Department of Microbiology & Immunology, Virginia Commonwealth University, Richmond, Virginia 23298-0678, USA.
Gastroenterology. 2010 Jan;138(1):197-209. doi: 10.1053/j.gastro.2009.08.054. Epub 2009 Sep 2.
BACKGROUND & AIMS: Human immunodeficiency virus (HIV) protease inhibitor (PI)-induced adverse effects have become a serious clinical problem. In addition to their metabolic and cardiovascular complications, these drugs also frequently cause severe gastrointestinal disorders, including mucosal erosions, epithelial barrier dysfunction, and diarrhea. However, the exact mechanisms underlying gastrointestinal adverse effects of HIV PIs remain unknown. This study investigated whether HIV PIs disrupt intestinal epithelial barrier integrity by activating endoplasmic reticulum (ER) stress.
The most commonly used HIV PIs (lopinavir, ritonavir, and amprenavir) were used; their effects on ER stress activation and epithelial paracellular permeability were examined in vitro as well as in vivo using wild-type and CHOP(-)/(-) mice.
Treatment with lopinavir and ritonavir, but not amprenavir, induced ER stress, as indicated by a decrease in secreted alkaline phosphatase activities and an increase in the unfolded protein response. This activated ER stress partially impaired the epithelial barrier integrity by promoting intestinal epithelial cell apoptosis. CHOP silencing by specific small hairpin RNA prevented lopinavir- and ritonavir-induced barrier dysfunction in cultured intestinal epithelial cells, whereas CHOP(-)/(-) mice exhibited decreased mucosal injury after exposure to lopinavir and ritonavir.
HIV PIs induce ER stress and activate the unfolded protein response in intestinal epithelial cells, thus resulting in disruption of the epithelial barrier integrity.
人类免疫缺陷病毒（HIV）蛋白酶抑制剂（PI）引起的不良反应已成为严重的临床问题。除了代谢和心血管并发症外，这些药物还经常引起严重的胃肠道疾病，包括黏膜糜烂、上皮屏障功能障碍和腹泻。然而，HIV PIs 引起胃肠道不良反应的确切机制尚不清楚。本研究旨在探讨 HIV PIs 是否通过激活内质网（ER）应激来破坏肠道上皮屏障完整性。
使用最常用的 HIV PIs（洛匹那韦、利托那韦和阿巴卡韦）；在体外和野生型和 CHOP(-)/(-) 小鼠体内研究它们对 ER 应激激活和上皮细胞旁通透性的影响。
洛匹那韦和利托那韦治疗，但不是阿巴卡韦，诱导 ER 应激，表现为分泌碱性磷酸酶活性降低和未折叠蛋白反应增加。这种激活的 ER 应激部分通过促进肠上皮细胞凋亡来损害上皮屏障完整性。特异性短发夹 RNA 沉默 CHOP 可防止洛匹那韦和利托那韦诱导的培养肠上皮细胞屏障功能障碍，而 CHOP(-)/(-) 小鼠在暴露于洛匹那韦和利托那韦后粘膜损伤减少。
HIV PIs 诱导肠上皮细胞内质网应激和未折叠蛋白反应激活，从而破坏上皮屏障完整性。
