Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS). Although prostaglandin (PG) concentrations are increased in cerebrospinal fluid of MS patients, the role of PGs in MS is unknown. We examined this issue by subjecting mice deficient in each PG receptor type or subtype to EAE induction and using agonists or antagonists selective for each of the four PGE receptor (EP) subtypes. Among PG receptor-deficient mice, only EP4(-/-) mice manifested significant suppression of EAE, which was mimicked in wild-type mice and to a greater extent, in EP2(-/-) mice by administration of the EP4 antagonist ONO-AE3-208 during the immunization phase. EP4 antagonism during immunization also suppressed the generation of antigen-specific T helper (Th) 1 and Th17 cells in wild-type mice and to a greater extent, in EP2(-/-) mice. ONO-AE3-208 administration at EAE onset had little effect on disease severity, and its administration throughout the experimental period did not cause significant reduction of the peak of disease, suggesting that, in addition to its facilitative action during the immunization phase, EP4 exerts a preventive action in the elicitation phase. Administration of the EP4 agonist ONO-AE1-329 at EAE onset delayed and suppressed disease progression as well as inhibited the associated increase in permeability of the blood-brain barrier. Thus, PGE(2) exerts dual functions in EAE, facilitating Th1 and Th17 cell generation redundantly through EP4 and EP2 during immunization and attenuating invasion of these cells into the brain by protecting the blood-brain barrier through EP4.

Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion.

Two distinct helper T (TH) subsets, TH1 and TH17, mediate tissue damage and inflammation in animal models of various immune diseases such as multiple sclerosis, rheumatoid arthritis, inflammatory bowel diseases and allergic skin disorders. These experimental findings, and the implication of these TH subsets in human diseases, suggest the need for pharmacological measures to manipulate these TH subsets. Here we show that prostaglandin E2 (PGE2) acting on its receptor EP4 on T cells and dendritic cells not only facilitates TH1 cell differentiation but also amplifies interleukin-23-mediated TH17 cell expansion in vitro. Administration of an EP4-selective antagonist in vivo decreases accumulation of both TH1 and TH17 cells in regional lymph nodes and suppresses the disease progression in mice subjected to experimental autoimmune encephalomyelitis or contact hypersensitivity. Thus, PGE2-EP4 signaling promotes immune inflammation through TH1 differentiation and TH17 expansion, and EP4 antagonism may be therapeutically useful for various immune diseases.

Newly developed T-wave inversion with cardiac wall-motion abnormality predominantly occurs in middle-aged or elderly women after noncardiac surgery.

PURPOSE: The study was done to determine the characteristics and prevalence of myocardial ischemia with inverted T waves after noncardiac surgery. METHODS: A list of patients who developed electrocardiogram (ECG) T-wave inversion associated with wall-motion abnormalities observed by transthoracic echocardiography (TTE) following noncardiac surgery was generated from the intensive care unit (ICU) medical records database between January 1, 1995, and December 31, 2000. The hospital records of these patients were analyzed retrospectively. RESULTS: Among 4219 patients (2187 men and 2032 women) who were admitted to the ICU after noncardiac surgery, 13 developed myocardial ischemia with inverted T waves postoperatively. All of the patients were middle-aged or elderly women with no history of coronary artery disease; nine of them had undergone intraabdominal surgery. Characteristic ECG findings included inverted T waves in the left precordial leads, which subsequently became prominent with QT prolongation. In all of these patients, wall-motion abnormalities were observed on the anterior wall, but these resolved within 60 days of the episode. Myocardial ischemia was asymptomatic, with neither hemodynamic changes nor adverse cardiac events. CONCLUSION: Newly developed giant negative T waves with QT prolongation in the ECG may indicate myocardial stunning, but do not in themselves imply a poor prognosis. The marked preponderance of middle-aged and elderly women with this type of myocardial ischemia remains to be explained.

[Anaphylactoid reaction to dibucaine during spinal anesthesia].

A 71-year-old man with a history of allergic rhinitis for 6 years received spinal anesthesia using 2 ml of 0.3% dibucaine for transurethral prostatectomy. Two months previously he had undergone prostate biopsy and cystoscopy under spinal anesthesia with isobaric bupivacaine uneventfully. Forty five minutes after injection of dibucaine he complained of itching in the periorbital area, and developed tremor and muscle rigidity followed by loss of consciousness. Soon after, his blood pressure decreased to 40 mmHg, and erythema appeared over his body. Symptoms were relieved by epinephrine, hydrocortisone and antihistamine agents, but ten minutes after the treatment he again developed hypotension and erythema. Continuous infusion of epinephrine was needed for complete relief of symptoms. An intradermal test with 0.3% dibucaine carried out 6 days after surgery demonstrated a 12 x 8 mm wheal with flare. Although anaphylactic reaction to an amide local anesthetic has been reported to be quite rare, this is the 7th case report of anaphylactic reaction to dibucaine used for spinal anesthesia in Japan.