Faculdade de Farmácia, UFRGS, Porto Alegre 90610-000, RS, Brasil.
Serviço de Genética Médica, HCPA, UFRGS, Rua Ramiro Barcelos, Porto Alegre, 90035-903, RS, Brasil.
Biochem Cell Biol. 2023 Aug 1;101(4):294-302. doi: 10.1139/bcb-2022-0330. Epub 2023 Apr 12.
Lysosomal acid lipase deficiency (LALD) is an inborn error of metabolism that lacks satisfactory treatment, which leads to the development of severe hepatic and cardiac complications and may even lead to death. In this sense, knowledge of the mechanisms involved in the pathophysiology of this disorder becomes essential to allow the search for new therapeutic strategies. There are no studies in the literature investigating the role of reactive species and inflammatory processes in the pathophysiology of this disorder. Therefore, the aim of this work was to investigate parameters of oxidative and inflammatory stress in LALD patients. In this work, we obtained results that demonstrate that LALD patients are susceptible to oxidative stress caused by an increase in the production of free radicals, observed by the increase of 2-7-dihydrodichlorofluorescein. The decrease in sulfhydryl content reflects oxidative damage to proteins, as well as a decrease in antioxidant defenses. Likewise, the increase in urinary levels of di-tyrosine observed also demonstrates oxidative damage to proteins. Furthermore, the determination of chitotriosidase activity in the plasma of patients with LALD was significantly higher, suggesting a pro-inflammatory state. An increase in plasma oxysterol levels was observed in patients with LALD, indicating an important relationship between this disease and cholesterol metabolism and oxidative stress. Also, we observed in LALD patients increased levels of nitrate production. The positive correlation found between oxysterol levels and activity of chitotriosidase in these patients indicates a possible link between the production of reactive species and inflammation. In addition, an increase in lipid profile biomarkers such as total and low-density lipoprotein cholesterol were demonstrated in the patients, which reinforces the involvement of cholesterol metabolism. Thus, we can assume that, in LALD, oxidative and nitrosative damage, in addition to inflammatory process, play an important role in its evolution and future clinical manifestations. In this way, we can suggest that the study of the potential benefit of the use of antioxidant and anti-inflammatory substances as an adjuvant tool in the treatment will be important, which should be associated with the already recommended therapy.
溶酶体酸性脂肪酶缺乏症（LALD）是一种代谢性先天缺陷，缺乏令人满意的治疗方法，这会导致严重的肝和心脏并发症，甚至可能导致死亡。从这个意义上说，了解这种疾病病理生理学中涉及的机制对于寻找新的治疗策略变得至关重要。目前，文献中没有研究活性氧物质和炎症过程在这种疾病病理生理学中的作用。因此，本工作的目的是研究 LALD 患者氧化和炎症应激的参数。在这项工作中，我们获得的结果表明，LALD 患者易受到自由基产生增加引起的氧化应激的影响，这可以通过二氢二氯荧光素的增加来观察到。巯基含量的减少反映了蛋白质的氧化损伤，以及抗氧化防御的减少。同样，观察到尿中二酪氨酸水平的增加也表明了蛋白质的氧化损伤。此外，LALD 患者血浆中几丁质酶活性的测定显著升高，表明存在炎症前状态。在 LALD 患者中观察到血浆氧化固醇水平升高，表明该疾病与胆固醇代谢和氧化应激之间存在重要关系。此外，我们在 LALD 患者中观察到硝酸盐产生水平增加。在这些患者中发现的氧化固醇水平与几丁质酶活性之间的正相关表明，活性物质的产生和炎症之间可能存在联系。此外，在患者中证明了脂质谱生物标志物（如总胆固醇和低密度脂蛋白胆固醇）的增加，这加强了胆固醇代谢的参与。因此，我们可以假设，在 LALD 中，氧化和硝化损伤以及炎症过程在其演变和未来临床表现中起着重要作用。因此，我们可以建议，研究使用抗氧化和抗炎物质作为辅助治疗工具的潜在益处将是重要的，这应与已建议的治疗相结合。
