Cerebrospinal fluid interleukin-1 receptor antagonist and tumor necrosis factor—α following subarachnoid hemorrhage

Abstract

Subarachnoid hemorrhage (SAH) causes an inflammatory reaction and may lead to ischemic brain damage. Experimental ischemia has been shown to be connected with the alarm-reaction cytokines interleukin-1 receptor antagonist (IL-1Ra) and tumor necrosis factor-alpha (TNF alpha). Increased levels of these cytokines, however, have not been detected thus far in patients following an SAH event. For this reason daily cerebrospinal fluid (CSF) samples were collected from 22 consecutively enrolled patients with SAH and from 10 non-SAH patients (controls). The CSF samples were studied using immunoassays for IL-1Ra and TNF alpha to investigate whether an SAH caused increased cytokine levels. The mean IL-1Ra levels were significantly higher in patients with SAH who were in poor clinical condition on admission than in those who were in good condition (318 pg/ml vs. 82 pg/ml, p < 0.02). The IL-1Ra levels increased during delayed ischemic episodes and after surgery in patients who were in poor clinical condition. Significant increases in IL-1Ra and TNF alpha were detected during Days 4 through 10 in patients suffering from SAH who eventually had a poor outcome (p < 0.05). Patients with good outcomes and control patients had low levels of these cytokines. The levels of IL-1Ra increased after surgery in patients with Hunt and Hess Grades III through V, but not in those with Grade I or II. This finding indicates that patients in poor clinical condition have a labile biochemical state in the brain that is reflected in increased cytokine levels following the surgical trauma. Both IL-1Ra and TNF alpha are known to induce fever, malaise, leukocytosis, and nitric oxide synthesis and to mediate ischemic and traumatic brain injuries. The present study shows that levels of these cytokines increase after SAH occurs and that high cytokine levels correlate with brain damage. It is therefore likely that fever, leukocytosis, and nitric oxide synthesis are also mediated by IL-1 in patients suffering from SAH and it is probable that the inflammatory mediators contribute to brain damage.

Cerebrovascular Inflammation Following Subarachnoid Hemorrhage

“…In human studies, it was found that on admission, the IL-1ra level was higher (318 ± 302 pg /ml) in patients who were in poor clinical condition (Hunt and Hess Grades III -IV), and in patients with an unfavorable outcome or who experienced an episode of delayed ischemic deficit, there were marked increases in CSF IL-1ra levels between days 3 and 12 (>1000 pg /ml). On the contrary, patients with favorable outcome and good clinical condition had levels of IL-1ra only slightly higher than control patients (228,229).…”

“…Mathiesen et al (228) showed that on admission of patients suffering from SAH, CSF levels of TNF-a were similar to control patients (means 25 -52 pg /ml), and that in patients with an unfavorable outcome, i.e., Glasgow outcome scale 1 to 3, CSF levels of TNF-a were increased between days 4 and 10 to the range 200 -300 pg /ml. As for IL-1ra, the pattern of TNF-a levels fits with the time course of symptomatic VS or DID (delayed ischemic deficit) in humans.…”

Therapeutically Targeting Tumor Necrosis Factor-α/Sphingosine-1-Phosphate Signaling Corrects Myogenic Reactivity in Subarachnoid Hemorrhage

“…11,12,29 There is broad consensus that SAH changes cerebrovascular function by inducing an inflammatory reaction within the vascular wall. 9,[30][31][32] Although several cytokines may be involved, [33][34][35][36] TNFα has garnered special attention because (1) cerebrospinal 33 and interstitial fluid 34 TNFα levels rise and peak between 4 and 10 days post-SAH (ie, a time-frame consistent with a role in DCI); (2) elevated TNFα levels associate with angiographic vasospasm, abnormal cerebral flow velocities, and poor clinical outcome [35][36][37] ; and (3) anti-TNFα therapy (infliximab) prevents basilar artery vasospasm in experimental SAH. 9 Our results demonstrate that TNFα augments olfactory artery myogenic tone in vitro; targeted disruption of TNFα signaling (TNFα and TNFα receptor 1 knockout models) confirmed this function in vivo after SAH.…”

Inhibitory Effect With Antisense Mitogen-Activated Protein Kinase Oligodeoxynucleotide Against Cerebral Vasospasm in Rats

“…Considering that free radicals or cytokines are associated with the pathogenesis of cerebral vasospasm after SAH, 31,32 part of the mechanisms of vasospasm might be mediated by the activation of MAPK. Gerthoffer et al 7 and Hedges et al 8 have speculated that MAPK activation mediates cerebral vasospasm because MAPK activation induces the phosphorylation of caldesmon that, in turn, leads to vascular smooth muscle contraction.…”