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2.  IL6 and CRP haplotypes are associated with COPD risk and systemic inflammation: a case-control study 
BMC Medical Genetics  2009;10:23.
Elevated circulating levels of C-reactive protein (CRP), interleukin (IL)-6 and fibrinogen (FG) have been repeatedly associated with many adverse outcomes in patients with chronic obstructive pulmonary disease (COPD). To date, it remains unclear whether and to what extent systemic inflammation is primary or secondary in the pathogenesis of COPD.
The aim of this study was to examine the association between haplotypes of CRP, IL6 and FGB genes, systemic inflammation, COPD risk and COPD-related phenotypes (respiratory impairment, exercise capacity and body composition).
Eighteen SNPs in three genes, representing optimal haplotype-tagging sets, were genotyped in 355 COPD patients and 195 healthy smokers. Plasma levels of CRP, IL-6 and FG were measured in the total study group. Differences in haplotype distributions were tested using the global and haplotype-specific statistics.
Raised plasma levels of CRP, IL-6 and fibrinogen were demonstrated in COPD patients. However, COPD population was very heterogeneous: about 40% of patients had no evidence of systemic inflammation (CRP < 3 mg/uL or no inflammatory markers in their top quartile). Global test for haplotype effect indicated association of CRP gene and CRP plasma levels (P = 0.0004) and IL6 gene and COPD (P = 0.003). Subsequent analysis has shown that IL6 haplotype H2, associated with an increased COPD risk (p = 0.004, OR = 4.82; 1.64 to 4.18), was also associated with very low CRP levels (p = 0.0005). None of the genes were associated with COPD-related phenotypes.
Our findings suggest that common genetic variation in CRP and IL6 genes may contribute to heterogeneity of COPD population associated with systemic inflammation.
PMCID: PMC2660301  PMID: 19272152
3.  Patterns of inflammation and the use of reversibility testing in smokers with airway complaints 
Although both smoking and respiratory complaints are very common, tools to improve diagnostic accuracy are scarce in primary care. This study aimed to reveal what inflammatory patterns prevail in clinically established diagnosis groups, and what factors are associated with eosinophilia.
Induced sputum and blood plasma of 59 primary care patients with COPD (n = 17), asthma (n = 11), chronic bronchitis (CB, n = 14) and smokers with no respiratory complaints ('healthy smokers', n = 17) were collected, as well as lung function, smoking history and clinical work-up. Patterns of inflammatory markers per clinical diagnosis and factors associated with eosinophilia were analyzed by multiple regression analyses, the differences expressed in odds ratios (OR) with 95% confidence intervals.
Multivariately, COPD was significantly associated with raised plasma-LBP (OR 1.2 [1.04–1.37]) and sTNF-R55 in sputum (OR 1.01 [1.001–1.01]), while HS expressed significantly lowered plasma-LBP (OR 0.8 [0.72–0.95]). Asthma was characterized by higher sputum eosinophilic counts (OR 1.3 [1.05–1.54]), while CB showed a significantly higher proportion of sputum lymphocytic counts (OR 1.5 [1.12–1.9]). Sputum eosinophilia was significantly associated with reversibility after adjusting for smoking, lung function, age, gender and allergy.
Patterns of inflammatory markers in a panel of blood plasma and sputum cells and mediators were discernable in clinical diagnosis groups of respiratory disease. COPD and so-called healthy smokers showed consistent opposite associations with plasma LBP, while chronic bronchitics showed relatively predominant lymphocytic inflammation compared to other diagnosis groups. Only sputum eosinophilia remained significantly associated with reversibility across the spectrum of respiratory disease in smokers with airway complaints.
PMCID: PMC1513598  PMID: 16740168
4.  Tumor Necrosis Factor-α +489G/A gene polymorphism is associated with chronic obstructive pulmonary disease 
Respiratory Research  2002;3(1):29.
Chronic obstructive pulmonary disease (COPD) is characterized by a chronic inflammatory process, in which the pro-inflammatory cytokine Tumor Necrosis Factor (TNF)-α is considered to play a role. In the present study the putative involvement of TNF-α gene polymorphisms in pathogenesis of COPD was studied by analysis of four TNF-α gene polymorphisms in a Caucasian COPD population.
TNF-α gene polymorphisms at positions -376G/A, -308G/A, -238G/A, and +489G/A were examined in 169 Dutch COPD patients, who had a mean forced expiratory volume in one second (FEV1) of 37 ± 13%, and compared with a Dutch population control group of 358 subjects.
The data showed that the TNF-α +489G/A genotype frequency tended to be different in COPD patients as compared to population controls, which was due to an enhanced frequency of the GA genotype. In line herewith, carriership of the minor allele was associated with enhanced risk of development of COPD (odds ratio = 1.9, p = 0.009). The other TNF-α gene polymorphisms studied revealed no discrimination between patients and controls. No differences in the examined four TNF-α polymorphisms were found between subtypes of COPD, which were stratified for the presence of radiological emphysema. However, comparison of the COPD subtypes with controls showed a significant difference in the TNF-α +489G/A genotype in patients without radiological emphysema (χ2-test: p < 0.025 [Bonferroni adjusted]), while no differences between COPD patients with radiological emphysema and controls were observed.
Based on the reported data, it is concluded that COPD, and especially a subgroup of COPD patients without radiological emphysema, is associated with TNF-α +489G/A gene polymorphism.
PMCID: PMC150514  PMID: 12537602
Caucasians; COPD; Gene polymorphism; Susceptibility; Tumor necrosis factor-α
5.  Changes in Endotoxin-Binding Proteins during Major Elective Surgery: Important Role for Soluble CD14 in Regulation of Biological Activity of Systemic Endotoxin 
Assessment of circulating endotoxin during the perioperative period, which is only demonstrated by the Limulus amebocyte lysate (LAL) test, may be modulated by several endotoxin-binding proteins. Endotoxin-neutralizing capacity (ENC) and the plasma levels of soluble CD14 (sCD14), lipopolysaccharide-binding protein, and bactericidal/permeability-increasing protein (BPI) were determined in 40 patients 6 h prior to skin incision for major abdominal surgery. The bioactivity of plasma endotoxin was tested by the polymyxin B-inhibited stimulatory activity of the plasma samples on healthy monocytes as measured by the release of tumor necrosis factor alpha. Plasma endotoxin levels in almost all patients increased from 0.05 ± 0.01 to 0.23 ± 0.03 experimental units (EU) per ml (P < 0.001); more specifically, 17 of 40 samples showed endotoxin levels of greater than 0.2 EU per ml and corresponding reductions in ENC. Soluble CD14 plasma levels were decreased from 5.6 ± 0.3 to 4.6 ± 0.3 μg per ml (P < 0.05). ENC was strongly correlated with the sCD14 plasma concentration throughout the period of observation. The addition of sCD14-neutralizing monoclonal anti-sCD14 antibodies reduced ENC both pre- and postoperatively. No correlation could be established between ENC and the plasma levels of BPI, high-density lipoproteins, or low-density lipoproteins determined by measuring the concentrations of apoprotein A and apoprotein B. Biologically active endotoxin was found in only 6 of 17 samples with endotoxin levels greater than 0.2 EU per ml in the LAL test. These samples could be characterized by their perioperative loss of at least 35% of their sCD14. No change in sCD14 was detected in the remaining 11 samples. The perioperative loss of ENC is partly caused by the loss of sCD14 resulting from its consumption by endotoxin reaching the bloodstream. This study demonstrated the role of sCD14 on the bioactivity of circulating endotoxin in a human model of endotoxemia after major abdominal surgery.
PMCID: PMC95786  PMID: 10548574
6.  Epinephrine Exerts Anticoagulant Effects during Human Endotoxemia 
The Journal of Experimental Medicine  1997;185(6):1143-1148.
To determine the effect of a physiologically relevant elevation in the plasma concentrations of epinephrine on the activation of the hemostatic mechanism during endotoxemia, 17 healthy men were studied after intravenous injection of lipopolysaccharide (LPS, 2 ng/kg), while receiving a continuous infusion of epinephrine (30 ng/kg/min) started either 3 h (n = 5) or 24 h (n = 6) before LPS injection, or an infusion of normal saline (n = 6). Activation of the coagulation system (plasma concentrations of thrombin–antithrombin III complexes and prothrombin fragment F1+2) was significantly attenuated in the groups treated with epinephrine when compared with subjects injected with LPS only (P <0.05). Epinephrine enhanced LPS-induced activation of fibrinolysis (plasma levels of tissue-type plasminogen activator and plasmin-α2–antiplasmin complexes; P <0.05), but did not influence inhibition of fibrinolysis (plasminogen activator inhibitor type I). In subjects infused with epinephrine, the ratio of maximal activation of coagulation and maximal activation of fibrinolysis was reduced by >50%. Hence, epinephrine exerts antithrombotic effects during endotoxemia by concurrent inhibition of coagulation, and stimulation of fibrinolysis. Epinephrine, whether endogenously produced or administered as a component of treatment, may limit the development of disseminated intravascular coagulation during systemic infection.
PMCID: PMC2196238  PMID: 9091588

Results 1-6 (6)