气管内LPS模型大鼠急性肺损伤的进展:氟替卡松、地塞米松和吡非尼酮的疗效。

IF 2.9 4区 医学 Q2 PHARMACOLOGY & PHARMACY
Pharmacology Pub Date : 2024-01-01 Epub Date: 2023-11-17 DOI:10.1159/000534329
Anil H Kadam, Jan E Schnitzer
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引用次数: 0

摘要

前言:我们研究了经气管(i.t)给药LPS(10-300µg/大鼠)诱导急性肺损伤(ALI)重现特征的潜力,并比较了抗炎糖皮质激素和抗纤维化药物减少疾病的药理作用。此外,我们还研究了LPS大鼠模型中ALI的时间依赖性进展。方法:(1)分别以10、30、100、300 μg/大鼠为剂量点,研究LPS对ALI的剂量效应;(2)在4 h时间点采用氟替卡松(100和300 μg/大鼠)、吡非尼酮(4000 μg/大鼠)和地塞米松(1 mg/kg)的药物干预;(3) lps刺激后0、2、4、6、8、10和24 h的动力学研究。使用预先确定的ALI特征(如肺部炎症、水肿和炎症介质)评估表型或药理学疗效。结果:所有LPS剂量均引起炎症、水肿和炎症介质(如il - 6、il -1 β、tnf - α和cnc -1)相似的增加。在药物干预研究中,我们发现氟替卡松和地塞米松通过抑制炎症(60-80%)、水肿(70-100%)和细胞因子IL6、il -1 β和tnf - α的增加(≥70-90%)来改善ALI。我们还注意到氟替卡松和地塞米松对CINC-1(25-35%)和TIMP1(57%)的抑制作用有所增加。相反,吡非尼酮不能抑制炎症、水肿和炎症介质。最后,在ALI动力学研究中,我们观察到进行性肺部炎症和TIMP1水平,在6小时达到峰值,并在24小时保持升高。进行性肺水肿在2至4小时之间开始,并在以后的时间点持续。平均而言,lps刺激后,il -6 (6-8 h达到峰值)、il -1 β (2-10 h达到峰值)、tnf - α (2 h达到峰值)、cinc1 (2-6 h达到峰值)和tgf - β1 (8 h达到峰值)的水平在2-10 h之间升高,并在24 h内下降。结论:我们的数据表明,10 μg/大鼠LPS获得了稳健、深刻和可重复的实验性ALI表型。糖皮质激素在4小时时间点改善了ALI的主要特征,但抗纤维化吡非尼酮不起作用。进行性炎症和持续肺水肿持续24小时,而炎症介质水平在ALI进展过程中是动态的。这项研究的数据可能有助于设计适当的实验来测试治疗ALI的新疗法的潜力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Progression of Acute Lung Injury in Intratracheal LPS Rat Model: Efficacy of Fluticasone, Dexamethasone, and Pirfenidone.

Introduction: We investigated the potential of LPS (10-300 µg/rat) administered intratracheally (i.t.) to induce reproducible features of acute lung injury (ALI) and compared the pharmacological efficacy of anti-inflammatory glucocorticoids and antifibrotic drugs to reduce the disease. Additionally, we studied the time-dependent progression of ALI in this LPS rat model.

Methods: We conducted (1) dose effect studies of LPS administered i.t. at 10, 30, 100, and 300 μg/rat on ALI at 4 h timepoint; (2) pharmacological interventions using i.t. fluticasone (100 and 300 μg/rat), i.t. pirfenidone (4,000 μg/rat), and peroral dexamethasone (1 mg/kg) at 4 h timepoint; (3) kinetic studies at 0, 2, 4, 6, 8, 10, and 24 h post-LPS challenge. Phenotype or pharmacological efficacy was assessed using predetermined ALI features such as pulmonary inflammation, edema, and inflammatory mediators.

Results: All LPS doses induced a similar increase of inflammation, edema, and inflammatory mediators, e.g., IL6, IL1β, TNFα, and CINC-1. In pharmacological intervention studies, we showed fluticasone and dexamethasone ameliorated ALI by inhibiting inflammation (>60-80%), edema (>70-100%), and the increase of cytokines IL6, IL1β, and TNFα (≥70-90%). We also noticed some inhibition of CINC-1 (25-35%) and TIMP1 (57%) increase with fluticasone and dexamethasone. Conversely, pirfenidone failed to inhibit inflammation, edema, and mediators of inflammation. Last, in ALI kinetic studies, we observed progressive pulmonary inflammation and TIMP1 levels, which peaked at 6 h and remained elevated up to 24 h. Progressive pulmonary edema started between 2 and 4 h and was sustained at later timepoints. On average, levels of IL6 (peak at 6-8 h), IL1β (peak at 2-10 h), TNFα (peak at 2 h), CINC-1 (peak at 2-6 h), and TGFβ1 (peak at 8 h) were elevated between 2 and 10 h and declined toward 24 h post-LPS challenge.

Conclusion: Our data show that 10 μg/rat LPS achieved a robust, profound, and reproducible experimental ALI phenotype. Glucocorticoids ameliorated key ALI features at the 4-h timepoint, but the antifibrotic pirfenidone failed. Progressive inflammation and sustained pulmonary edema were present up to 24 h, whereas levels of inflammatory mediators were dynamic during ALI progression. This study's data might be helpful in designing appropriate experiments to test the potential of new therapeutics to cure ALI.

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来源期刊
Pharmacology
Pharmacology 医学-药学
CiteScore
5.60
自引率
0.00%
发文量
52
审稿时长
6-12 weeks
期刊介绍: ''Pharmacology'' is an international forum to present and discuss current perspectives in drug research. The journal communicates research in basic and clinical pharmacology and related fields. It covers biochemical pharmacology, molecular pharmacology, immunopharmacology, drug metabolism, pharmacogenetics, analytical toxicology, neuropsychopharmacology, pharmacokinetics and clinical pharmacology. In addition to original papers and short communications of investigative findings and pharmacological profiles the journal contains reviews, comments and perspective notes; research communications of novel therapeutic agents are encouraged.
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