The Contributions of Adrenal Hormones, Hemodynamic Factors, and the Endotoxin-Related Stress Reaction to Stable Prostaglandin Analog-Induced Peripheral Lymphopenia and Neutrophilia

Abstract

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)

Acute stress reduces intraparenchymal lung natural killer cells via beta-adrenergic stimulation

“…This is supported by the facts that adrenalectomy attenuates lymphopenia induced under stress [44,46], and that corticosterone causes lymphopenia in adrenalectomized rats [45,46]. Glucocorticoids seem to cause lymphopenia both in humans [47–49] and animals [44,45,50], whereas catecholamines induce lymphocytosis [34,49] and a marked increase of the number of blood NK cells [34,49,51] in humans. It has also been shown that the redistribution of human NK cells is caused via beta2‐adrenoceptor stimulation [34], and that the adhesion of human NK cells to cultured endothelium was down‐regulated by beta‐adrenoceptor stimulation [52].…”

“…It has also been shown that the redistribution of human NK cells is caused via beta2‐adrenoceptor stimulation [34], and that the adhesion of human NK cells to cultured endothelium was down‐regulated by beta‐adrenoceptor stimulation [52]. In contrast to these studies in humans, it was reported that epinephrine induces lymphopenia as well as neutrophilia in rats [50], although the effect of catecholamines on the redistribution of lymphocytes including NK cells has not been well investigated in animals yet.…”

Acute Stress Enhances While Chronic Stress Suppresses Skin Immunity: The Role of Stress Hormones and Leukocyte Trafficking

“…21,22 Cyanoketone treatment, which virtually eliminates the corticosterone stress response, also virtually eliminates the stress‐induced decrease in blood lymphocyte numbers, and significantly enhances the stress‐induced increase in blood neutrophil numbers. 22 Several studies have shown that glucocorticoid treatment induces changes in leukocyte distribution in mice, 44‐47 guinea pigs, 48 rats, 22,49,50 rabbits, 51 and humans. 52‐54 It has been shown in rats that both adrenalectomy (which eliminates the corticosterone and epinephrine stress response) 21,22,35,55 or cyanoketone treatment (which eliminates only the corticosterone stress response), virtually eliminate the stress‐induced redistribution of blood leukocytes.…”

The utility of animal models in developing immunosuppressive agents

“…Lymphocyte numbers in the bone marrow are increased. Both lymphocyte and neutrophil function is suppressed, as measured by concanavalin-A proliferation and reactive oxygen species production respectively (Ulich et al, 1988). Understanding of the complex effects that these agents have on the body could not be easily understood with in vitro models alone.…”