Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, Minia, 61519, Egypt.
Department of Pathology, Faculty of Medicine, Minia University, Minia, Egypt.
Drug Des Devel Ther. 2022 Sep 8;16:3023-3039. doi: 10.2147/DDDT.S370460. eCollection 2022.
Inflammation and oxidative stress play a major role in the development of sepsis and its associated complications, leading to multiple organ failure and death. The lungs, liver, and kidneys are among the early affected organs correlated with mortality in sepsis. Alpha-chymotrypsin (α-ch) is a serine protease that exerts anti-inflammatory, anti-edematous, and anti-oxidant properties.
This study was undertaken to elucidate if the anti-inflammatory and anti-oxidant effects of α-ch observed in previous studies can alleviate lung, liver, and kidney injuries in a cecal ligation and puncture (CLP)-induced sepsis model, and thus decrease mortality.
Septic animals were given α-ch 2 h post CLP procedure. Sepsis outcomes were assessed in the lungs, liver, and kidneys. Separate animal groups were investigated for a survival study.
CLP resulted in 0% survival, while α-chymotrypsin post-treatment led to 50% survival at the end of the study. Administration of α-chymotrypsin resulted in a significant attenuation of sepsis-induced elevated malonaldehyde (MDA) and total nitrite/nitrate (NOx) levels. In addition, there was a significant increase in reduced glutathione (GSH) content and superoxide dismutase (SOD) activity in the lungs, liver, and kidneys. Administration of α-ch reduced elevated tissue expression of toll-like receptor-4 (TLR4), nuclear factor kappa-B (NF-κB), myeloperoxidase (MPO), and inducible nitric oxide synthase (iNOS). Alpha-chymotrypsin resulted in a significant reduction in serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and interleukin-6 (IL-6). Alpha-chymotrypsin attenuated the rise in serum creatinine, cystatin C, blood urea nitrogen (BUN), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) levels that was observed in the septic group. In addition, α-ch significantly reduced the lung wet/dry weight ratio, total protein content, and leukocytic counts in bronchoalveolar lavage fluid (BALF). Histopathological examination of the lungs, liver, and kidneys confirmed the protective effects of α-ch on those organs.
α-ch has protective potential against sepsis through lowering tissue expression of TLR4, NF-κB, MPO, and iNOS leading to decreased oxidative stress and inflammatory signals induced by sepsis. This effect appeared to alleviate the damage to the lungs, liver, and kidneys and increase survival in rats subjected to sepsis.
炎症和氧化应激在脓毒症及其相关并发症的发展中起着重要作用，导致多器官衰竭和死亡。肺部、肝脏和肾脏是与脓毒症死亡率相关的早期受累器官之一。糜蛋白酶（α-ch）是一种丝氨酸蛋白酶，具有抗炎、抗水肿和抗氧化特性。
本研究旨在阐明先前研究中观察到的α-ch 的抗炎和抗氧化作用是否能减轻盲肠结扎和穿刺（CLP）诱导的脓毒症模型中的肺、肝和肾损伤，从而降低死亡率。
CLP 术后 2 小时给予脓毒症动物 α-ch。在肺部、肝脏和肾脏中评估脓毒症结局。对单独的动物组进行了生存研究。
CLP 导致 0%的存活率，而 α-ch 治疗后在研究结束时导致 50%的存活率。α-糜蛋白酶的给药显著减弱了脓毒症诱导的丙二醛（MDA）和总亚硝酸盐/硝酸盐（NOx）水平的升高。此外，肺、肝和肾组织中的还原型谷胱甘肽（GSH）含量和超氧化物歧化酶（SOD）活性显著增加。α-ch 的给药降低了 Toll 样受体-4（TLR4）、核因子 kappa-B（NF-κB）、髓过氧化物酶（MPO）和诱导型一氧化氮合酶（iNOS）的升高组织表达。α-糜蛋白酶导致肿瘤坏死因子-α（TNF-α）、白细胞介素-1β（IL-1β）和白细胞介素-6（IL-6）的血清水平显著降低。α-糜蛋白酶降低了脓毒症组观察到的血清肌酐、胱抑素 C、血尿素氮（BUN）、丙氨酸氨基转移酶（ALT）和天冬氨酸氨基转移酶（AST）水平的升高。此外，α-ch 显著降低了支气管肺泡灌洗液（BALF）中的肺湿/干重比、总蛋白含量和白细胞计数。肺、肝和肾的组织病理学检查证实了 α-ch 对这些器官的保护作用。
α-ch 通过降低 TLR4、NF-κB、MPO 和 iNOS 的组织表达，降低脓毒症引起的氧化应激和炎症信号，从而具有针对脓毒症的保护潜力。这种作用似乎减轻了肺、肝和肾的损伤，并增加了脓毒症大鼠的存活率。
