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(Stroke. 1996;27:1734-1738.)
© 1996 American Heart Association, Inc.

Articles

Leukocyte Activation Detected by Increased Plasma Levels of Inflammatory Mediators in Patients With Ischemic Cerebrovascular Diseases

A.M. Elneihoum, MD; P. Falke, MD, PhD; L. Axelsson, BS; E. Lundberg, BS; F. Lindgarde, MD, PhD K. Ohlsson, MD, PhD

the Departments of Medicine (A.M.E., P.F., F.L.) and Surgical Pathophysiology (L.A., E.L., K.O.), Lund University, University Hospital, Malmo, Sweden.

Correspondence to Dr Ali M. Elneihoum, Department of Medicine, Lund University, University Hospital, S-20502 Malmo, Sweden.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Background and Purpose Leukocytes have been implicated in the development of ischemic atherosclerotic vascular diseases. In a prospective study we investigated whether the plasma concentrations of inflammatory mediators, ie, proteases and cytokines, as markers for systemic leukocyte activation, are increased in patients with acute ischemic cerebrovascular diseases.

Methods Using enzyme-linked immunosorbent assays, we measured the plasma levels of neutrophil gelatinase-associated lipocalin (NGAL), neutrophil proteinase 4 (NP4), tumor necrosis factor- (TNF), and soluble TNF receptor protein-1 p55 (sTNFR-1) in 120 patients with acute ischemic cerebrovascular insult (72 with stroke and 48 with transient ischemic attack [TIA]) and in 35 age- and sex-matched healthy subjects.

Results Compared with the control group, plasma NGAL levels were higher in the stroke group (P<.0001) and the TIA group (P<.01); plasma NP4 levels were higher in the stroke group (P<.0001) and the TIA group (P<.01); and plasma sTNFR-1 levels were higher in the stroke group (P<.04). There was significant correlation between the plasma levels of fibrinogen and those of both sTNFR-1 (r=.32; P=.005) and NGAL (r=.40; P=.0001) and between the erythrocyte sedimentation rate and the plasma levels of both sTNFR-1 (r=.35; P=.001) and NGAL (r=.34; P=.002).

Conclusions Our study demonstrated that markers for systemic leukocyte activation, ie, plasma levels of cytokines and proteases, were higher in patients with acute ischemic cerebrovascular disease than in healthy control subjects. Activated leukocytes and leukocytic mediators may have an important role in acute cerebrovascular ischemia and its consequences.

Key Words: cerebral ischemia • cytokines • leukocytes

	Introduction

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Over the last two decades, abundant evidence has accumulated implicating leukocytes in the etiology and pathophysiology of ischemic/thrombotic vascular diseases, and numerous abnormalities of leukocyte function have been described in patients with acute and chronic ischemic vascular diseases.^{1 2 3} Leukocyte activation can be assessed by measuring the plasma concentrations of various secretory mediators, ie, cytokines and proteases.

TNF is a potent inflammatory cytokine produced by various cells (eg, fibroblast, endothelial, and neuronal cells) but mainly by activated mononuclear leukocytes.⁴ sTNFR-1, the shedded extracellular portion of the TNF receptor,⁵ is secreted mainly by mononuclear cells, and its concentration correlates well with that of TNF and appears to reflect the activational status of the TNF/TNF-receptor system.⁶ Both TNF and sTNFR-1 were found to be elevated in various infectious, inflammatory, autoimmune, and malignant diseases.^{4 6}

NP4, a major neutral protease of human PMN leukocytes,⁷ can degrade structural and soluble proteins in the tissues and body fluids and is elevated in various infectious and inflammatory diseases.⁸ NGAL, which is present in neutrophil granules, can cleave various collagens and gelatins and has been found to have an important role in inflammation.^{9 10} Both NP4 and NGAL have been considered good markers of PMN leukocyte activity.

Activated mononuclear and PMN cells and their secretory mediators are believed to have an important role in the pathogenesis of ischemic vascular diseases, thrombus formation, and tissue injury after ischemia and reperfusion.^{11 12}

As an initial study of a follow-up study, we examined the plasma level of leukocytic mediators in patients with acute ischemic stroke and TIAs as well as normal subjects. The purpose of the present study was to determine whether the plasma levels of these mediators, as markers for systemic leukocyte activation, are increased in those patients. We therefore investigated marker(s) for leukocyte involvement in such diseases and their prognostic importance in identifying patients at higher risk for further vascular ischemic insults.

	Subjects and Methods

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Patient Groups
The series as a whole comprised 120 consecutive patients with acute ischemic cerebrovascular insult who were admitted to the Angiology Section of the Department of Medicine, University Hospital, Malmo, Sweden, from May 1992 through October 1993. Seventy-two patients had ischemic stroke, and 48 had TIAs. Ischemic stroke was defined as outlined by Bonita,¹³ and TIA was defined as complete recovery from neurological symptoms within 24 hours.¹⁴

No patients with CT-verified intracranial hemorrhage, manifesting evidence of renal deficit (ie, serum creatinine >150 mmol/L), clinical evidence (symptoms and signs) of acute infection, or evidence of other acute vascular ischemia (eg, acute myocardial infarction) were included in the series.

All patients underwent complete, detailed recording of their history (including smoking habits) and physical and neurological examinations by an experienced physician at the department. Hypertension was defined as current treatment for hypertension or blood pressure greater than 160/90 mm Hg on two separate occasions. Diabetes mellitus was defined as previously diagnosed disease or a fasting blood glucose level greater than 7.0 mmol/L on two separate occasions. Smokers were defined as currently smoking during the study period.

Blood Variables
Venous blood was collected in the morning soon after admission (ie, 1 to 3 days after the cerebrovascular event). The following variables were measured: ESR, hemoglobin, total leukocyte count, blood glucose, HbA_1c, serum fibrinogen, serum total cholesterol, HDL cholesterol, and triglycerides. All variables were analyzed by routine methods at the Department of Clinical Chemistry, University Hospital, Malmo. In all cases cerebral CT and duplex ultrasound scanning of the carotid arteries were performed within 4 days of the cerebrovascular event (range, 2 to 4 days).

Control Group
Thirty-five age- and sex-matched healthy subjects (20 men and 15 women; mean age, 68 years; range, 66 to 69 years) from an ongoing health screening program, all without history of ischemic vascular diseases, were selected as a control group for the comparison of cytokine and protease levels.

ELISA
Venous blood was collected in commercially available EDTA tubes, kept in ice and centrifuged at 1360g for 10 minutes at 4°C. The plasma was separated within 1 hour and stored at -80°C until analyzed. We measured NP4 with an ELISA using a monoclonal antibody as the catching antibody,⁸ which measures both free and -1PI–bound NP4. We measured NGAL,¹⁰ TNF,¹⁵ and sTNFR-1¹⁵ with ELISAs using monoclonal or polyclonal antibodies as catching antibodies, as described earlier.

Statistical Analysis
Values are presented as median (range) or mean±SD as appropriate. For statistical comparisons, the unpaired t test, Mann-Whitney U test, or ANOVA model was used as appropriate. Spearman correlation coefficients were used to assess correlation between variables. Values of P<.05 were considered statistically significant.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Patient subgroup characteristics are presented in Table 1.

View this table: [in this window] [in a new window]   Table 1. Patient Subgroup Characteristics

Plasma NGAL Level
Plasma NGAL level was significantly higher in the stroke group (122 µg/L [67 to 625 µg/L]; P<.0001] and the TIA group (110 µg/L [69 to 351 µg/L]; P<.01) than in the control group (97 µg/L [37 to 212 µg/L]) (Table 2, Fig 1).

View this table: [in this window] [in a new window]   Table 2. Plasma Cytokine and Protease Levels in Patient Subgroups and Control Subjects

View larger version (16K): [in this window] [in a new window]   Figure 1. Plasma NGAL levels in patient and control groups. The symbol + indicates median; probability values are compared with control group.

Plasma NP4 Level
Plasma NP4 level was significantly higher in the stroke group (35 µg/L [12 to 154 µg/L]; P<.0001) and the TIA group (31 µg/L [17 to 112]; P<.01) than in the control group (24 µg/L [10 to 54 µg/L]) (Table 2, Fig 2).

View larger version (12K): [in this window] [in a new window]   Figure 2. Plasma NP4 levels in patient and control groups. The symbol + indicates median; probability values are compared with control group.

Plasma sTNFR-1 Level
Plasma sTNFR-1 level was significantly higher in the stroke group (3.1 µg/L [0 to 11.6 µg/L]; P<.04) than in the control group (2.1 µg/L [1 to 2.7 µg/L]) (Table 2, Fig 3).

View larger version (16K): [in this window] [in a new window]   Figure 3. Plasma sTNFR-1 levels in patient and control groups. The symbol + indicates median; probability values are compared with control group.

Plasma TNF Level
TNF was detectable in only 22 (18%) of the patient group as a whole (range, 0.6 to 15.3 µg/L) and in only 6 (17%) of the control group (range, 0.9 to 2.6 µg/L) (Table 2). There was no significant difference between the patient group as a whole and the control group with respect to plasma TNF concentration.

Correlation Between Variables (Within Patient Groups, n=120)
We found significant correlations between plasma levels of fibrinogen and those of both sTNFR-1 (r=.32; P=.005) and NGAL (r=.40; P=.0001); between ESR and the plasma levels of both sTNFR-1 (r=.37; P=.001) and NGAL (r=.35; P=.002); between leukocyte counts and plasma NGAL levels (r=.3; P=.0007); between plasma levels of sTNFR-1 and those of TNF (r=.5; P<.0006), NGAL (r=.45; P=.0001), and NP4 (r=.38; P=.0001); and between the plasma levels of NP4 and NGAL (r=.45; P<.001).

There were no significant correlations between the levels of these inflammatory mediators and age, blood glucose, HbA_1c, serum lipid levels, or the degree of carotid artery atherosclerotic changes detected by duplex ultrasonography.

There were no significant differences in the plasma levels of inflammatory mediators between subgroups with or without hypertension, diabetes mellitus, or history of smoking or between men and women.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Our study demonstrated that patients with acute ischemic cerebrovascular diseases have higher plasma levels of NGAL, NP4, and sTNFR-1, as markers of leukocyte activation, than control subjects. This suggests that activated leukocytes and their secretory inflammatory mediators are involved in acute cerebrovascular ischemia and its consequences.

Activated mononuclear cells, through the secretion of cytokines such as TNF with subsequent activation of receptor proteins, may exert procoagulant/prothrombotic effects by impairing the normal nonthrombogenicity of the endothelial wall,^{16 17} causing activation of other leukocytes,¹⁸ inducing platelet activation and aggregation, and causing activation of certain coagulation factors.^{19 20} This may cause further injury to the atherosclerotic endothelium and may be a crucial factor in the initiation, formation, and progression of arterial thrombosis.

Activated PMN leukocytes, on the other hand, appear to play a crucial role in tissue injury after ischemia and reperfusion, probably through the release of proteolytic enzymes such as NP4 and NGAL and the release of oxygen free radicals.^{12 21} Activated leukocytes with altered rheology can also cause mechanical obstruction of capillaries and collateral microvasculature,²² resulting in further ischemia and tissue injury. Our findings support those of previous studies that demonstrated altered leukocyte function and increased plasma levels of some cytokines in patients with other ischemic vascular diseases.^{23 24 25 26 27}

Our finding of a significant correlation between plasma levels of NGAL, sTNFR-1, and both plasma fibrinogen level and ESR suggests that a relationship exists between these important markers for ischemic vascular disease and the leukocytic mediators. However, from our data we could not conclude whether increased mediators reflect a chronic state or an acute postischemic alteration. However, we are performing a 3-year follow-up study to elucidate the nature of such a process. Vaddi and coworkers²³ found that mononuclear leukocytes from patients with stable as well as unstable angina pectoris secrete significantly more TNF than do cells from the control group. Previous studies have also demonstrated altered leukocyte function, increased aggregation and adhesion, and decreased leukocyte deformability in patients with acute as well as chronic ischemic vascular diseases.^{25 26 27} We suggest that systemic leukocyte activation could be a response to chronic vascular injury and inflammation in atherosclerosis, although this suggestion can only be determined by longitudinal study with prospective determination of leukocyte activation.

The significant correlations between different mediators may indicate a generalized activation of different leukocyte subtypes through similar stimuli, eg, inflammation or acute ischemia in our patient groups. Furthermore, cytokines such as TNF are known to stimulate other leukocytes,¹⁸ with subsequent activation and increase in mediators secretions.

The lack of any significant difference in plasma levels of TNF between the patient subgroups and the control group may be explained by the manifest dilution in peripheral blood, the very unstable nature of TNF, or the low sensitivity of the methods used, and we believe the effect of leukocyte activation and the release of some cytokines to be more pronounced locally at the site of injury and inflammation. The absence of correlation between the leukocyte count and the plasma levels of some inflammatory mediators (NP4, TNF, and sTNFR-1) may indicate the level of leukocyte activation to be independent of the leukocyte count. The plasma levels of inflammatory mediators probably reflect the level of leukocyte activation rather than leukocyte counts, and thus the level of leukocyte activation may be a more reliable marker of ischemic vascular disease and its complications than is the count itself. On the other hand, some mediators like TNF can be secreted by other cells, eg, fibroblast, endothelial, and neuronal cells.⁴

In our study we failed to demonstrate any correlation between the plasma cytokines, protease levels, and other risk factors for ischemic vascular diseases; this could be due to alteration of these variables after the acute ischemic insult in our patients. We believe that the study of any correlation between these mediators and risk factors for ischemic vascular diseases requires a group of asymptomatic atherosclerotic subjects, and we plan to study that aspect. In a previous study, Collier and coworkers²⁸ demonstrated plasma elastase levels to be higher in patients with type 1 (insulin-dependent) diabetes, although plasma elastase levels were demonstrated to lack correlation with neutrophil count, age, or plasma glucose and HbA_1c concentrations.

To summarize, we demonstrated evidence of increased systemic leukocyte activation reflected by high plasma levels of certain inflammatory mediators in patients with acute ischemic cerebrovascular diseases. We suggest that these may have an important role in acute cerebrovascular ischemia and its consequences. Further studies are needed to evaluate the nature of leukocyte activation, its role in atherosclerosis, and its prognostic importance.

	Selected Abbreviations and Acronyms

 

ELISA = enzyme-linked immunosorbent assay ESR = erythrocyte sedimentation rate HbA1c = glycosylated hemoglobin NGAL = neutrophil gelatinase-associated lipocalin NP4 = neutrophil protease 4 PMN = polymorphonuclear sTNFR-1 = soluble TNF receptor protein-1 p55 TIA = transient ischemic attack TNF = tumor necrosis factor-

	Acknowledgments

 
This study was supported by the Swedish Medical Research Council (project No. 3910), the Ernhold Lundstrom Foundation, the Swedish Heart Lung Foundation, the Funds of the Medical Faculty, University of Lund, and the Medical Research Foundations at University Hospital, Malmo. The help of Jan-Åke Nilsson with statistical analysis is gratefully acknowledged.

	Footnotes

 
Presented in part in abstract form at the Pan-European Consensus Meeting on Stroke Management, Helsingborg, Sweden, November 8-10, 1995.

Received April 12, 1996; revision received July 1, 1996; accepted July 5, 1996.

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This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Elneihoum, A.M. Articles by Ohlsson, K. Search for Related Content PubMed PubMed Citation Articles by Elneihoum, A.M. Articles by Ohlsson, K.