CD8+ T lymphocytes in bronchoalveolar lavage in idiopathic pulmonary fibrosis

<p>Abstract</p> <p>Background</p> <p>Recently it was shown that in Idiopathic Pulmonary Fibrosis (IPF) tissue infiltrating CD₈₊T lymphocytes (TLs) are associated with breathlessness and physiological indices of disease severity, as well as that CD₈₊TLs recovered by bronchoalveolar lavage (BAL) relate to those infiltrating lung tissue. Since BAL is a far less invasive technique than tissue biopsy to study mechanisms in IPF we further investigated the usefulness offered by this means by studying the relationship between BAL macrophages, neutrophils, eosinophils, CD₃₊, CD₄₊, CD₈₊, CD_8+/38+TLs and CD₄₊/CD₈₊ratio with breathlessness and physiological indices.</p> <p>Patients and methods</p> <p>27 IPF patients, 63 ± 9 years of age were examined. Cell counts were expressed as percentages of total cells and TLs were evaluated by flow cytometry. FEV₁, FVC, TLC, RV, <it>D</it>LCO, PaO₂, and PaCO₂were measured in all. Breathlessness was assessed by the Medical Research Council (MRC) chronic dyspnoea scale.</p> <p>Results</p> <p>CD₈₊TLs correlated positively (r_s= 0.46, p = 0.02), while CD₄₊/CD₈₊ratio negatively (r_s= -0.54, p = 0.006) with the MRC grade. CD₈₊TLs correlated negatively with RV (r_s= -0.50, p = 0.017). CD_8+/38+TLs were negatively related to the FEV₁and FVC (r_s= -0.53, p = 0.03 and r_s= -0.59, p = 0.02, respectively). Neutrophils correlated positively with the MRC grade (r_s= 0.42, p = 0.03), and negatively with the <it>D</it>LCO (r_s= -0.54, p = 0.005), PaO₂(r_s= -0.44, p = 0.03), and PaCO₂(r_s= -0.52, p = 0.01).</p> <p>Conclusion</p> <p>BAL CD₈₊TLs associations with physiological and clinical indices seem to indicate their implication in IPF pathogenesis, confirming our previous tissue study.</p

Vascular endothelial growth factor: An angiogenic factor reflecting airway inflammation in healthy smokers and in patients with bronchitis type of chronic obstructive pulmonary disease?

Background: Patients with bronchitis type of chronic obstructive pulmonary disease (COPD) have raised vascular endothelial growth factor (VEGF) levels in induced sputum. This has been associated with the pathogenesis of COPD through apoptotic and oxidative stress mechanisms. Since, chronic airway inflammation is an important pathological feature of COPD mainly initiated by cigarette smoking, aim of this study was to assess smoking as a potential cause of raised airway VEGF levels in bronchitis type COPD and to test the association between VEGF levels in induced sputum and airway inflammation in these patients.Methods: 14 current smokers with bronchitis type COPD, 17 asymptomatic current smokers with normal spirometry and 16 non-smokers were included in the study. VEGF, IL-8, and TNF-α levels in induced sputum were measured and the correlations between these markers, as well as between VEGF levels and pulmonary function were assessed.Results: The median concentrations of VEGF, IL-8, and TNF-α were significantly higher in induced sputum of COPD patients (1,070 pg/ml, 5.6 ng/ml and 50 pg/ml, respectively) compared to nonsmokers (260 pg/ml, 0.73 ng/ml, and 15.4 pg/ml, respectively, p &lt; 0.05) and asymptomatic smokers (421 pg/ml, 1.27 ng/ml, p &lt; 0.05, and 18.6 pg/ml, p &gt; 0.05, respectively). Significant correlations were found between VEGF levels and pack years (r = 0.56, p = 0.046), IL-8 (r = 0.64, p = 0.026) and TNF-α (r = 0.62, p = 0.031) levels both in asymptomatic and COPD smokers (r = 0.66, p = 0.027, r = 0.67, p = 0.023, and r = 0.82, p = 0.002, respectively). No correlation was found between VEGF levels in sputum and pulmonary function parameters.Conclusion: VEGF levels are raised in the airways of both asymptomatic and COPD smokers. The close correlation observed between VEGF levels in the airways and markers of airway inflammation in healthy smokers and in smokers with bronchitis type of COPD is suggestive of VEGF as a marker reflecting the inflammatory process that occurs in smoking subjects without alveolar destruction. © 2007 Rovina et al; licensee BioMed Central Ltd

IL-18 in induced sputum and airway hyperresponsiveness in mild asthmatics: Effect of smoking

Interleukin 18 (IL-18) is a pro-inflammatory cytokine, which has been shown to be implicated in the induction of airway hyperresponsiveness (AHR) in murine asthma models. The association of IL-18 with AHR in human bronchial asthma is not clear as yet. As cigarette smoking modifies airway inflammation we aimed to assess the relationship of IL-18 with airway hyperresponsiveness (AHR) in non-smoking versus smoking asthmatics. IL-18 was measured in sputum supernatants obtained from asthmatic (24 smokers and 22 non-smokers) and healthy subjects (16 smokers and 17 non-smokers). All subjects were assessed by spirometry, skin-prick tests to common aeroallergens and bronchial provocation to methacholine (Mch). There was no significant difference in IL-18 levels between healthy and asthmatic smokers and between healthy and asthmatic non-smokers. IL-18 levels in sputum were significantly lower in healthy smokers compared to non-smokers (p = 0.048); similarly, in asthmatic smokers as compared to non-smokers (p = 0.037). An inverse correlation was found between IL-18 levels, FEV1 (% pred) (r = -0.495, p = 0.043), and PD20Mch in non-smoking asthmatics (r = -0.621, p = 0.024). A positive correlation was found in smoking asthmatics between IL-18 levels in sputum and FEV1 (% pred) (r = 0.627, p = 0.002), FVC (% pred) (r = 0.460, p = 0.031), and PD20Mch (r = 0.809, p = 0.005). Cigarette smoking reduced IL-18 levels in induced sputum in healthy and asthmatic smokers. IL-18 levels were correlated with airway obstruction and AHR in an inverse way in smoking and non-smoking asthmatics. These results suggest the implication of IL-18 in airway hyperresponsiveness characterizing bronchial asthma, which is modified by smoking. © 2009 Elsevier Ltd. All rights reserved

Interleukin-18 in induced sputum: Association with lung function in chronic obstructive pulmonary disease

Background: It has been shown that interleukin (IL)-18 levels in induced sputum are reduced in asthmatic and healthy smokers. However, in chronic obstructive pulmonary disease (COPD) patients, recent data show an overproduction in the lungs and increased serum levels of IL-18, suggesting that IL-18 may be involved in the pathogenesis of COPD. Method: In order to assess the relation of IL-18 with pulmonary function and airway inflammation in COPD, IL-18, tumour necrosis factor-α, and IL-8 levels were measured by ELISA in sputum supernatants obtained from patients with bronchitis type COPD (n = 28), and healthy subjects (18 smokers and 17 non-smokers). Cellular localization of IL-18 was assessed by immunocytochemistry. Results: The levels of IL-18 were significantly higher in sputum supernatants of COPD patients compared to healthy smokers and non-smokers (p &amp;lt; 0.05). IL-18 production was localized to sputum macrophages. IL-18 levels were inversely correlated with FEV1 (% predicted) (r = -0.572, p = 0.002) and FEV1/FVC ratio in COPD smokers (r = -0.608, p = 0.001). No correlations were found between IL-18 levels and inflammatory markers studied in induced sputum obtained from COPD patients, healthy smokers and non-smokers. Conclusion: In patients with COPD, increased levels of IL-18 in induced sputum were associated with airflow limitation, suggesting that IL-18 may be implicated in the pathogenesis of COPD. © 2009

Angiopoietin-2 levels are elevated in exudative pleural effusions

Objective: To examine the pleural fluid (PF) and serum levels of angiopoietin (Ang)-1, Ang-2, and vascular endothelial growth factor (VEGF) in patients with pleural effusions (PEs). Methods: One hundred fifteen patients, 16 with transudative PEs due to heart failure and 99 with exudative PEs (malignant, 40; parapneumonic, 24; tuberculous, 13; miscellaneous etiologies, 22) were included in the study. PF and serum levels of the growth factors were measured using enzyme-linked immunosorbent assay. Results: PF Ang-2 and VEGF levels but not Ang-1 levels were higher (p &lt; 0.001) in exudates than in transudates. PF Ang-2 levels were higher in tuberculous PEs than in PEs of any other etiology and were lower in heart failure PEs than in PEs of any other etiology. The highest PF VEGF levels were observed in patients with malignant and parapneumonic PEs. The lowest PF VEGF levels were observed in patients with transudates. In PEs, Ang-2 levels correlate with VEGF levels (p &lt; 0.001), RBC count (p = 0.002), nucleated cell count (p &lt; 0.001), total protein levels (p &lt; 0.001), and lactate dehydrogenase levels (p &lt; 0.001). PF Ang-1 levels were lower than serum Ang-1 levels both in patients with exudates (p &lt; 0.001) and in those with transudates (p = 0.001). PF Ang-2 levels were higher than serum Ang-2 levels both in patients with exudates (p &lt; 0.001) and in those with transudates (p = 0.045). PF VEGF levels were higher than serum VEGF levels in patients with malignant PEs (p &lt; 0.001) and parapneumonic PEs (p = 0.003), but lower than serum NTGF levels in heart failure PEs (p &lt; 0.001). In patients with tuberculous PEs and exudative PEs of miscellaneous etiology, PF and serum VEGF levels did not differ significantly. Conclusion: Ang-2 levels but not Ang-1 levels are elevated in exudative PEs, and they correlate with levels of VEGF and markers of pleural inflammation. It is thus possible that Ang-1 along with VEGF participate in pleural inflammation and the pathogenesis of exudative PEs

Interleukin-17A is involved in bacteria-related acute pleural inflammation

Background and objective The role of pro-inflammatory interleukin-17A (IL-17A), in pleural diseases is unknown. We sought to investigate IL-17A expression and its clinical implications in patients with pleural effusion (PE) and IL-17A involvement in the pathobiology of pleural inflammation elicited by bacterial products. Methods Pleural and blood IL-17A content was examined in 84 patients with PE of different aetiologies, and the diagnostic value of pleural IL-17A was explored in 92 patients with neutrophil-predominant PE. IL-17A contribution in pleural inflammation was evaluated in mice injected intrapleurally with either IL-17A or bacterial products with or without IL-17A-neutralizing antibodies. Results IL-17A was upregulated in the pleural space of patients with parapneumonic PE. It was detected in a minority of patients with tuberculous PE and very uncommonly in patients with malignant or other pleural exudates. Pleural fluid (PF) IL-17A levels were correlated with markers of acute pleural inflammation, as well as vascular endothelial growth factor and IL-8 levels. Among patients with neutrophil-predominant PE, PF IL-17A was detected only in those with parapneumonic PE, although the sensitivity of the test was low (&lt;50%). Intrapleural injection of IL-17A elicited a neutrophil-predominant inflammatory response in mice, and IL-17A neutralization partially blocked pleural neutrophilia induced by intrapleural administration of bacterial products. Conclusions IL-17A is involved in pleural inflammation related to bacterial infection. Moreover, pleural IL-17A levels may be helpful in uncovering an infectious aetiology among patients with neutrophil-predominant PE. We investigated the pleural and systemic IL-17 expression in patients with pleural effusions, and the contribution of IL-17A in experimental pleural inflammation. Novel findings include a possible role of IL-17A in recognizing parapneumonic pleural effusions among neutrophil-predominant effusions and involvement of the cytokine in bacterial product-related pleural inflammation. © 2013 The Authors. Respirology © 2013 Asian Pacific Society of Respirology

Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest

Background: Animal data on cardiac arrest showed improved long-term survival with combined vasopressin-epinephrine. In cardiac arrest, cortisol levels are relatively low during and after cardiopulmonary resuscitation. We hypothesized that combined vasopressin-epinephrine and corticosteroid supplementation during and after resuscitation may improve survival in refractory in-hospital cardiac arrest. Methods: We conducted a single-center, prospective, randomized, double-blind, placebo-controlled, parallel-group trial. We enrolled 100 consecutive patients with cardiac arrest requiring epinephrine according to current resuscitation guidelines. Patients received either vasopressin (20 IU per cardiopulmonary resuscitation cycle) plus epinephrine (1 mg per resuscitation cycle) (study group; n=48) or isotonic sodium chloride solution placebo plus epinephrine (1 mg per resuscitation cycle) (control group; n=52) for the first 5 resuscitation cycles after randomization, followed by additional epinephrine if needed. On the first resuscitation cycle, study group patients received methylprednisolone sodium succinate (40 mg) and controls received saline placebo. Postresuscitation shock was treated with stress-dose hydrocortisone sodium succinate (300 mg daily for 7 days maximum, with gradual taper) (27 patients in the study group) or saline placebo (15 patients in the control group). Primary end points were return of spontaneous circulation for 15 minutes or longer and survival to hospital discharge. Results: Study group patients vs controls had more frequent return of spontaneous circulation (39 of 48 patients [81%] vs 27 of 52 [52%]; P=.003) and improved survival to hospital discharge (9 [19%] vs 2 [4%]; P=.02). Study group patients with postresuscitation shock vs corresponding controls had improved survival to hospital discharge (8 of 27 patients [30%] vs 0 of 15 [0%]; P=.02), improved hemodynamics and central venous oxygen saturation, and more organ failure-free days. Adverse events were similar in the 2 groups. Conclusion: In this single-center trial, combined vasopressin-epinephrine and methylprednisolone during resuscitation and stress-dose hydrocortisone in postresuscitation shock improved survival in refractory inhospital cardiac arrest. Trial Registration: clinicaltrials.gov Identifier: NCT00411879. ©2009 American Medical Association. All rights reserved

Osteopontin is upregulated in malignant and inflammatory pleural effusions

Background and objective: Osteopontin (OPN) is an important mediator of inflammation and cancer progression. In the present study, we asked whether pleural fluid (PF) and serum OPN concentrations differed between patients with pleural effusions of different aetiologies, and whether assessment of OPN levels was useful for diagnostic purposes. Methods: One hundred and nine consecutive patients with pleural effusions of different aetiologies were recruited prospectively during daily clinics. OPN levels were measured by ELISA. Results: PF OPN levels were 10-fold higher in exudates than in transudates and were significantly correlated with markers of pleural inflammation and vascular hyper-permeability, such as PF/serum LDH or protein ratios, PF protein and PF vascular endothelial growth factor levels. Patients with malignant pleural effusions had higher PF and lower serum OPN concentrations than those with benign disease. The diagnostic accuracies of PF and PF/serum OPN for malignancy were 71.5% (95% CI: 64-80) and 70.6% (95% CI: 62-80), respectively. Conclusions: OPN levels were elevated in exudative pleural effusions, as compared with the levels in blood or transudative pleural effusions. While PF and PF/serum OPN were higher in patients with malignancies, the diagnostic accuracy of the tests was not sufficient to permit routine use in clinical practice. © 2009 Asian Pacific Society of Respirology

Role of angiopoietins in mesothelioma progression.

Background and objective: Anti-angiogenic treatment has been recently shown to be clinically beneficial for mesothelioma patients. Angiopoietins-1 and -2 are key regulators of tumor angiogenesis. Ang-1 is mainly known to promote angiogenesis and vessel stability, while Ang-2 could serve as an antagonist of Ang-1 causing vessel regression and destabilization or enhance angiogenesis in a context-dependent manner. We hypothesized that Ang-1 would promote and Ang2 would halt experimental mesothelioma by affecting tumor angiogenesis. Methods: To examine the effects of angiopoietins in mesothelioma angiogenesis and in vivo growth we constructed Ang-1 or Ang-2 overexpressing AE17 and AB1 mesothelioma cells and implanted them in the respective syngeneic animals. We also explored the clinical relevance of our observations using the human tumoral mRNAseq data available in the TCGA database. Results and conclusions: Ang-1 promotes mesothelioma angiogenesis and growth while the effect of Ang-2 is context-dependent. Low Ang-1 levels in human mesotheliomas are associated with the epitheloid subtype. Tumors of high Ang-1, or concurrent high Ang-2 and VEGF expression present high PECAM-1 and CDH5 expression, markers of vascularity and vascular stability, respectively. Our results highlight the importance of angiopoietins in mesothelioma pathophysiology and pave the way for the clinical development of novel anti-angiogenic strategies