Sunitinib treatment reduces proinflammatory cytokine levels and mortality rates by suppressing the NLRP3 inflammasome signaling pathway in sepsis.

IF 5.3 2区 医学 Q2 IMMUNOLOGY
Inflammopharmacology Pub Date : 2025-09-01 Epub Date: 2025-07-29 DOI:10.1007/s10787-025-01862-3
Ahmet Kucuk, Nurhak Aksungur, Zekai Halici, Taha Tavaci, Mustafa Ozkaraca, Behzat Tebrizi
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引用次数: 0

Abstract

Background: Given the elevated mortality rates and significant treatment costs associated with sepsis, characterized by a dysregulated host response to infection and life-threatening organ dysfunction, the search for treatment strategies involving new and potentially effective agents is essential. Sunitinib, a tyrosine kinase inhibitor, shows promise for mitigating increased inflammation in sepsis through its modulation of specific molecular pathways. This study investigates the effects of sunitinib in the treatment of sepsis.

Methods: Sepsis was induced in rats using the cecal ligation and puncture (CLP) model and sunitinib treatment was administered orally at various dosages. The effects of sunitinib treatment were evaluated through molecular and histopathological methods. The impact of sunitinib treatment on survival was analyzed using Kaplan-Meier survival analysis.

Results: With low-dose treatment, sunitinib was observed to reduce the levels of proinflammatory cytokines, including interleukin-6, interleukin-8, and TNF-α. However, no reduction was observed with high-dose sunitinib in comparison to the sepsis group. Polymerase chain reaction results indicated that the NLRP3 inflammasome pathway was attenuated with low-dose sunitinib treatment. Furthermore, the extent of sepsis associated histopathological and immunohistochemical changes was reduced with sunitinib treatment, as demonstrated by hematoxylin and eosin staining and immunohistochemical analysis. Survival analysis revealed that the group receiving low-dose sunitinib had the highest survival rate.

Conclusion: Different sunitinib doses in sepsis treatment yield significantly different molecular results, histopathological outcomes, and survival rates. A comprehensive investigation of tyrosine kinase inhibitor drugs such as sunitinib in the treatment of sepsis will enhance the efficacy of sepsis therapies.

舒尼替尼治疗通过抑制脓毒症中NLRP3炎性小体信号通路降低促炎细胞因子水平和死亡率。
背景:脓毒症的特点是宿主对感染的反应失调和危及生命的器官功能障碍,鉴于与脓毒症相关的死亡率升高和显著的治疗费用,寻找涉及新的和潜在有效药物的治疗策略是必不可少的。舒尼替尼是一种酪氨酸激酶抑制剂,通过调节特定的分子途径,有望减轻败血症中增加的炎症。本研究探讨舒尼替尼在脓毒症治疗中的作用。方法:采用盲肠结扎穿刺(CLP)模型诱导大鼠脓毒症,口服不同剂量舒尼替尼治疗。通过分子和组织病理学方法评价舒尼替尼治疗的效果。采用Kaplan-Meier生存分析分析舒尼替尼治疗对生存的影响。结果:在低剂量治疗下,舒尼替尼可降低促炎细胞因子水平,包括白细胞介素-6、白细胞介素-8和TNF-α。然而,与败血症组相比,大剂量舒尼替尼未观察到减少。聚合酶链反应结果显示,低剂量舒尼替尼可减弱NLRP3炎性小体通路。此外,苏尼替尼治疗脓毒症相关的组织病理学和免疫组织化学变化的程度减轻,苏尼替尼染色和伊红染色以及免疫组织化学分析证实了这一点。生存分析显示,低剂量舒尼替尼组生存率最高。结论:不同剂量舒尼替尼治疗脓毒症的分子结果、组织病理学结果和生存率有显著差异。全面研究酪氨酸激酶抑制剂药物如舒尼替尼在脓毒症治疗中的作用,将提高脓毒症治疗的疗效。
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来源期刊
Inflammopharmacology
Inflammopharmacology IMMUNOLOGYTOXICOLOGY-TOXICOLOGY
CiteScore
8.00
自引率
3.40%
发文量
200
期刊介绍: Inflammopharmacology is the official publication of the Gastrointestinal Section of the International Union of Basic and Clinical Pharmacology (IUPHAR) and the Hungarian Experimental and Clinical Pharmacology Society (HECPS). Inflammopharmacology publishes papers on all aspects of inflammation and its pharmacological control emphasizing comparisons of (a) different inflammatory states, and (b) the actions, therapeutic efficacy and safety of drugs employed in the treatment of inflammatory conditions. The comparative aspects of the types of inflammatory conditions include gastrointestinal disease (e.g. ulcerative colitis, Crohn''s disease), parasitic diseases, toxicological manifestations of the effects of drugs and environmental agents, arthritic conditions, and inflammatory effects of injury or aging on skeletal muscle. The journal has seven main interest areas: -Drug-Disease Interactions - Conditional Pharmacology - i.e. where the condition (disease or stress state) influences the therapeutic response and side (adverse) effects from anti-inflammatory drugs. Mechanisms of drug-disease and drug disease interactions and the role of different stress states -Rheumatology - particular emphasis on methods of measurement of clinical response effects of new agents, adverse effects from anti-rheumatic drugs -Gastroenterology - with particular emphasis on animal and human models, mechanisms of mucosal inflammation and ulceration and effects of novel and established anti-ulcer, anti-inflammatory agents, or antiparasitic agents -Neuro-Inflammation and Pain - model systems, pharmacology of new analgesic agents and mechanisms of neuro-inflammation and pain -Novel drugs, natural products and nutraceuticals - and their effects on inflammatory processes, especially where there are indications of novel modes action compared with conventional drugs e.g. NSAIDs -Muscle-immune interactions during inflammation [...]
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