ABSTRACT
BACKGROUND AND PURPOSE: The most potent vasoconstrictor known, endothelin-1, is currently considered to mediate cerebral vasospasm in subarachnoid hemorrhage (SAH), which can cause delayed cerebral ischemia. In our study, we performed clinical and in vitro experiments to investigate the origin and the mechanisms of the secretion of endothelin-1 in SAH. METHODS: Endothelin-1 and markers of inflammatory host response (interleukin [IL]-1ss, IL-6, and tumor necrosis factor-alpha) were comparatively quantified in the cerebrospinal fluid (CSF) of SAH patients and control subjects, and concentrations were related to clinical characteristics. Furthermore, mononuclear leukocytes isolated from the CSF of SAH patients and control subjects were analyzed regarding their mRNA expression of endothelin-1 and inflammatory cytokines. Finally, complementary in vitro experiments were performed to investigate whether coincubation of blood and CSF can trigger leukocytic mRNA expression and release of these factors. RESULTS: Activated mononuclear leukocytes in the CSF of SAH patients synthesize and release endothelin-1 in parallel with known acute-phase reactants (IL-1ss, IL-6, and tumor necrosis factor-alpha). Complementary in vitro experiments not only further confirmed this leukocytic origin of endothelin-1 but also showed that aging and subsequent hemolysis of blood is sufficient to induce such endothelin-1 production. CONCLUSIONS: The demonstration that endothelin-1 is produced by activated CSF mononuclear leukocytes suggests that subarachnoid inflammation may represent a therapeutic target to prevent vasospasm and delayed cerebral ischemia after SAH.
Subject(s)
Acute-Phase Proteins/biosynthesis , Cerebrospinal Fluid/cytology , Endothelin-1/blood , Leukocytes/metabolism , Subarachnoid Hemorrhage/blood , Acute-Phase Proteins/analysis , Adult , Aged , Cytokines/blood , Cytokines/cerebrospinal fluid , Endothelin-1/biosynthesis , Female , Humans , Leukocytes/chemistry , Male , Middle Aged , Reverse Transcriptase Polymerase Chain Reaction , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/cerebrospinal fluidABSTRACT
Subarachnoidal release of inflammatory cytokines (interleukin (IL)-1beta, IL-6, and tumour necrosis factor (TNF)-alpha) was characterised in 35 patients with subarachnoid haemorrhage (SAH) and control subjects and compared with development of complicating haemodynamic abnormalities in basal cerebral arteries and clinical outcome. Serial analysis allowed the observation of a subacute response profile of these key mediators of inflammation in the subarachnoidal space. This compartmentalised inflammatory host response was closely associated in time and extent with development of increased blood flow velocities in the basal cerebral vessels as recorded by transcranial Doppler sonography. Moreover, intrathecal secretion of inflammatory cytokines was significantly increased in patients with poor clinical outcome. Together, these findings suggest a role of excessive compartmentalised inflammatory host response in pathogenesis of cerebrovascular complications after SAH.
Subject(s)
Cerebral Arteries/physiopathology , Cerebrovascular Circulation/physiology , Cytokines/blood , Subarachnoid Hemorrhage/blood , Subarachnoid Hemorrhage/physiopathology , Vasospasm, Intracranial/blood , Vasospasm, Intracranial/physiopathology , Adult , Aged , Cytokines/cerebrospinal fluid , Cytokines/physiology , Female , Humans , Inflammation/blood , Inflammation/physiopathology , Interleukin-1/blood , Interleukin-1/cerebrospinal fluid , Interleukin-1/physiology , Interleukin-6/blood , Interleukin-6/cerebrospinal fluid , Interleukin-6/physiology , Male , Middle Aged , Prognosis , Subarachnoid Hemorrhage/cerebrospinal fluid , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/cerebrospinal fluid , Tumor Necrosis Factor-alpha/physiologyABSTRACT
Endothelin-1 is the most potent vasoconstrictor known to date. This peptide is believed to play a pathophysiological role in the development of vasospasm, the most important complication of subarachnoid hemorrhage (SAH). In the present study we investigated the release of endothelin-1 in SAH and analyzed the cellular source of this peptide. At a protein and mRNA level we were able to show that endothelin-1 is produced by mononuclear leukocytes. Complementary in vitro studies revealed that aging and subsequent hemolysis of blood is sufficient to induce production of endothelin-1 by mononuclear leukocytes. Thus, cerebrospinal fluid-derived mononuclear leukocytes are a source of endothelin-1 in patients suffering from SAH. This finding may have important therapeutic implications as anti-leukocyte strategies could prevent cerebrovascular complications in SAH patients.