Cella S G, Locatelli V, Mennini T, Zanini A, Bendotti C, Forloni G L, Fumagalli G, Arce V M, de Gennaro Colonna V, Wehrenberg W B
Department of Pharmacology, Chemotherapy and Toxicology, University of Milan, Italy.
Endocrinology. 1990 Oct;127(4):1625-34. doi: 10.1210/endo-127-4-1625.
This work investigated in rats whether passive immunization against the endogenous GHRF in the early postnatal period led to permanent alterations of somatotropic function, similar to those observed in several human growth disorders, e.g. constitutional growth delay (CGD). On postnatal days 1, 2, 4, 6, 8, and 10, rats were given an anti-GHRF-serum (GHRH-Ab, 100 microliters/rat, sc) and were tested 1, 30, and 60 days after this treatment for basal and GHRH-stimulated GH secretion both in vivo and in vitro. GHRH-Ab reduced both basal and GHRF-stimulated GH secretion at all intervals and induced marked and chronic impairment of growth rate. The following differences were observed in the GHRH-Ab treated rats compared to normal rabbit serum-treated controls: 1) GH biosynthesis (incorporation of L-[3H]leucine into the electrophoretic band of GH): reduction of about 70%, 1 day but not 30 days after treatment; 2) Pituitary weight: significant reduction in absolute weight (30-40%) at all posttreatment intervals, and relative weight, 1 and 30 days after treatment. 3) Pituitary GH concentration: significant reduction in GH content (about 40%) but not concentration, at all posttreatment intervals; 4) Percentage of somatotrophs (immunocytochemistry): about 40% reduction 1 day, but not 30 and 60 days after treatment; 5) Hypothalamic somatostatin messenger RNA (mRNA) levels in situ hybridization): selective reduction (40%) in the periventricular nucleus 1 day but not 30 days after treatment; 6) Hypothalamic somatostatin cell number (immunocytochemistry): no significant changes in any hypothalamic area at any interval; 7) Pituitary somatostatin binding (in situ autoradiography): significant reduction, 1 day and 30 days after treatment; 8) Somatostatin inhibition of GH release "in vitro": somatostatin effect on GH release was reduced 30 days after treatment. These and previous data indicate that: 1) Transient deprivation of GHRF in the immediate postnatal period of the rat leads to permanent impairment of growth rate and somatotropic function; 2) GHRF deficiency itself or through reduction of GH secretion impairs somatostatin functions temporarily in the hypothalamus and permanently in the pituitary; 3) This rat model may mimic some forms of growth disorders in humans and holds promise as useful tools for investigating the underlying pathophysiological mechanisms.
本研究在大鼠中探究了出生后早期对内源性生长激素释放因子（GHRF）进行被动免疫是否会导致生长激素功能的永久性改变，类似于在几种人类生长障碍中观察到的情况，例如体质性生长延迟（CGD）。在出生后第1、2、4、6、8和10天，给大鼠注射抗GHRF血清（GHRH - Ab，100微升/只，皮下注射），并在该处理后的1、30和60天对其进行体内和体外基础及GHRH刺激的生长激素分泌测试。GHRH - Ab在所有时间间隔均降低了基础及GHRF刺激的生长激素分泌，并导致生长速率显著且慢性受损。与正常兔血清处理的对照组相比，在GHRH - Ab处理的大鼠中观察到以下差异：1）生长激素生物合成（L - [3H]亮氨酸掺入生长激素的电泳条带）：处理后1天降低约70%，但30天后未降低；2）垂体重量：在所有处理后的时间间隔，绝对重量显著降低（30 - 40%），处理后1天和30天相对重量也降低；3）垂体生长激素浓度：在所有处理后的时间间隔，生长激素含量显著降低（约40%），但浓度未降低；4）生长激素细胞百分比（免疫细胞化学）：处理后1天降低约40%，但30天和60天后未降低；5）下丘脑生长抑素信使核糖核酸（mRNA）水平（原位杂交）：处理后1天，室周核选择性降低（40%），但30天后未降低；6）下丘脑生长抑素细胞数量（免疫细胞化学）：在任何时间间隔，任何下丘脑区域均无显著变化；7）垂体生长抑素结合（原位放射自显影）：处理后1天和30天显著降低；8）生长抑素对生长激素释放的“体外”抑制作用：处理后30天，生长抑素对生长激素释放的作用降低。这些及先前的数据表明：1）大鼠出生后早期短暂缺乏GHRF会导致生长速率和生长激素功能的永久性损害；2）GHRF缺乏本身或通过降低生长激素分泌，会暂时损害下丘脑的生长抑素功能，并永久性损害垂体的生长抑素功能；3）该大鼠模型可能模拟人类某些形式的生长障碍，并有望成为研究潜在病理生理机制的有用工具。
