Resolution of inflammation in neuromyelitis optica spectrum disorders.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are a spectrum of neuroinflammatory disorders associated with autoimmune antibodies against aquaporin-4 (AQP4). Accumulating evidence suggests that inflammation is involved in NMOSD pathogenesis. Resolution of inflammation, which is a highly regulated process mediated by specialized pro-resolving lipid mediators (SPMs) is important to prevent over-responsive inflammation. Deficiency in resolution of inflammation may lead to or accelerates inflammatory diseases. However, whether resolution of inflammation is impaired in NMOSD is not known. The objective of this study was to analyze the levels of SPMs in the serum and cerebrospinal fluid (CSF) of NMOSD patients, and to explore the roles of SPMs in clinical features of NMOSD. METHODS: Thirty-five patients with NMOSD, 34 patients with multiple sclerosis, and 36 patients with non-inflammatory neurological diseases were enrolled in this study. Pro-resolving mediators including Annexin A1 (ANXA1) and resolvin D1 (RvD1), as well as pro-inflammatory lipid mediator leukotriene B4 (LTB4) levels were analyzed by enzyme-linked immunosorbent assay. Pro- and anti-inflammatory cytokines as well as chemokine levels were analyzed using cytometric beads array (CBA). RESULTS: Our results showed RvD1 levels were significantly decreased, whereas LTB4 levels were significantly increased in the CSF of NMOSD patients. AQP4-IgG titer was negatively correlated with RvD1 levels in the CSF of NMOSD patients. CONCLUSIONS: Decreased RvD1 levels indicate impaired resolution of inflammation in NMOSD patients. AQP4-IgG may contribute to increased inflammation and lead to unresolved inflammation in NMOSD.

[Leukotriene B4 level in cerebrospinal fluid of patients with tuberculosis meningitis and clinical significance].

OBJECTIVE: To investigate the level of leukotriene B4 (LTB4) in the cerebrospinal fluid (CSF) of patients with tuberculosis meningitis (TBM) and analyze the relationships of LTB4 level with cytological parameters and disease severity. METHODS: By ELISA, LTB4 levels were measured in the CSF of the patients with TBM (diagnosed by modified Ziehl-Neelsen staining), cryptococcal meningitis (CM), central nervous system leukemia (CNSL) or non-inflammatory neurological disease (NIND). CSF cytological testing was performed in TBM patients. Disease severity was evaluated by modified Rankin scale (mRS). LTB4 levels were compared between different disease groups, and the relationships of LTB4 level with white blood cell (WBC) counts, neutrophil counts and disease severity were analyzed statistically. RESULTS: Compared with CM, CNSL or NIND patients, CSF LTB4 level in TBM patients was remarkably higher. CSF LTB4 level in TBM patients was related to neutrophil counts and neutrophil percentages, but not related to WBC counts. No simple linear correlation was found between CSF LTB4 level and disease severity. CONCLUSION: CSF LTB4 level in TBM patients can be used as a predictor of inflammation degree, but its relationship with disease severity and prognosis need further exploration.

Temporal profiles of cerebrospinal fluid leukotrienes, brain edema and inflammatory response following experimental brain injury.

The post-traumatic changes of leukotrienes LTC4, LTD4, LTE4, and LTB4 in cerebrospinal fluid of rats from 10 min to 7 days were investigated after controlled cortical impact in relation to brain edema and cellular inflammatory response. LTC4 increased five-fold at 4 h, normalized at 24 h, and showed another four-fold increase at 7 days. The same pattern was observed for LTD4 and LTE4. LTB4 however, behaved differently: concentrations were lower and levels peaked two-fold at 24 h. Edema in the injured hemisphere increased continuously up to 24 h without change contralaterally. Leukocyte infiltration, macrophage presence and microglia activation were most prominent at 24 h, 7 days and 24 h respectively. Leukotriene changes in CSF seem to reflect those in the affected tissue, with a time delay and in lower concentrations, and were not linearly correlated to brain edema. The initially high leukotriene levels are rather likely to contribute to the cytotoxic edema than to enhance a vasogenic edema component. The profile of LTB4 was parallel to the time course of leukocyte infiltration, indicating initiation of infiltration as well as prolonged production by leukocytes themselves. The second leukotriene peak at 7 days is likely to follow a different pathway and might be related to a production in macrophages or activated glia.

Leukotrienes in patients with clinically active multiple sclerosis.

OBJECTIVES: The role of leukotrienes (LTs) in the pathophysiology of multiple sclerosis (MS) has been controversially discussed in the past. Studies of LTs in the cerebrospinal fluid (CSF) revealed different results mainly because of analytical difficulties. MATERIAL AND METHODS: In the present study we used highly sensitive and specific analytical methods for measuring LTs in the CSF as well as in urine samples from 20 patients with active MS and 20 control patients with noninflammatory neurological disorders. RESULTS: LTB4 concentrations in CSF were almost twice as high in MS patients compared with controls (P < 0.001). CSF concentrations of the cysteinyl-LTs (LTC4, LTD4 and LTE4) as well as urinary LTE4 showed no significant differences compared with controls (P > 0.05). In addition, there was no significant association between CSF pleocytosis, clinical severity or time of disease onset. CONCLUSIONS: The increased concentration of LTB4 in the CSF of MS patients may indicate a biological importance for this mediator in MS.

Analysis of leukotrienes in cerebrospinal fluid of a reference population and patients with inborn errors of metabolism: further evidence for a pathognomonic profile in LTC(4)-synthesis deficiency.

Cysteinyl leukotrienes (LTC(4), LTD(4), LTE(4)) are potent lipid mediators derived from arachidonate in the 5-lipoxygenase pathway. Recently, the first inborn error of leukotriene synthesis, LTC(4)-synthesis deficiency, has been identified in association with a fatal developmental syndrome. The absence of leukotrienes in cerebrospinal fluid was one of the most striking biochemical findings in this disorder. We analysed leukotrienes in cerebrospinal fluid of patients with a broad spectrum of other well-defined inborn errors of metabolism, including glutathione synthetase deficiency (n=2), Zellweger syndrome (n=3), mitochondrial disorders (n=8), fatty acid oxidation defects (n=7), organic acidurias (n=7), neurotransmitter defects (n=5) and patients with non-specific neurological symptoms, as a reference population (n=120). The concentrations of leukotrienes were not related to age. Representative percentiles were calculated as reference intervals of each leukotriene. In all patients with an inborn error of metabolism concentration of cysteinyl leukotrienes and LTB(4) did not differ from the reference group. Our results indicate that absence of cysteinyl leukotrienes (<5 pg/ml) in association with normal or increased LTB(4) (50.0-67.3 pg/ml) is pathognomonic for LTC(4)-synthesis deficiency. The unique profile of leukotrienes in cerebrospinal fluid in this new disorder is primarily related to the defect and represents a new diagnostic approach.

LTB4 and LTC4 are absent in the cerebrospinal fluid of human immunodeficiency virus type 1-seropositive persons with toxoplasmic encephalitis: evidence for inhibition of 5-lipoxygenase by Toxoplasma gondii.

Previous studies on macrophages have shown that Toxoplasma gondii alters the metabolism of arachidonic acid with subsequent inability to generate leukotrienes (LT)s. LTB4 and LTC4 were analyzed in cerebrospinal fluid of 3 groups of human immunodeficiency virus (HIV) type 1-seropositive patients: with toxoplasmic encephalitis (TE) (n=10), with herpes simplex encephalitis (n=5), and without encephalitis (n=10) and in HIV-1-seronegative controls without inflammatory diseases (n=30) by specific immunoassays and gas chromatography-mass spectrometry. In HIV-1-seropositive subjects with TE, LTB4 and LTC4 were below the detection limit (<5.0 pg/mL) and thus significantly decreased (P<.01) compared with HIV-1-seropositive patients with herpes simplex encephalitis (LTB4, 148.5+/-47.6 pg/mL; LTC4, 116.4+/-36.9 pg/mL) and in those without encephalitis (LTB4, 46.1+/-16.8 pg/mL; LTC4, 48.3+/-21.3 pg/mL), and in controls (LTB4, 43.6+/-21.2; LTC4, 45.2+/-18.9 pg/mL). These results point to an essential role of inhibition of 5-lipoxygenase with subsequent failure of LT release as an important mechanism for the survival of T. gondii in vivo.

[Leukotrienes B4 and C4 in cerebrospinal of patients with multiple sclerosis]. / Leukotrieny B4 i C4 w plynie mózgowo--rdzeniowym chorych na stwardnienie rozsiane.

Leukotrienes B4 and C4 have been assayed in CSF of 24 patients with the attacks or slowing-progressing course of multiple sclerosis, and in 23 patients with other noninflammatory diseases. Leukotrienes concentrations have been assayed with RIA technique with the use of commercially available kits manufactured by Amersham. Leukotrienes B4 and C4 levels in CSF of patients with multiple sclerosis have been 91.8 +/- 5.6, and 88.6 +/- 7.5 pg, and have been significantly higher than those in other neurological disorders (p < 0.01). Mean LTB4 and LTC4 levels have been significantly lower in patients with atherosclerotic dementia (69, 12.2 and 63, 02.9 pg/ml) or in patients with headache (72.7 +/- 2.8 and 64.5 +/- 8.2 pg/ml). Higher LTB4 and LTC4 levels in patients with multiple sclerosis is probably due to both increased penetration through blood-brain barrier and their synthesis in blood-brain barrier, and cerebral nervous tissue. Further investigations are necessary to show whether LTB4 and LTC4 levels may indicate a stage of inflammatory process activity and enable to draw any conclusions on efficacy of anti-inflammatory therapy.

Cerebrospinal fluid concentrations of leukotriene B4 in bacterial meningitis.

We investigated whether leukotriene B4 (LTB4), a granulocyte inflammatory mediator, is detectable in cerebrospinal fluid using a high performance liquid chromatographic method. In non-pleocytotic cerebrospinal fluid (n = 5) and in cerebrospinal fluid from children with aseptic meningitis (n = 8), LTB4 concentrations were below the detection limit (< 0.2 ng ml-1). In the range 0-20 ng ml-1, the recovery rate of LTB4 that had been added to non-pleocytotic cerebrospinal fluid was > 90%. In cerebrospinal fluid with a polymorphonuclear leucocyte (PMN) count higher than 1,000/ml, LTB4 was detectable in six out of seven specimens with a concentration of 0.35-3.3 ng ml-1. LTB4 concentration was significantly correlated with PMN number. These results, together with observations in animal models, are discussed with regard to a pathophysiological role of LTB4 in bacterial meningitis.

Leukotriene B4 and C4 in cerebrospinal fluid from children with meningitis and febrile seizures.

Concentrations of immunoreactive leukotriene C4 (LTC4) and leukotriene B4 (LTB4) in the cerebrospinal fluid from 18 patients with aseptic meningitis, including 2 patients with encephalitis and 4 patients with febrile seizures, were measured by a sensitive and specific radioimmunoassay; these results were compared with those from control subjects. The concentrations of both LTC4 and LTB4 were elevated significantly in patients with meningitis (LTC4: 115.6 +/- 47.7 pg/ml; LTB4: 1,603.0 +/- 273.5 pg/ml; n = 18) compared to controls (LTC4: 83.2 +/- 21.6 pg/ml; LTB4: 1,219.3 +/- 161.5 pg/ml; n = 12; P < .05 and P < .01, respectively). However, there was no significant increase in LT levels in patients with febrile seizures. These findings suggest that LTs may play an important role in the inflammatory response induced by viral infections of the central nervous system.

Low levels of LTB4 in cerebrospinal fluid of AIDS patients with cryptococcal meningitis.

In this study we evaluated the release of leukotriene B4 (LTB4) in the cerebrospinal fluid (CSF) of 12 patients with Acquired Immunodeficiency Syndrome (AIDS), which disease was complicated by Cryptococcal Meninigitis and in CSF of 12 control subjects with inflammatory and degenerative pathologies of the Central Nervous System (CNS). We obtained low levels of LTB4 in all the AIDS patients (mean 60.5 pg/ml), while the HIV negative subjects with degenerative and inflammatory pathologies of CNS showed a mean of 91.5 pg/ml. The finding of low levels of this inflammatory reaction mediator agrees with the limited clinical symptoms of cryptococcal meningoencephalitis in patients affected by AIDS.

[Leukotrienes in cerebrospinal fluid of patients with subacute sclerosing panencephalitis]. / Leukotrieny w plynie mózgowo-rdzeniowym chorych na podostre stwardniajace zapalenie mózgu.

In the cerebrospinal fluid of two groups of patients with subacute sclerosing panencephalitis (SSPE), the determinations of LTB4 and LTC4 leukotriene concentrations were performed by radioimmunoassay (RIA). In the first group of 10 patients with chronic SSPE (from 2 to 11 years), the LTB4 and LTC4 levels were 94.8 +/- 17.0 and 97.4 +/- 16.8 pg/ml respectively, and were significantly higher than those in six patients with discopathy, epilepsy and headache (p < 0.01). In the second group of 10 patients with beginning SSPE (disease duration from 1 to 11 months) LTB4 level was lower (was not different from that in the control group), while LTC4 concentration was 97.6 +/- 10.8 pg/ml and again was significantly raised. Higher LTB4 and LTC4 levels in the cerebrospinal fluid of patients with SSPE indicate that these compounds participate in chronic inflammatory reaction around cerebral veins.

Leukotrienes in the cerebrospinal fluid of multiple sclerosis patients.

The concentration of the leukotrienes B4 (LTB4) and C4 (LTC4) was measured in the cerebrospinal fluid (CSF) of 38 multiple sclerosis (MS) patients and 51 with other neurological diseases. The LTB4 and LTC4 levels were significantly elevated in MS compared with the controls. The findings suggest that lipoxygenase products might play a pathogenetic role in the early, encephalitogenic phase of MS. The administration of lipoxygenase inhibitors or leukotriene antagonists might well open new perspectives for the treatment of MS.

Mediator release in cerebrospinal fluid of human immunodeficiency virus-positive patients with central nervous system involvement.

In this study we evaluated the release of some mediators of inflammatory reactions such as histamine (H), leukotriene B4 (LTB4), leukotriene C4 (LTC4) and prostaglandin D2 (PGD2) in the cerebrospinal fluid (CSF) of 15 patients with acquired immunodeficiency syndrome (AIDS), eight with opportunistic infections of the central nervous system (CNS) and seven without HIV-related neurological pathology, and of 25 HIV-negative control subjects with other neurological diseases. The cerebrospinal LTB4 level was increased in all the AIDS patients (mean 348 pg/ml); the control group revealed normal levels of LTB4 in the CSF (mean 63.2 pg/ml). The PGD2 level in the HIV-positive (mean 264 pg/ml) patients was higher than of the control subjects (mean 50 pg/ml), while low LTC4 levels were found both in the HIV-positive and control groups. We did not find any significant concentration of H in the CSF of either the HIV-positive or the control subjects. These findings may be due to the presence of chronic HIV infection or to the opportunistic infections of the CNS that so often occur in the latest stages of the disease.

Eicosanoids in human ventricular cerebrospinal fluid following severe brain injury.

Recent evidence has shown that a variety of prostaglandins and leukotrienes can be produced in brain tissue after injury in animals. It has also been speculated that increases in brain prostaglandins occur in humans following injury. Ventricular cerebrospinal fluid (CSF) samples have been obtained from children with static lesions (controls) as well as children with acute brain injury and eicosanoids measured by immunologic techniques. Metabolites of prostacyclin (6-keto-PGF1 a) and thromboxane A2 (thromboxane B2) were the major eicosanoids found in CSF, and levels of these compounds were increased 3-10 times in acutely injured patients. Prostaglandin E2 was also found in lower amounts, although in one case its level was very high. Prostaglandin D2 was also present, but in low amounts. No leukotrienes were found in CSF samples that were purified by HPLC prior to immunoassay. Elevated levels of hydroxyeicosatetraenoic acids (HETEs) were observed in those samples stored frozen, but these metabolites were most probably due to autooxidation of arachidonic acid in CSF. Arachidonic acid concentration in CSF was typically found to be in the range of 10-200 ng/ml, but was found to be 5-10 fold higher in one severely injured patient. Thus, elevated free arachidonic acid and various oxygenated metabolites were observed in CSF following brain injury.