Modulation of airway responses by prostaglandins in young and fully grown rabbits

Maturational changes have been noted in neurally mediated contractile and relaxant responses in airways from New Zealand White rabbits. In this study, we focused on prostaglandins with bronchoprotective properties as potential modulators of airway tone in maturing rabbits. Tracheal rings from 1-, 2-, and 13-wk-old rabbits were assessed for neurally mediated contractile and relaxant responses produced by electrical field stimulation (EFS) of nerves in the presence and absence of the prostaglandin inhibitor, indomethacin (Indo). We also measured EFS-induced release of prostaglandin E2 (PGE2) and the stable metabolite of prostacyclin, 6-keto-prostaglandin F1α (6-keto-PGF1α). In the presence of Indo, EFS produced significant increases in contractile responses in segments from 1- and 2-wk-old animals but not in segments from 13-wk adult rabbits. Tracheal rings from 1- and 2-wk-old animals precontracted with neurokinin A (NKA) relaxed 100% in response to EFS when Indo was not in the bath. In rings from 13-wk-old animals, relaxation was 40%. With Indo, relaxation was abolished in 1-wk-old animals and reduced to 30% in the 2- and 13-wk-old groups. Buffer from baths collected after EFS had significant increases in PGE2 and 6-keto-PGF1α released from tissues from 1- vs. 2- and 13-wk-old animals. Dose response curves to PGE2 using tissues precontracted to NKA showed significant increases in relaxant responses in 1- and 2- vs. 13-wk-old rabbits. In rabbit airways, this study demonstrates enhanced modulation of airway tone by PGE2 and greater release of the bronchoprotective prostaglandins PGE2 and prostacyclin early in life.

Indomethacin does not influence natural cell-mediated cytotoxic response to endurance exercise

Natural cell-mediated cytotoxicity (NCMC) has been shown to be attenuated during recovery from high-intensity or prolonged exercise. Two theories have been proposed to explain the transient suppression of NCMC: prostaglandin-induced inhibition of natural killer (NK) cell activity or a numerical redistribution of NK cells. This study was designed to examine the effects of oral indomethacin (a prostaglandin inhibitor) on NCMC before and after 1 h of high-intensity running (85% maximal oxygen uptake). A secondary purpose was to compare whole blood and isolated peripheral blood mononuclear cell assay procedures for assessing NCMC. Ten male distance runners completed two trials that were preceded by either 48 h of indomethacin (Indo; 150 mg/day) or no treatment (control). NK (CD3−/CD16+/CD56+) cell concentrations were significantly elevated postexercise but were not affected by Indo. NCMC was significantly suppressed at 1.5 h of recovery relative to preexercise only with the whole blood assay procedure. Indo was not found to influence NCMC, leukocyte, or lymphocyte subset concentrations. Mean cytotoxic response was significantly greater with the whole blood method.

Diagnostic value of specific T cell reactivity to drugs in 95 cases of drug induced liver injury

Background—Diagnosis of drug induced liver injury is usually based on a temporal relation between drug intake and clinical picture as well as on the exclusion of alternative causes. More precise diagnosis has been attempted by using in vitro specific T cell reactivity to drugs but the test has never reached general acceptability because of frequent negative results which could be explained, in part, by prostaglandin producing suppressor cells (PPSC).Aim—To analyse the diagnostic value of a modified test where lymphocyte responses to drugs are detected in the presence of a prostaglandin inhibitor.Patients—Ninety five patients with a clinical diagnosis of drug induced liver injury, 106 healthy controls, 35 individuals with recent exposure to the same drugs without adverse effects, and 15 patients with liver disease unrelated to drugs.Methods—Peripheral blood mononuclear cells (PBMC) were cultured in the presence of drugs alone and in the presence of drugs and a prostaglandin inhibitor. Responses were assessed by3H-thymidine incorporation in lymphocytes. Results were expressed as counts per minute and as stimulation indexes (SI).Results—When PBMC were stimulated with drugs alone, lymphocyte sensitisation to drugs (SI>2) was detected in 26% of the cases. This was noticeably increased (56%) when a prostaglandin inhibitor was added to the cultures. No reactivity was found in controls. In patients with possible sensitivity to several drugs, lymphocyte reactivity was detected to only one drug. The severity of the lesions, as assessed by aminotransferase concentrations and disease duration, was lower in patients with evidence of PPSC.Conclusions—This new approach is useful for the diagnosis of drug induced liver injury, particularly in patients exposed to more than one drug; furthermore, the presence of putative PPSC is associated with less severe forms of drug induced hepatitis.