Al-Harbi Naif O, Imam Faisal, Al-Harbi Mohammad Matar, Qamar Wajhul, Aljerian Khaldoon, Khalid Anwer Md, Alharbi Mohammed, Almudimeegh Sultan, Alhamed Abdullah S, Alshamrani Ali A
Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Department of Pathology, College of Medicine, King Saud University, P.O. Box 2457, Riyadh 11451, Saudi Arabia.
Saudi Pharm J. 2023 Jul;31(7):1327-1338. doi: 10.1016/j.jsps.2023.05.022. Epub 2023 May 29.
Lipopolysaccharides (LPS), the lipid component of gram-negative bacterial cell wall, is recognized as the key factor in acute lung inflammation and is found to exhibit severe immunologic reactions. Phosphodiesterase-4 (PDE-4) inhibitor: "apremilast (AP)" is an immune suppressant and anti-inflammatory drug which introduced to treat psoriatic arthritis. The contemporary experiment designed to study the protective influences of AP against LPS induced lung injury in rodents. Twenty-four (24) male experimental Wistar rats selected, acclimatized, and administered with normal saline, LPS, or AP + LPS respectively from 1 to 4 groups. The lung tissues were evaluated for biochemical parameters (MPO), Enzyme Linked Immunosorbent Assay (ELISA), flowcytometry assay, gene expressions, proteins expression and histopathological examination. AP ameliorates the lung injuries by attenuating immunomodulation and inflammation. LPS exposure upregulated IL-6, TNF-α, and MPO while downregulating IL-4 which were restored in AP pretreated rats. The changes in immunomodulation markers by LPS were reduced by AP treatment. Furthermore, results from the qPCR analysis represented an upregulation in IL-1β, MPO, TNF-α, and p38 whereas downregulated in IL-10 and p53 gene expressions in disease control animals while AP pretreated rats exhibited significant reversal in these expressions. Western blot analysis suggested an upregulation of MCP-1, and NOS-2, whereas HO-1, and Nrf-2 expression were suppressed in LPS exposed animals, while pretreatment with AP showed down regulation in the expression MCP-1, NOS-2, and upregulation of HO-1, and Nrf-2 expression of the mentioned intracellular proteins. Histological studies further affirmed the toxic influences of LPS on the pulmonary tissues. It is concluded that, LPS exposure causes pulmonary toxicities via up regulation of oxidative stress, inflammatory cytokines and stimulation of IL-1β, MPO, TNF-α, p38, MCP-1, and NOS-2 while downregulation of IL-4, IL-10, p53, HO-1, and Nrf-2 at different expression level. Pretreatment with AP controlled the toxic influences of LPS by modulating these signaling pathways.
脂多糖（LPS）是革兰氏阴性菌细胞壁的脂质成分，被认为是急性肺炎症的关键因素，并被发现会引发严重的免疫反应。磷酸二酯酶4（PDE - 4）抑制剂：“阿普司特（AP）”是一种免疫抑制剂和抗炎药物，用于治疗银屑病关节炎。当代实验旨在研究AP对啮齿动物中LPS诱导的肺损伤的保护作用。选取24只雄性实验性Wistar大鼠，使其适应环境，并分别从1至4组给予生理盐水、LPS或AP + LPS。对肺组织进行生化参数（MPO）、酶联免疫吸附测定（ELISA）、流式细胞术测定、基因表达、蛋白质表达和组织病理学检查。AP通过减弱免疫调节和炎症来改善肺损伤。LPS暴露上调了IL - 6、TNF - α和MPO，同时下调了IL - 4，而在AP预处理的大鼠中这些指标恢复正常。AP处理降低了LPS对免疫调节标志物的影响改变。此外，qPCR分析结果表明，疾病对照动物中IL - 1β、MPO、TNF - α和p38上调，而IL - 10和p53基因表达下调，而AP预处理的大鼠在这些表达上表现出显著逆转。蛋白质印迹分析表明，LPS暴露动物中MCP - 1和NOS - 2上调，而HO - 1和Nrf - 2表达受到抑制，而AP预处理显示MCP - 1、NOS - 2表达下调，上述细胞内蛋白质的HO - 1和Nrf - 2表达上调。组织学研究进一步证实了LPS对肺组织的毒性影响。结论是，LPS暴露通过上调氧化应激、炎性细胞因子以及刺激IL - 1β、MPO、TNF - α、p38、MCP - 1和NOS - 2，同时在不同表达水平下调IL - 4、IL - 10、p53、HO - 1和Nrf - 2，从而导致肺毒性。AP预处理通过调节这些信号通路控制了LPS的毒性影响。
