The contributions of adrenal hormones, hemodynamic factors, and the endotoxin-related stress reaction to stable prostaglandin analog-induced peripheral lymphopenia and neutrophilia.

Stable prostaglandin analogs are known to induce lymphopenia and neutrophilia in a dose-dependent fashion after subcutaneous injection in rats. The purpose of the present investigation is to determine whether the prostaglandin-induced changes in circulating leukocytes might be secondary to hypotension with the ensuing release of adrenal hormones. The adrenal medullary catecholamine epinephrine was found to induce neutrophilia in both intact and adrenalectomized rats, and the glucocorticosteroid analog dexamethasone induced a profound lymphopenia in rats as reported by previous investigators. A stable analog of PGF2 alpha (15-S-15-methyl PGF2 alpha; M-PGF2 alpha) at the dose of 1 mg/kg induced marked systemic hypotension 1 h after injection, with lymphopenia and neutrophilia 6 h after injection. The non-prostanoid hypotensive agent captopril, at a dose of 63 mg/kg, induced a hypotension of similar magnitude and kinetics to that induced by prostaglandin. Captopril also induced lymphopenia and neutrophilia at 6 h, although the neutrophilia was of lesser magnitude than that induced by prostaglandins. The prostaglandin-induced lymphopenia was found to be mediated, at least in part, by the hypotension-induced release of adrenal hormones, as evidenced by the abrogation of lymphopenia in prostaglandin-treated adrenalectomized rats. Captopril-treated adrenalectomized rats, however, did develop a significant lymphopenia, suggesting that hypotension can result in lymphopenia even in adrenalectomized rats. The M-PGF2 alpha-induced neutrophilia in adrenalectomized rats, by comparison to captopril-induced neutrophilia in adrenalectomized rats, was greater than the neutrophilia expected as the result of hypotension alone. Indeed, the M-PGF2 alpha-induced neutrophilia in adrenalectomized rats was greater than the captopril-induced neutrophilia in sham-adrenalectomized rats. Thus, a portion of the neutrophilia induced by M-PGF2 alpha in intact rats may be mediated through adrenal-independent, hemodynamic-independent mechanisms. The possibility that M-PGF2 alpha might be inducing neutrophilia via an endotoxin-like stress reaction was investigated by examining changes in circulating white blood cells in intact and adrenalectomized C3H/HeN (endotoxin-sensitive) and C3H/HeJ (endotoxin-resistant) mice after prostaglandin administration. No quantitative differences in the prostaglandin-induced neutrophilia were noted in C3H/HeJ mice as compared to the C3H/HeN mice.(ABSTRACT TRUNCATED AT 400 WORDS)

In vivo induction of neutrophilia, lymphopenia, and diminution of neutrophil adhesion by stable analogs of prostaglandins E1, E2, and F2 alpha.

Stable analogs of prostaglandins E1, E2, and F2 alpha (M-PGE1, DM-PGE2, and M-PGF2 alpha) were found to induce marked changes in circulating white blood cell subsets in Brown-Norway rats after subcutaneous injection. Dose-response studies demonstrated that 1000 micrograms/kg of each prostaglandin induced a maximum neutrophilia in the range of 40-70% of the total white blood cell count (normal, 5-20%) and that as little as 5 micrograms/kg of M-PGE1 induced a significant neutrophilia (P less than 0.05). Kinetic studies demonstrated that the maximum neutrophilia occurred 4-6 hours after injection of each prostaglandin and was not accompanied by the release of morphologically immature neutrophil forms from the bone marrow. Splenectomy slightly diminished the average neutrophilia at 2 hours but not at 4-6 hours after injection, which suggests that release of neutrophils from the spleen partially contributed to the early neutrophilia. Adherence experiments employing whole heparinized blood from rats given prostaglandins 6 hours prior to sacrifice demonstrated that neutrophils exposed to prostaglandins in vivo have diminished adherence to nylon wool columns, which suggests that diminished adherence of the marginated neutrophil pool may contribute to the neutrophilia. The prostaglandin-induced neutrophilia was accompanied not by a significant change in total numbers of circulating white blood cells, but, rather, by a significant decrease in circulating mononuclear white blood cells, including T-helper, T-suppressor, and B cells. The combination of neutrophilia with lymphopenia has classically been attributed to the release of adrenal hormones and suggests 1) that prostaglandins may directly or indirectly cause the release of adrenal hormones, or 2) that adrenal hormones may mediate their effects on circulating white blood cell subsets via prostaglandins, or 3) that prostaglandins activate intracellular messenger systems that are also activated by adrenal hormones.

(15S)-15-methyl prostaglandin E1-induced neutrophilia in Brown-Norway rats.

A stable analogue of prostaglandin E1, (15S)-15-methyl prostaglandin E1 (M-PGE1), induces a marked relative and absolute neutrophilia after subcutaneous injection at a pharmacologic dose of 1 mg/kg in Brown-Norway rats. The neutrophils reached a peak of 6 hours after injection at which time the absolute neutrophil count was 13,457 +/- 6,038/mm3 versus 2,451 +/- 1,298/mm3 before injection (p less than 0.001). The absolute white blood cell count/mm3 did not change significantly at 6 hours after injection, but a significant eosinopenia was noted, as has been described by previous investigators, after the administration of prostaglandins. A possible physiologic in vivo role for prostaglandin in the causation of neutrophilia remains to be elucidated.