The Role Of Macrophage Migration Inhibitory Factor And Matrix Metalloproteinase-9 In Atherothrombotic Cerebral Infarction

Objective: Macrophage migration inhibitory factor (MIF) is an unique type of cytokine, which plays a key role on regulating inflammatory reaction and immune response .MIF was founded by Bloom and Bennett in 1966 when the two men were investigating delayed-type hypersensitivity. MIF, mainly generated by the activated T cells, could inhibit macrophage from moving, and promote macrophage to accumulate in vitro. In the year of 2000, Lin and other persons discovered that MIF participated in the pathophysiological process of atherosclerosis. Another study found that MIF might increase the expression of matrix metalloproteinase-9 (MMP-9). MMP-9 could degradate the lipid pool of plaque and the matrix of fibrous cap. Thereby the fibrous cap would be weaken and the plaque would rupture. And then acute cardiovascular and cerebrovascular events would occur.As an important inflammatory cytokine, whether MIF was involved in the occurrence of atherothrombotic cerebral infaction? At present, there is few of clinical studies about the relation between MIF and atherothrombotic cerebral infaction. By measuring the serum concentration of them in patients with acute cerebral infarction, we wanted to explore the mechanism of MIF, MMP-9 in cerebral atherosclerosis and verify whether they were significant in cerebral infarction as biochemical indicators.Methods: Subjects:①Cerebral Infarction group: 50 patiens (34 males, 16 females) with atherothrombotic cerebral infaction within three days, aged from 37 to 83 years old (mean age 59.74±9.06).②Case-control group: 20 patiens (14 males, 6 females) with cerebral hemorrhage within three days, aged from 43 to 85 years old (mean age 60.65±11.18).③Fifteen individuals were choosed as normal control group, (9 males, 6 females), aged from 44 to 71 years old (mean age 59.47±6.82). The three groups were age- and gender-matched. Fasting blood was taken from the ulnar vein. The concentration of MIF in serum was detected by the enzyme-linked immunosorbent assay (ELISA) kit produced by the United States R & D systems and MMP-9 by ShenZhen JingMei ELISA kit. Also blood glucose and blood lipid were measured. Cerebral infarction group was divided into three groups by infarct volume: small infarction group (<5 cm3), moderate infarction group (5~10 cm3) and big infarction group (>10 cm3). Also by neurologic impairment which was measured by National Instutes of Health stroke scale(NIHSS) it was divided into three groups: mild injury group (<4), moderate injury group (4 to 15) and severe injury group (>15). Forty-five patients with cerebral infarction and all cases of normal control group were examined by color doppler ultrasonograph to observe the atherosclerotic plaque and carotid artery intima-media thickness. According to the occurrence of plaque,they were divided into plaque positive and negative group. We also divided them into four groups: cerebral infaction patients with plaque group, cerebral infaction patients without plaque group, nomal person with plaque and nomal person without plaque group.Results: The concentration of MIF in Serum in cerebral infarction group (40.380±23.393 ng/mL)was higher than in cerebral hemorrhage group (27.783±14.898 ng/mL) and it significantly higher than in normal control group (25.824±10.423 ng/mL, P<0.01). The MMP-9 concentration of in serum in Cerebral hemorrhage group (3625.826±868.459 pg/ml) was statistically significantly higher than in normal control group (2873.656±1097.437 pg/ml, P<0.05) and slightly higher than in cerebral infarction group (3467.010±1041.45 pg/ml). We also found that the MIF concentrations in cerebral infarction patiens with and without carotid artery plaque (38.679±21.826 ng/ml and 47.057±26.498 ng/ml) were higher than in normal individual with carotid artery plaque (24.425±7.166 ng/ml). However, in different infarct volume groups and different neurologic impairment groups MIF and MMP-9 levels in serum did not differ statistically. In addition there was no significant difference between plaque positive and negative group. The study showed that there was a significantly positive correlation between MIF and MMP-9 in patients with cerebral infarction (r=0.367, P<0.01). After adjustment for gender, age and influences of plaque, MIF and MMP-9 were significantly associated with (P<0.01). In mild injury group, they were significantly positive correlated (r=0.588, P<0.01), and in small infarction group, they were positive correlated (r=0.392, P<0.05), while in other groups there was no correlation. A positive correlation was demonstrated between serum MIF levels and MMP-9 in normal control group (r=0.688, P<0.01). In cerebral hemorrhage group, analogous correlation was not found (r=0.123, P>0.05). In cerebral infarction and cerebral hemorrhage group, the level of MIF and MMP-9 did not significant correlated with NIHSS score. Our data show that MMP-9 positively correlated with cholesterol (CHOL), low-density lipoprotein (LDL), glucose (GLU) in cerebral hemorrhage group, but analogous correlation was not found in cerebral infarction group and the normal control group.Conclusion: Our data show clearly that individuals with acute cerebral infarction exhibit significantly elevated serum levels of MIF. After adjustment for the influence of plaque, MIF levels are still high. Moreover, MIF is significantly positivly correlated with MMP-9 in patients with cerebral infarction. In a word, MIF may be involved in the pathogenesis of acute cerebral infarction, because of it's inflammatory role, the promotion of angiogenesis and the elevation of MMP-9. The lipid pool of plaque and the matrix of fibrous cap will degradate. And then fiber caps will be weaken and the plaque will rupture. At last acute cerebrovascular events will be happen. If MIF, MMP-9 were early intervented, the inflammation-related damages to blood vessels will be delayed or prevented, the atherosclerosis development will be retarded and the occurrence and development of cerebral infarction will be delayed. It provided prospects for anti-atherosclerosis as well as the prevention and treatment of cerebral infarction in future.