eosinophil and tended to have a raised sputum neutrophil count (mean, 70.1%; normal, less than 65%). Organ-specific autoimmune disease was present in 7 of the 22 patients (32%) and was particularly prevalent in those without sputum eosinophilia (6 of 13). In conclusion, COPD in nonsmokers predominantly affects females and has at least two pathologic subgroups, one of which may be associated with organ-specific autoimmune disease. Further investigation of this group may disclose novel mechanisms of fixed airflow obstruction.     

Reciprocal activation of leukocyte-endothelial adhesion molecules in acute coronary syndromes

Background: The acute coronary syndromes are associated with an intense inflammatory response and sustained leukocyte activation. This inflammatory state has been correlated with an adverse prognosis, but the source of this inflammation remains controversial, with evidence that it may arise either from the coronary vasculature or from the systemic endothelium. Methods: Levels of soluble cell adhesion molecules, and of their respective monocyte cell surface ligands, were measured in the peripheral serum of 21 patients presenting with acute coronary syndromes. Soluble intercellular adhesion molecule-1 and soluble vascular cell adhesion molecule-1 were measured by enzyme linked immunosorbent assay and expression of the monocyte integrins CD11b (Mac-1) and CD49d (VLA-4) was measured by direct immunofluorescence using flow cytometry. Results: High levels of the monocyte receptor CD11b (531 vs. 345 MFI, P<0.01), and its soluble intercellular adhesion molecule-1 (329 vs. 232 ng/ml, P<0.01), were noted in patients with acute coronary syndromes compared to healthy controls. Conclusions: Reciprocal activation of monocyte receptor ligands and endothelial adhesion molecules was found in the peripheral blood of patients with acute coronary syndromes. This may indicate a coordinated state of pro-inflammatory upregulation with widespread activation of both leukocytes and endothelium and suggests a systemic rather than local source for inflammation in acute coronary disease.     

Circulating adhesion molecules in patients with chronic obstructive pulmonary disease

The place of adhesion molecules that have a role in the immigration of intravascular leukocytes to the tissue with inflammation in the pathogenesis of chronic obstructive pulmonary disease (COPD) is controversial. Our purpose in this study was to examine the levels of soluble intracellular adhesion molecule-1 (sICAM-1) and Mac-1 (CD11b/CD18), lymphocyte function associated antigen-1 (LFA-1) in both neutrophils and lymphocytes in stable patients with COPD and in the healthy control groups consisting of non-smokers, and in smokers without COPD and also to evaluate the relationship between the parameters related to the severity of the disease. Peripheral venous blood samples of all the individuals were collected, and levels of sICAM-1 was measured quantitatively with ELISA method. Flow cytometry was used for Mac-1 and LFA-1 levels. Twenty-four stable patients with COPD (group I), 13 smokers (group II) and 14 healthy non-smokers (group III) were included in this study. In the COPD group, 12 smokers patients were considered as group IA, and 12 patients with non-smokers and biomass exposure were considered as group IB. No statistically significant differences were seen in LFA-1 examined in peripheric blood (PB) neutrophils and lymphocytes and sICAM in groups I, II, and III. Mac-1 examined in PB neutrophils was found to be significantly lower in group I when compared to groups II and III, however no difference could be seen in smokers' group of II and the control group III. Mac-1 examined in PB lymphocytes were found to be higher in group I according to group II, however no statistically significant difference was seen between group I and control group. No statistically significant differences were seen in all adhesion molecules levels in group IA and group IB. As a result; it was found that Mac-1 levels in PB neutrophils were decreased with the developing of COPD and Mac-1 levels in PB lymphocytes were decreased in smokers, however increased following the development of COPD. No differences existed in sICAM and LFA-1 levels dependent on smoking and/or COPD.     

盐酸氨溴索对慢性阻塞性肺疾病诱导痰巨噬细胞NF-κB的影响

目的探讨盐酸氨溴索对稳定期慢性阻塞性肺疾病(COPD)患者诱导痰巨噬细胞核转录因子kappaB(NF-κB)的影响。方法将2004年1~10月河南省人民医院门诊及住院47例稳定期COPD患者,随机分为治疗组和对照组,治疗组除给予常规治疗外,加用盐酸氨溴索(每次30 mg,每日3次,连用2个月);对照组仅给予常规治疗。观察治疗前后所有患者超氧化物歧化酶(SOD)活力和丙二醛(MDA)浓度,诱导痰上清液IL-8质量浓度及巨噬细胞NF-κB P65表达。结果两组治疗后IL-8、NF-κB水平较治疗前均下降,差异有显著性意义(P<0.05),治疗组治疗后的IL-8、NF-κB下降较对照组显著(P<0.05)。结论盐酸氨溴索可降低稳定期COPD患者诱导痰巨噬细胞NF-κB表达程度。