Filaretova Ludmila, Komkova Olga, Sudalina Maria, Yarushkina Natalia
Laboratory of Experimental Endocrinology, Pavlov Institute of Physiology, Russian Academy of Sciences, St. Petersburg, Russia.
Front Pharmacol. 2021 Oct 20;12:682643. doi: 10.3389/fphar.2021.682643. eCollection 2021.
Remote ischemic preconditioning (RIPC) is one of the most effective approaches to attenuate tissue injury caused by severe ischemia-reperfusion (I/R). Experimental studies have demonstrated that RIPC is capable of producing a protective effect not only on heart, but also on brain, lungs, kidneys, liver, intestine, and stomach. We previously demonstrated that glucocorticoids participate in protective effect of local gastric ischemic preconditioning against I/R-induced gastric injury. In the present study we investigated whether RIPC may protect the gastric mucosa against I/R-induced injury through involvement of glucocorticoids. Anesthetized fasted Sprague Dawley male rats were exposed to prolonged gastric I/R (30 min occlusion of celiac artery followed by 3 h of reperfusion) alone or with preliminary brief RIPC (10 min non-invasive occlusion of right hind limb blood flow followed by reperfusion for 30 min). First, we investigated the effect of RIPC on I/R-induced injury by itself. Then to study the role of glucocorticoids similar experiments were carried out: 1) in rats pretreated with the inhibitor of glucocorticoid synthesis, metyrapone (30 mg/kg, i.p), and in control animals; 2) in adrenalectomized rats without or with corticosterone replacement (4 mg/kg, s.c.) and in sham-operated animals; 3) in rats pretreated with glucocorticoid receptor antagonist RU-38486 (20 mg/kg, s.c.) and in control animals. I/R induced corticosterone rise and resulted in the gastric erosion formation. RIPC significantly reduced the erosion area in control animals. Metyrapone injected shortly before RIPC caused a decrease in plasma corticosterone levels and prevented the gastroprotective effect of RIPC and, moreover, further aggravated the deleterious effect of I/R. Adrenalectomy performed 1 week before experiment created long-lasting corticosterone deficiency and had no effect on the gastroprotective effect of RIPC. Nevertheless, corticosterone replacement which mimics the corticosterone rise, similar to RIPS, significantly reduced erosion areas of gastric mucosa in adrenalectomized rats supporting the role of glucocorticoids in gastroprotection. RU-38486, which occupied glucocorticoid receptors, similar to metyrapone prevented the gastroprotective effect of RIPC and, moreover, further aggravated the deleterious effect of I/R. The results of the present study demonstrate for the first time that RIPC may protect the gastric mucosa against I/R-induced injury through involvement of glucocorticoids.
远程缺血预处理（RIPC）是减轻严重缺血再灌注（I/R）所致组织损伤的最有效方法之一。实验研究表明，RIPC不仅能对心脏产生保护作用，还能对脑、肺、肾、肝、肠和胃产生保护作用。我们之前证明，糖皮质激素参与局部胃缺血预处理对I/R诱导的胃损伤的保护作用。在本研究中，我们调查了RIPC是否可能通过糖皮质激素的参与来保护胃黏膜免受I/R诱导的损伤。将麻醉的禁食Sprague Dawley雄性大鼠单独暴露于长时间的胃I/R（腹腔动脉闭塞30分钟，随后再灌注3小时），或进行初步短暂的RIPC（右后肢血流无创闭塞10分钟，随后再灌注30分钟）。首先，我们研究了RIPC本身对I/R诱导损伤的影响。然后为了研究糖皮质激素的作用，进行了类似的实验：1）在预先用糖皮质激素合成抑制剂美替拉酮（30mg/kg，腹腔注射）处理的大鼠和对照动物中；2）在未进行或进行皮质酮替代（4mg/kg，皮下注射）的肾上腺切除大鼠和假手术动物中；3）在预先用糖皮质激素受体拮抗剂RU-38486（20mg/kg，皮下注射）处理的大鼠和对照动物中。I/R导致皮质酮升高并导致胃糜烂形成。RIPC显著减少了对照动物的糜烂面积。在RIPC之前不久注射美替拉酮导致血浆皮质酮水平降低，并阻止了RIPC的胃保护作用，此外，还进一步加重了I/R的有害作用。在实验前1周进行肾上腺切除术造成了长期的皮质酮缺乏，且对RIPC的胃保护作用没有影响。然而，类似于RIPS的模拟皮质酮升高的皮质酮替代，显著减少了肾上腺切除大鼠胃黏膜的糜烂面积，支持了糖皮质激素在胃保护中的作用。占据糖皮质激素受体的RU-38486与美替拉酮类似，阻止了RIPC的胃保护作用，此外，还进一步加重了I/R的有害作用。本研究结果首次表明，RIPC可能通过糖皮质激素的参与来保护胃黏膜免受I/R诱导的损伤。
