Circulating inflammatory factors associated with worse long-term prognosis in colorectal cancer.

AIM: To investigate association of circulating inflammatory factors at the time of colorectal cancer (CRC) surgery with survival. METHODS: Plasma levels from 174 CRC patients (69 females and 105 men), with median age 70 years (range 29-90), localized in the colon (n = 105) or rectum (n = 69), with stage I (n = 24), stage II (n = 54), stage III (n = 67) and stage IV (n = 29) were measured using commercially available Bio-Plex Pro™ Human Chemokine Panel 40-Plex, including 40 different chemokines, cytokines and interleukins. The prognostic association of each inflammatory factor was analysed as CRC-specific and total mortality. RESULTS: Out of 174 patients, 66 died during the follow-up, 40 because of CRC specific mortality. High tertile levels of 8 factors were significantly associated with increased CRC-specific mortality, of which CCL1, CCL20, CCL24, CX3CL1, IL-4 and TNF-α remained significant in a multivariate Cox regression analysis. High tertile levels of 14 factors were associated with increased total mortality, of which CCL1, CCL15, CCL20, CX3CL1, CXCL13, IFN-γ, IL-2, IL-4 and IL-10 remained significant after adjustment for clinical covariates. For most of the inflammatory factors the association between higher tertile levels and an increased mortality in general appeared two years after surgery. High tertile levels of TNF-α and CCL24 were exclusively associated with CRC-specific mortality. The distribution of these factors were not associated with TNM stage with exception for CCL20. CONCLUSION: High plasma levels of inflammatory factors are associated with increased risk of mortality among CRC patients and could be potential biomarkers for revealing prognosis.

Enhanced neutrophil expression of annexin-1 in coronary artery disease.

The systemic inflammatory activity in patients with stable coronary artery disease (CAD) is associated with a dysregulated cortisol response. Moreover, an aberrant activation status of neutrophils in CAD has been discussed; and the question of glucocorticoid resistance has been raised. The anti-inflammatory actions of glucocorticoids are mediated by annexin-1 (ANXA1). We investigated the expression of glucocorticoid receptors (GR) and ANXA1, as well as the exogenous effects of ANXA1 on neutrophils in CAD patients and related the data to diurnal salivary cortisol. Salivary cortisol levels were measured in the morning and evening during 3 consecutive days in 30 CAD patients and 30 healthy individuals. The neutrophil expression of GR and ANXA1 was determined by flow cytometry. The effect of exogenous ANXA1 was determined in a neutrophil stimulation assay. The patients showed a flattened diurnal cortisol pattern compared with healthy subjects, involving higher levels in the evening. The neutrophil expression of GR-total and GR-alpha was decreased, whereas the GR-beta expression did not differ compared with controls. The neutrophil expression of ANXA1 was significantly increased in patients. Ex vivo, ANXA1 impaired the leukotriene B(4)-induced neutrophil production of reactive oxygen species in patients but not in controls. Our findings indicate a persistent overactivation of the hypothalamic-pituitary-adrenal axis in CAD patients but do not give any evidence for glucocorticoid resistance, as assessed by the neutrophil expression of GR and ANXA1. The altered neutrophil phenotype in CAD may thus represent a long-term response to disease-related activation.

Inflammation and cortisol response in coronary artery disease.

Atherosclerosis is characterized by chronic inflammation involving autoimmune components. The degree of inflammatory activity, as detectable both within the atherosclerotic plaque and in the circulation, is associated with plaque destabilization and atherothrombotic complications. Endogenous glucocorticoids are modulators of innate and acquired immune responses, and as such play a key role in the reciprocal interaction between neuroendocrine and immune systems. Abnormalities in hypothalamic-pituitary-adrenal axis (HPA) function have been described in several chronic inflammatory disorders, and evidence has emerged lately that HPA dysfunction may be implicated also in the pathogenesis of coronary artery disease. This review is an outline of knowledge gained so far by previous studies of glucocorticoids in coronary atherosclerosis and myocardial infarction. The results consistently point towards a dysregulated cortisol secretion that may involve a failure to contain inflammatory activity. A dysfunctional HPA axis and its possible implications for coronary artery disease progress, including the hypothetical link between stress and inflammation, are discussed.

Neutrophil activation status in stable coronary artery disease.

BACKGROUND: During the last years, neutrophils have emerged as important players in atherogenesis. They are highly activated in peripheral blood of patients with unstable angina. Moreover, a primed state of circulating neutrophils has been proposed in patients with stable angina. Our aim was to investigate the neutrophil activation status in patients with stable coronary artery disease (CAD) at conventional drug treatment. METHODOLOGY AND PRINCIPAL FINDINGS: Thirty patients with stable CAD and 30 healthy controls were included using a paired design. The neutrophil expression of CD18 and high-affinity state of CD11b was analysed by flow cytometry before and after stimulation with chemoattractants. Also, the production of reactive oxygen species (ROS) was determined by chemiluminescence. During basal conditions, the neutrophil expression of CD18 or high-affinity state of CD11b did not differ between patients and controls. Chemoattractants (Interleukin-8 and Leukotriene B(4)) did not increase either the expression or the amount of high-affinity CD11b/CD18-integrins in CAD patients compared to controls, and had no effect on the production of ROS. On the other hand, the ROS production in response to C3bi-opsonised yeast particles and the neutrophils' inherent capacity to produce ROS were both significantly decreased in patients. CONCLUSION/SIGNIFICANCE: We could not find any evidence that neutrophils in patients with stable CAD were primed, i.e. more prone to activation, compared to cells from healthy controls. According to our data, the circulating neutrophils in CAD patients rather showed an impaired activation status. It remains to be elucidated whether the neutrophil dysfunction in CAD is mainly a marker of chronic disease, an atherogenic factor or a consequence of the drug treatment.

Increased plasma concentration of matrix metalloproteinase-7 in patients with coronary artery disease.

BACKGROUND: Plaque rupture is often associated with breakdown of the extracellular matrix in the shoulder region of a plaque. We tested whether plasma concentrations of various matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinase-1 (TIMP-1) could serve as markers for plaque instability as well as relationships between plasma MMPs and inflammatory markers. METHODS: The study group included 65 men with angiographically verified CAD (45 with stable and 20 with unstable CAD) and 28 healthy controls. Circulating MMP, TIMP-1, C-reactive protein, and cytokine concentrations were measured by ELISA. Leukocyte subtype counts in whole blood were determined, and T-cell subsets and natural killer cells were measured by flow cytometry. Differences in continuous variables between groups were tested by ANOVA with the Scheffé F-test used as a post hoc test, and correlations were analyzed by a linear regression method. RESULTS: The plasma concentration of MMP-7 was increased in patients with stable and unstable CAD, whereas MMP-2 and -3 concentrations were decreased. The plasma concentration of TIMP-1 was significantly increased in patients with unstable CAD. MMP-2, -3, and -7 showed no correlations with established markers of inflammation. However, MMP-2 correlated positively with the number of natural killer cells in patients with stable and unstable CAD. CONCLUSION: Plasma concentrations of MMPs and TIMPs may be markers of CAD but appear to be differentially regulated.

Denial in patients with a first-time myocardial infarction: relations to pre-hospital delay and attendance to a cardiac rehabilitation programme.

BACKGROUND: Survival of a myocardial infarction and subsequent prognosis are highly dependent on the time between onset of symptoms and medical intervention. DESIGN: This cross-sectional study examines whether patients who used the psychological defence mechanism of denial when faced with symptoms of a first-time myocardial infarction tended to also show a prolonged delay in going to the hospital and to be less willing to participate in a cardiac rehabilitation programme. METHODS: One hundred and seven patients, 78 men and 29 women, were enrolled in this study. The sample was divided into two groups depending on whether the patients sought medical help within 4 h after they began experiencing myocardial infarction symptoms (non-delayers) or whether they waited longer (delayers). Denial was measured with the Hackett and Cassem semi-structured interview 3-5 days after the patients entered the hospital. Data on participation (attenders) or not (non-attenders) in the rehabilitation programme was also obtained. RESULTS: Forty-nine patients exhibited a prolonged delay and 76 patients did not attend the rehabilitation programme. Both prolonged delay and a lesser readiness to attend the rehabilitation programme that was offered were related to a greater use of denial. In addition, the great majority of the patients categorized as being high deniers were found to also be both delayers and non-attenders. CONCLUSIONS: The results suggest denial to increase the health risks of persons potentially prone to myocardial infarction. If our knowledge about this psychological defence mechanism is increased, we might be able to reach more patients in alternative and individually based cardiac rehabilitation programmes.

Circulating levels of proinflammatory cytokines and neutrophil-platelet aggregates in patients with coronary artery disease.

Several lines of evidence indicate that increased inflammatory activity in peripheral blood is associated with the acute coronary syndrome. Systemic inflammation in clinically stable conditions of coronary artery disease has been less studied. We examined cytokine profiles in 20 patients who had acute coronary syndrome, 45 who had angiographically verified coronary artery disease and stable angina pectoris, and 45 healthy controls. Circulating levels of C-reactive protein, interleukin-1 receptor antagonist, interleukin-2 receptor, interleukin-6, interleukin-10, and interleukin-18 were determined. Subpopulations of peripheral immune cells, including neutrophil-platelet aggregates, were analyzed by 3-color flow cytometry using a panel of monoclonal antibodies. Patients who had acute coronary syndrome and stable angina pectoris had significantly higher levels of C-reactive protein, interleukin-6, and interleukin-1 receptor antagonist than did controls, whereas levels of interleukin-2 receptor, interleukin-10, and interleukin-18 were similar across groups. Patients had significantly more neutrophils, and the numbers of neutrophil-platelet aggregates were particularly large in patients who had stable angina pectoris. High levels of C-reactive protein, interleukin-6, and interleukin-1 receptor antagonist in patients were significantly related to numbers of neutrophils and neutrophil-platelet aggregates but not to other immune cell subpopulations. The data suggest that the interaction between neutrophils and platelets is an important component of proinflammatory activity seen in peripheral blood of stable and unstable forms of coronary artery disease.