Shih Chih-Chin, Liao Wei-Chieh, Ke Hung-Yen, Kuo Chia-Wen, Tsao Cheng-Ming, Tsai Wen-Chiuan, Chiu Yi-Lin, Huang Hsieh-Chou, Wu Chin-Chen
Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan, ROC.
Department and Graduate Institute of Pharmacology, National Defense Medical Center, Taipei, Taiwan, ROC.
Biomed Pharmacother. 2023 May;161:114565. doi: 10.1016/j.biopha.2023.114565. Epub 2023 Mar 21.
Global warming increases the incidence of heat stroke (HS) and HS causes the reduction of visceral blood flow during hyperthermia, leading to intestinal barrier disruption, microbial translocation, systemic inflammation and multiple organ failure. Cathelicidin LL-37 exhibits antimicrobial activities, helps innate immunity within the gut to maintain intestinal homeostasis, and augments intestinal wound healing and barrier function. Thus, we evaluated the effects and possible mechanisms of cathelicidin LL-37 on HS. Wistar rats were placed in a heating-chamber of 42 ̊C to induce HS. Changes in rectal temperature, hemodynamic parameters, and survival rate were measured during the experimental period. Blood samples and ilea were collected to analyze the effects of LL-37 on systemic inflammation, multiple organ dysfunction, and intestinal injury. Furthermore, LS174T and HT-29 cells were used to assess the underlying mechanisms. Our data showed cathelicidin LL-37 ameliorated the damage of intestinal cells induced by HS. Intestinal injury, systemic inflammation, and nitrosative stress (high nitric oxide level) caused by continuous hyperthermia were attenuated in HS rats treated with cathelicidin LL-37, and hence, improved multiple organ dysfunction, coagulopathy, and survival rate. These beneficial effects of cathelicidin LL-37 were attributed to the protection of intestinal goblet cells (by increasing transepithelial resistance, mucin-2 and Nrf2 expression) and the improvement of intestinal barrier function (less cyclooxygenase-2 expression and FITC-dextran translocation). Interestingly, high cathelicidin expression in the ileal samples of inflammatory bowel disease patients was associated with better clinical outcome. These results suggest that cathelicidin LL-37 could prevent heat stress-induced intestinal damage and heat-related illnesses.
全球变暖增加了中暑（HS）的发生率，而中暑会导致高温期间内脏血流减少，进而引发肠道屏障破坏、微生物易位、全身炎症和多器官功能衰竭。抗菌肽LL-37具有抗菌活性，有助于肠道内的先天免疫维持肠道稳态，并促进肠道伤口愈合和屏障功能。因此，我们评估了抗菌肽LL-37对中暑的影响及可能机制。将Wistar大鼠置于42℃的加热室中诱导中暑。在实验期间测量直肠温度、血流动力学参数和存活率。采集血样和回肠，分析LL-37对全身炎症、多器官功能障碍和肠道损伤的影响。此外，使用LS174T和HT-29细胞评估潜在机制。我们的数据表明，抗菌肽LL-37改善了中暑诱导的肠道细胞损伤。用抗菌肽LL-37治疗的中暑大鼠中，持续高温引起的肠道损伤、全身炎症和氧化应激（高一氧化氮水平）得到减轻，从而改善了多器官功能障碍、凝血病和存活率。抗菌肽LL-37的这些有益作用归因于对肠道杯状细胞的保护（通过增加跨上皮电阻、粘蛋白-2和Nrf2表达）和肠道屏障功能的改善（较少的环氧化酶-2表达和FITC-葡聚糖易位）。有趣的是，炎症性肠病患者回肠样本中高抗菌肽表达与更好的临床结果相关。这些结果表明，抗菌肽LL-37可以预防热应激诱导的肠道损伤和与热相关的疾病。
