检索问题
治疗急性肺损伤的有哪些药物？是否有进一步改良的价值？
急性肺损伤（ALI）是一种严重的临床疾病，通常会导致呼吸衰竭和高死亡率，目前尚无FDA批准的特异性药物疗法，主要依赖支持性治疗，如机械通气。然而，有多种药物和疗法在动物模型和临床试验中显示出治疗潜力，并且许多现有疗法仍有进一步改良的价值 。
现有及潜在的ALI治疗药物和疗法：
1. 支持性护理与机械通气：
- 机械通气： 尽管机械通气是ALI治疗的基石，但如果使用高潮气量和压力，也可能导致或加重呼吸机相关性肺损伤（VILI）。因此，目前的临床建议旨在通过限制潮气量和通气压力来避免VILI，这已被证明能降低ALI/ARDS患者的死亡率。
- 液体管理： 针对ALI患者，保守的液体管理策略已被证明可以改善肺功能，缩短机械通气和重症监护的时间，而不会增加非肺器官衰竭的发生率，尽管对60天死亡率没有显著影响。
2. 靶向细胞死亡与炎症通路的小分子药物：
- 地西泮（Dipyridamole, DIPY）： 在肺上皮和内皮细胞中，地西泮被确定为一种有效的铁死亡抑制剂。铁死亡在ALI/ARDS的发病机制中起重要作用。地西泮通过下调血红素加氧酶1（HMOX1）来减轻铁死亡和肺损伤，其机制是结合并激活超氧化物歧化酶1（SOD1），进而抑制CREB1/HMOX1通路。一项概念验证性临床试验也证实了地西泮作为辅助疗法在ARDS患者中的治疗潜力，改善了患者预后。
- 阿瑞吡坦（Aprepitant, Ap）： 阿瑞吡坦是一种神经激肽-1受体（NK-1R）拮抗剂，在肝脏缺血再灌注（HIR）引起的ALI大鼠模型中，通过靶向NLRP3/IL-1β信号通路，显著减轻了氧化应激、炎症和细胞凋亡参数，并改善了组织病理学表现。
- N-乙酰半胱氨酸（NAC）： NAC被认为具有多种作用机制，可能对光气引起的ALI有治疗益处。然而，一项研究表明，在光气暴露后30分钟开始，通过雾化吸入多剂NAC，在所采用的时间和剂量下，对终末麻醉猪的光气诱导肺损伤并非有效疗法。
3. 生物制剂与细胞疗法：
- FGF1（成纤维细胞生长因子1）： FGF1预处理能显著改善LPS诱导的ALI模型中的病理变化，减少肺水肿、活性氧（ROS）和丙二醛（MDA）水平、炎性细胞浸润和促炎细胞因子水平，同时增加抗氧化蛋白（Nrf-2、HO-1、过氧化氢酶和SOD2）的表达。其保护作用可能归因于下调TLR4表达、抑制NF-κB活化以及促进抗氧化防御。
- 内皮细胞衍生的细胞外囊泡（EC-EVs）： 在脓毒症中，循环EC-EVs的数量增加，并通过靶向单核细胞并将其重编程为促炎巨噬细胞来加剧肺损伤。血管细胞粘附分子1（VCAM1）在脓毒症期间EC-EVs上过表达，通过与单核细胞表面的整合素亚基α4（ITGA4）相互作用，激活NF-κB通路，从而调节单核细胞分化。减少EC-EVs中的VCAM1水平或阻断单核细胞上的ITGA4可以减弱这种效应，这为脓毒症相关ALI/ARDS提供了新的治疗靶点。
- 间充质干细胞疗法： 间充质干细胞疗法是ALI预防和治疗的重点研究方向之一。
- 冷沉淀（Cryoprecipitate）： 冷沉淀主要用于补充获得性凝血功能障碍（如心脏手术、创伤、肝移植或产科出血导致的出血）患者的纤维蛋白原水平。虽然最初用于治疗血友病A，但由于安全问题（特别是血源性病原体传播和输血相关急性肺损伤）以及替代纤维蛋白原制剂的出现，已在一些欧洲国家停止使用。目前仍缺乏强有力的临床证据来支持其最佳剂量和给药方式。
4. 中草药及其活性成分：
- 桔梗外泌体样纳米颗粒（PGLNs）： 新鲜桔梗比其干制品在治疗LPS诱导的ALI方面表现出更好的疗效。PGLNs作为新鲜桔梗中最有效的活性物质之一，可能通过调节脂质代谢和糖酵解等代谢途径，调节巨噬细胞炎症和极化，从而减轻炎症并修复肺损伤。
- 金振口服液（Jinzhen Oral Liquid, JO）： 金振口服液是一种著名的中药处方，对ALI具有良好的治疗作用。研究表明，金振口服液能剂量依赖性地改善ALI小鼠的运动表现，降低肺湿/干重比以及IL-6和TNF-α的产生，并增加IL-10的释放。其作用机制可能通过抑制TLR4/MyD88/NF-κB信号通路来实现。
- 玉屏风散（Yupingfengsan, YPFS）： 玉屏风散是一种传统中药方剂，可减轻LPS诱导的ALI小鼠的肺损伤和肠道屏障功能障碍。YPFS能抑制IL-1β、IL-6和TNF-α等炎症因子的产生，并通过促进水通道蛋白和钠通道相关基因（AQP3、AQP4、AQP5、ENaCα、ENaCβ和EnaCγ）的表达来减少肺水肿。此外，YPFS通过抑制NLRP3炎性体和MAPK信号通路的激活来发挥治疗作用。
- 大承气汤（Dachengqi Decoction, DCQD）： 大承气汤是中医药中“肺肠同治”的代表方剂。研究发现DCQD通过抑制HIF-1α介导的糖酵解来减轻ALI的炎症反应。
- 清肺饮（Qingfeiyin, QFY）： 清肺饮是一种治疗ALI的常用中药方剂。其作用机制可能涉及炎症、细胞凋亡和氧化应激相关基因以及MAPK和PI3K-Akt信号通路的调节。
- 青蒿素类药物（Artemisinin-type drugs）： 青蒿素类药物具有免疫抑制活性，可通过抑制多种受体偶联信号通路（如IL-1、TNF-α、β3-整合素或RANKL、Toll样受体和生长因子受体）来发挥作用。它们可以抑制NF-κB以及其他转录因子（如mTOR、AP1、HIF-1α、NF-ATC1、STAT、NRF-2、ROR-γt和FOXP-3），从而下调细胞因子、趋化因子和免疫受体等NF-κB调节的下游基因。动物模型实验表明，青蒿素类药物对多种炎症和自身免疫疾病（包括ALI和肺纤维化）具有治疗效果。
- 植物来源的天然化合物： 大量研究表明，植物来源的天然化合物（PNCs）在治疗炎症性疾病方面具有潜在的治疗益处。PNCs通过调节免疫反应、减少炎症介质和细胞因子的释放来改善ALI。其分子机制部分与调节Th17/Treg反应、促进M1型巨噬细胞向M2型巨噬细胞极化、诱导免疫细胞凋亡、逆转肺和肠道微生物失调、表观遗传修饰以及调节炎症通路（如NF-κB、MAPK、TLR4/MyD88、NLRP3/Caspase-1、TGF-β/Smad、Nrf2/HO-1、Rho/ROCK、TLR7/MyD88和PI3K/AKT）有关。
5. 靶向氧化应激通路：
- 谷胱甘肽S-转移酶π（GSTP）： 氧化应激在ALI的发病机制中起重要作用。研究发现GSTP下调会加剧LPS诱导的肺上皮细胞和ALI小鼠模型的损伤，证实了GSTP对ALI的保护作用。GSTP通过促进KEAP1的S-谷胱甘肽化（PSSG）来抑制KEAP1-NRF2的相互作用，从而激活NRF2下游的抗氧化基因。靶向操纵GSTP水平或活性可能成为氧化应激诱导的ALI进展的有前景的治疗策略。
- 中药化合物靶向铁死亡： 铁死亡是一种新型的铁依赖性程序性细胞死亡，与多种呼吸系统疾病（包括ALI）的发生发展密切相关。中药化合物通过调节系统Xc--GSH-GPX4、NCOA4介导的铁自噬、Nrf2-GPX4和Nrf2/HO-1等关键信号通路来有效调节铁死亡，从而在改善呼吸系统疾病中发挥积极作用。
进一步改良的价值：
现有和潜在的ALI治疗策略都有巨大的进一步改良价值：
1. 精准靶向与机制深入研究：
- 针对铁死亡的精确干预： 地西泮作为铁死亡抑制剂的发现为ALI治疗提供了新方向。未来需要更深入研究铁死亡在不同类型ALI中的具体作用，开发更特异、高效的铁死亡调节剂，并探索与其他治疗的联合应用。
- NLRP3炎性体通路的精细调控： 阿瑞吡坦通过靶向NLRP3/IL-1β信号通路减轻ALI的发现，提示了炎性体抑制剂在ALI治疗中的潜力。进一步的研究可以探索其他针对NLRP3炎性体或其他炎症小体的药物，并评估其在不同病因ALI中的效果。
- 氧化应激通路的强化调控： GSTP通过S-谷胱甘肽化KEAP1并激活NRF2通路来减轻ALI的机制，揭示了调节氧化应激的重要作用。未来可开发能够增强GSTP活性或直接激活NRF2通路的药物，以更有效地对抗ALI中的氧化应激损伤。
- NF-κB通路的多点干预： 许多中药化合物（如金振口服液）和FGF1都通过抑制NF-κB通路发挥抗炎作用。考虑到NF-κB在炎症反应中的核心地位，开发能够更精确、副作用更小的NF-κB抑制剂，或结合其他抗炎机制的复合药物，具有重要的改良价值。
- 细胞因子网络的平衡调节： ALI的特征是弥漫性炎症反应，伴随着促炎细胞因子（如IL-6, TNF-α, IL-1β）的升高和抗炎细胞因子（如IL-10）的失衡。未来的研究可以探索更有效地平衡细胞因子网络的策略，例如通过靶向特定的细胞因子或其受体。
2. 纳米医学与新型递送系统：
- 解决药物递送挑战： 传统抗炎或抗氧化药物在ALI治疗中面临药代动力学差、非特异性副作用、难以跨越肺部屏障以及对异质性管理不足等问题。纳米医学通过被动、主动或理化靶向，可以与肺上皮/内皮细胞和炎性细胞相互作用，逆转异常变化并恢复肺部环境的稳态，从而显示出良好的治疗活性并降低毒性。肺部渗透性的增加在ARDS病理环境中可能有助于纳米颗粒介导的被动靶向递送。
- 优化纳米药物设计： 目前纳米医学在临床前ALI治疗中已展现出潜力，但仍需加强靶向肺部炎症的策略，并创新药物递送系统，以提高纳米药物的治疗效果。
- 外泌体样纳米颗粒的应用： 桔梗外泌体样纳米颗粒（PGLNs）作为新鲜草药的活性成分，展现了调节巨噬细胞极化和代谢途径以减轻肺损伤的潜力。植物来源的外泌体样纳米颗粒作为天然、生物相容性好的载体，有望发展成为安全有效的ALI治疗药物。
3. 中医药的现代化与机制阐明：
- 有效成分的筛选与标准化： 许多中药方剂（如金振口服液、玉屏风散、大承气汤、清肺饮）已被证明对ALI有效，但其活性成分和精确作用机制仍需进一步阐明。通过网络药理学、分子对接和分子动力学模拟等现代技术，可以更有效地筛选活性化合物，并系统性地揭示其在ALI治疗中的机制。
- 临床验证与推广： 目前大多数中药化合物的研究仍停留在动物和细胞实验阶段，迫切需要高质量的临床数据进行进一步验证。未来的工作应集中于将这些有前景的临床前结果转化为临床实践。
- 复方与单体的优化： 中药复方具有多靶点、多途径协同作用的优势，但其复杂性也增加了研究难度。可以进一步研究复方中不同成分的协同作用，或从复方中分离出具有特定活性的单体化合物进行开发，以实现更精准的治疗。
4. 联合疗法与个体化治疗：
- 多模式联合治疗： 鉴于ALI病理生理机制的复杂性，单一药物往往难以完全奏效。将不同作用机制的药物进行联合，例如抗炎药与抗氧化剂、铁死亡抑制剂与免疫调节剂等，可能取得更好的治疗效果。
- 个体化治疗方案： ALI具有高度异质性，不同患者的病因、临床表现和分子特征可能不同。通过识别潜在的生物标志物和遗传贡献，开发能够根据患者具体情况进行调整的个体化治疗方案，将是未来的重要发展方向。
5. 预防性策略：
- 早期干预： FGF1预处理对LPS诱导的ALI具有保护作用，提示了在特定高危人群中进行早期干预或预防性治疗的可能性。未来的研究可以探索如何在临床上识别高危患者，并开发有效的预防性药物。
总而言之，虽然ALI目前缺乏特效药，但从支持性治疗到靶向小分子药物、生物制剂、中药和纳米医学等多个领域，都存在有前景的治疗策略。这些策略在机制阐明、药物递送、临床验证和个体化应用等方面都有巨大的进一步改良价值，有望在未来为ALI患者带来更有效的治疗方案。
References
1Characterization of dipyridamole as a novel ferroptosis inhibitor and its therapeutic potential in acute respiratory distress syndrome management.PubMed
Xu Chen, Jiapan Shen, Xueqin Jiang, et al.
: Ferroptosis in lung epithelium and endothelium contributes to the pathogenesis of acute respiratory distress syndrome (ARDS), a critical and often fatal condition marked by acute inflammation and elevated pulmonary vascular permeability. Despite this, there are currently no FDA-approved therapeutics specifically targeting ferroptosis for ARDS management. : A screening of 259 FDA-approved drugs was conducted to identify an effective ferroptosis inhibitor in pulmonary epithelial and endothelial cells. The anti-ferroptotic and therapeutic efficacy of this screened drug was rigorously evaluated using two distinct ARDS mouse models (LPS-induced acute lung injury and CLP-induced sepsis) and human airway organoids (hAOs). The regulatory mechanism of this drug on ferroptosis inhibition was investigated via RNA-sequencing, qRT-PCR, western blotting, IF, luciferase reporter assay, chromatin immunoprecipitation assay, limited proteolysis-mass spectrometry assay, cellular thermal shift assay, and drug affinity responsive target stability assay. Furthermore, a proof-of-concept clinical trial was conducted, wherein ARDS patients were administered with the drug as adjunctive therapy. : Dipyridamole (DIPY) was identified as a potent inhibitor of ferroptosis in pulmonary epithelial and endothelial cells. DIPY effectively mitigated ferroptosis and pulmonary damage in both mouse models and hAOs, primarily by downregulating heme oxygenase 1 (HMOX1). The transcription factor cAMP responsive element binding protein 1 (CREB1) was identified as a key transactivator of HMOX1, which DIPY effectively downregulated. Mechanistically, DIPY binds to and activates superoxide dismutase 1 (SOD1), which in turn inhibits the CREB1/HMOX1 pathway, thereby suppressing ferroptosis. Notably, the clinical trial further corroborated the therapeutic potential of DIPY in ARDS patients, demonstrating improved outcomes with DIPY adjunctive therapy. : These findings provide compelling evidence that DIPY inhibits ferroptosis in pulmonary epithelial and endothelial cells by modulating the SOD1/CREB1/HMOX1 signaling axis and suggest DIPY as a promising therapeutic strategy for ARDS treatment.
2Acute lung injury: pathogenesis and treatment.PubMed
Huanqi Liu, Junli Dong, Cailin Xu, et al.
Acute lung injury (ALI) is a serious clinical condition that often leads to respiratory failure and high mortality. This review describes the pathogenesis of ALI, including the involvement of inflammatory cytokines, the activation of NLRP3 inflammasome, the generation of oxidative stress, the occurrence of apoptosis, the dysfunction of mitochondrial function, and the breakdown of lung endothelial and epithelial cell barriers. These mechanisms interact to cause significant damage and dysfunction of lung tissue. In addition, the current situation of prevention and treatment of ALI was discussed, with emphasis on lung protective ventilation, fluid management, mesenchymal stem cell therapy and drug therapy. We also analyze the latest research advances in advanced nanomedicine for the treatment of ALI, and the application of this nanomedicine could provide new ideas for the development of effective ALI therapeutics in the future.
3Platycodon grandiflorum exosome-like nanoparticles: the material basis of fresh platycodon grandiflorum optimality and its mechanism in regulating acute lung injury.PubMed
Jingmin Fu, Zhuolin Liu, Zhiying Feng, et al.
BACKGROUND: Acute lung injury (ALI) is a severe respiratory disease accompanied by diffuse inflammatory responses induced by various clinical causes. Many fresh medicinal plants have shown better efficacy than their dried forms in preventing and treating diseases like inflammation. As a classical Chinese herb, platycodon grandiflorum (PG) has been demonstrated effective in treating pneumonia, but most of previous studies focused on the efficacy of processed or dried PG formats, while the specific benefits of its fresh form are still underexplored. Exosome-like nanoparticles derived from medicinal plants are expected to point out an important direction for exploring the material basis and mechanism of this fresh herbal medicine. RESULTS: The fresh form of PG could effectively improve ALI induced by lipopolysaccharide (LPS), relieve lung histopathological injury and weight loss, and reduce levels of inflammatory factors in mice, exhibiting better efficacy than dried PG in the treatment of ALI. Further extraction and purification of PG exosome-like nanoparticles (PGLNs) demonstrated that PGLNs had good biocompatibility, with characteristics consistent with general exosome-like nanoparticles. Besides, proteomic analysis indicated that PGLNs were rich in a variety of proteins. Animal experiments showed that PGLNs improved the pathological changes in LPS-induced lung tissues, inhibited the expression of inflammatory factors and promoted the expression of anti-inflammatory factors, and exerted a regulatory effect on the polarization of lung macrophages. Cell experiments further confirmed that PGLNs could be effectively taken up by RAW264.7 cells and repolarize M1 macrophages into M2 type, therefore reducing the secretion of harmful cytokines. Moreover, non-targeted metabolomics analysis reveals that PGLNs reduce inflammation and control macrophage polarization in a manner closely linked to pathways including glycolysis and lipid metabolism, highlighting a potential mechanism by which PGLNs protect the lungs from inflammatory damage like ALI. CONCLUSION: Fresh PG has better anti-inflammatory and repair effects than its dried form. As one of the most effective active substances in fresh PG, PGLNs may regulate macrophage inflammation and polarization by regulating metabolic pathways including lipid metabolism and glycolysis, so as to reduce inflammation and repair lung injury.
4Mechanical ventilation during acute lung injury: current recommendations and new concepts.PubMed
Lorenzo Del Sorbo, Alberto Goffi, V Marco Ranieri
Despite a very large body of investigations, no effective pharmacological therapies have been found to cure acute lung injury. Hence, supportive care with mechanical ventilation remains the cornerstone of treatment. However, several experimental and clinical studies showed that mechanical ventilation, especially at high tidal volumes and pressures, can cause or aggravate ALI. Therefore, current clinical recommendations are developed with the aim of avoiding ventilator-induced lung injury (VILI) by limiting tidal volume and distending ventilatory pressure according to the results of the ARDS Network trial, which has been to date the only intervention that has showed success in decreasing mortality in patients with ALI/ARDS. In the past decade, a very large body of investigations has determined significant achievements on the pathophysiological knowledge of VILI. Therefore, new perspectives, which will be reviewed in this article, have been defined in terms of the efficiency and efficacy of recognizing, monitoring and treating VILI, which will eventually lead to further significant improvement of outcome in patients with ARDS.
5Jinzhen Oral Liquid alleviates lipopolysaccharide-induced acute lung injury through modulating TLR4/MyD88/NF-κB pathway.PubMed
Ya-Ling Li, Shu-Yan Qin, Qian Li, et al.
BACKGROUND: Acute lung injury (ALI) has the attribution of excessive inflammation of the lung. Jinzhen oral liquid (JO), a famous Chinese recipe used to treat ALI, has a favorable therapeutic effect on ALI. However, its anti-inflammatory mechanism has not been extensively studied. PURPOSE: This study was to elucidate the effects of JO on lipopolysaccharide (LPS)-induced ALI and its molecular mechanism. METHODS: An ALI model was established by intratracheal instillation of LPS (2 mg/50 μl). The open field experiment was carried out to explore the spontaneous movement and exploratory behavior of ALI mice. Cytokines levels concentrations (IL-6, IL-10 and TNF-α) were determined by enzyme-linked immunosorbent assay (ELISA). Network pharmacology was used to predict the mechanism of JO against ALI. Immunofluorescence, co-immunoprecipitation, fluorescence resonance energy transfer (FRET), Western blot and RT-PCR were used to verify the molecular mechanisms of JO. RESULTS: The in vivo results suggested that JO (1, 2, 4 g/kg) dose-dependently improved the exercise performance of mice and reduced the lung W/D weight ratio as well as the production of IL-6 and TNF-α, but increased the release of IL-10 in the ALI group. The network pharmacological analysis demonstrated that the Toll-like receptor (TLR) pathway might be the fundamental action mechanisms of JO against ALI. Immunofluorescence staining and co-immunoprecipitation analysis showed that JO decreased the expression levels of TLR4 and MyD88 and reduced their interaction in the lung tissue of ALI mice. Meanwhile, JO decreased nuclear translocation and phosphorylation of NF-κB P65. The results from cellular experiments were in line with those in vivo. The FRET experiment also confirmed that JO disturbed the interaction of TLR4 and MyD88. Subsequently, we also found that the six indicative components of JO have the similar therapeutic effect as JO. CONCLUSIONS: In summary, we suggested that JO suppressed the TLR4/MyD88/NF-κB signaling pathway, thus inhibiting LPS-induced ALI in vitro and in vivo. The clarified mechanism provided an important theoretical basis and a novel treatment strategy for the ALI treatment of JO.
6Translational medicine for acute lung injury.PubMed
Jianguo Zhang, Yumeng Guo, Michael Mak, et al.
Acute lung injury (ALI) is a complex disease with numerous causes. This review begins with a discussion of disease development from direct or indirect pulmonary insults, as well as varied pathogenesis. The heterogeneous nature of ALI is then elaborated upon, including its epidemiology, clinical manifestations, potential biomarkers, and genetic contributions. Although no medication is currently approved for this devastating illness, supportive care and pharmacological intervention for ALI treatment are summarized, followed by an assessment of the pathophysiological gap between human ALI and animal models. Lastly, current research progress on advanced nanomedicines for ALI therapeutics in preclinical and clinical settings is reviewed, demonstrating new opportunities towards developing an effective treatment for ALI.
7YuPingFengSan ameliorates LPS-induced acute lung injury and gut barrier dysfunction in mice.PubMed
Yao Wang, Yanchun Wang, Jun Ma, et al.
ETHNOPHARMACOLOGICAL RELEVANCE: Yupingfengsan (YPFS) is a traditional Chinese medicine decoction. YPFS comprises Astragalus mongholicus Bunge (Huangqi), Atractylodes rubra Dekker (Baizhu), and Saposhnikovia divaricata (Turcz.ex Ledeb.) Schischk (Fangfeng). YPFS is commonly used to treat chronic obstructive pulmonary disease, asthma, respiratory infections, and pneumonia, but the mechanism of action remains unclear. AIM OF THE STUDY: Acute lung injury (ALI) and its severe form of acute respiratory distress syndrome (ARDS) cause morbidity and mortality in critical patients. YPFS is a commonly used herbal soup to treat respiratory and immune system diseases. Nevertheless, the effect of YPFS on ALI remains unclear. This study aimed to investigate the effect of YPFS on lipopolysaccharide (LPS)-induced ALI in mice and elucidate its potential molecular mechanisms. MATERIALS AND METHODS: The major components of YPFS were detected by High-performance liquid chromatography (HPLC). C57BL/6J mice were given YPFS for seven days and then treated with LPS. IL-1β, IL-6, TNF-α, IL-8, iNOS, NLRP3, PPARγ, HO-1, ZO-1, Occludin, Claudin-1, AQP3, AQP4, AQP5, ENaCα, ENaCβ, EnaCγ mRNA in lung and ZO-1, Occludin, Claudin-1, AQP3, AQP4, AQP5, ENaCα, ENaCβ, and EnaCγ mRNA in colon tissues were measured by Real-Time Quantitative PCR (RT-qPCR). The expressions of TLR4, MyD88, NOD-like receptor thermal protein domain associated protein 3 (NLRP3), ASC, MAPK signaling pathway, Nrf2, and HO-1 in the lung were detected by Western blot. Plasma inflammatory factors Interleukin (IL)-1β, IL-6, and Tumor Necrosis Factor-α (TNF-α) were determined by Enzyme-linked Immunosorbent Assay (ELISA). Lung tissues were processed for H & E staining, and colon tissues for HE, WGA-FITC, and Alcian Blue staining. RESULTS: The results showed that YPFS administration alleviated lung injury and suppressed the production of inflammatory factors, including IL-1β, IL-6, and TNF-α. Additionally, YPFS reduced pulmonary edema by promoting the expressions of aquaporin and sodium channel-related genes (AQP3, AQP4, AQP5, ENaCα, ENaCβ, and EnaCγ). Further, YPFS intervention exhibited a therapeutic effect on ALI by inhibiting the activation of the NLRP3 inflammasome and MAPK signaling pathways. Finally, YPFS improved gut barrier integrity and suppressed intestinal inflammation in LPS-challenged mice. CONCLUSIONS: YPFS protected mice against LPS-induced ALI by attenuating lung and intestinal tissue damage. This study sheds light on the potential application of YPFS to treat ALI/ARDS.
8Plant-derived natural compounds for the treatment of acute lung injury: A systematic review of their anti-inflammatory effects in animal models.PubMed
Xiangyun Chen, Wenlai Wang, Hongrui Zhang, et al.
BACKGROUNDS AND AIMS: Acute lung injury (ALI) is a complex pulmonary disease characterized by a severe inflammatory response. The management of ALI presents a formidable challenge due to the intricate nature of its inflammatory cascade. Numerous studies have highlighted the potential therapeutic benefits of plant-derived natural compounds (PNCs) in treating inflammatory diseases. Our study aims to provide robust current evidence regarding the anti-inflammatory effects and underlying molecular mechanisms of PNCs for ALI treatment. MATERIALS AND METHODS: The systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, and the protocol was registered in PROSPERO (CRD42024468401). A comprehensive search was conducted in electronic databases including PubMed, Scopus, Web of Science, Embase, China National Knowledge Infrastructure (CNKI), Chinese Scientific Journal database (VIP), Wanfang database, and China biomedical literature service system (SinoMed) up until November 2023. Preclinical studies published in both English and Chinese were included. RESULTS: Our research encompassed 81 studies, comprising a total of 71 PNCs, including flavonoids, phenylpropanoids, terpenoids, polyphenols, alkaloids, saponins, glycosides, and miscellaneous compounds. This systematic review demonstrated that PNCs played a beneficial role on ALI by regulating the immune response and reducing the release of inflammatory mediators and cytokines. The molecular mechanisms were partially associated with the regulation of Th17/Treg responses, promotion of the polarization of M1-type macrophages to M2-type macrophages, induction of immune cell apoptosis, reversal of microbial dysbiosis in the lungs and the gut, epigenetic modification, and the modulation of inflammatory pathways, including NF-κB, MAPK, TLR4/MyD88, NLRP3/Caspase-1, TGF-β/Smad, Nrf2/HO-1, Rho/ROCK, TLR7/MyD88, and PI3K/AKT, thereby alleviating inflammatory responses and lung damage. CONCLUSION: The therapeutic effects of PNCs on ALI are mediated through the modulation of immunity and inflammatory pathways. In light of their potential, PNCs represent a promising pharmacological intervention for the treatment of ALI.
9Endothelial cell-derived extracellular vesicles expressing surface VCAM1 promote sepsis-related acute lung injury by targeting and reprogramming monocytes.PubMed
Lu Wang, Ying Tang, Jiajian Tang, et al.
Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is a common life-threatening syndrome with no effective pharmacotherapy. Sepsis-related ARDS is the main type of ARDS and is more fatal than other types. Extracellular vesicles (EVs) are considered novel mediators in the development of inflammatory diseases. Our previous research suggested that endothelial cell-derived EVs (EC-EVs) play a crucial role in ALI/ARDS development, but the mechanism remains largely unknown. Here, we demonstrated that the number of circulating EC-EVs was increased in sepsis, exacerbating lung injury by targeting monocytes and reprogramming them towards proinflammatory macrophages. Bioinformatics analysis and further mechanistic studies revealed that vascular cell adhesion molecule 1 (VCAM1), overexpressed on EC-EVs during sepsis, activated the NF-κB pathway by interacting with integrin subunit alpha 4 (ITGA4) on the monocyte surface, rather than the tissue resident macrophage surface, thereby regulating monocyte differentiation. This effect could be attenuated by decreasing VCAM1 levels in EC-EVs or blocking ITGA4 on monocytes. Furthermore, the number of VCAM1 EC-EVs was significantly increased in patients with sepsis-related ARDS. These findings not only shed light on a previously unidentified mechanism underling sepsis-related ALI/ARDS, but also provide potential novel targets and strategies for its precise treatment.
10Targeting ferroptosis using Chinese herbal compounds to treat respiratory diseases.PubMed
Mengjiao Xu, Di Zhang, Jun Yan
BACKGROUND: Respiratory diseases pose a grave threat to human life. Therefore, understanding their pathogenesis and therapeutic strategy is important. Ferroptosis is a novel type of iron-dependent programmed cell death, distinct from apoptosis, necroptosis, and autophagy, characterised by iron, reactive oxygen species, and lipid peroxide accumulation, as well as glutathione (GSH) depletion and GSH peroxidase 4 (GPX4) inactivation. A close association between ferroptosis and the onset and progression of respiratory diseases, including chronic obstructive pulmonary disease, acute lung injury, bronchial asthma, pulmonary fibrosis, and lung cancer, has been reported. Recent studies have shown that traditional Chinese medicine (TCM) compounds exhibit unique advantages in the treatment of respiratory diseases owing to their natural properties and potential efficacy. These compounds can effectively regulate ferroptosis by modulating several key signalling pathways such as system Xc -GSH-GPX4, NCOA4-mediated ferritinophagy, Nrf2-GPX4, and Nrf2/HO-1, thus playing a positive role in improving respiratory diseases. PURPOSE: This comprehensive review systematically outlines the regulatory role of ferroptosis in the onset and progression of respiratory diseases and provides evidence for treating respiratory diseases by targeting ferroptosis with TCM compounds. These insights aim to offer potential remedies for the clinical prevention and treatment of respiratory diseases. STUDY DESIGN AND METHODS: We searched scientific databases PubMed, Web of Science, Scopus, and CNKI using keywords such as "ferroptosis","respiratory diseases","chronic obstructive pulmonary disease","bronchial asthma","acute lung injury","pulmonary fibrosis","lung cancer","traditional Chinese medicine","traditional Chinese medicine compound","monomer", and "natural product" to retrieve studies on the therapeutic potential of TCM compounds in ameliorating respiratory diseases by targeting ferroptosis. The retrieved data followed PRISMA criteria (preferred reporting items for systematic review). RESULTS: TCM compounds possess unique advantages in treating respiratory diseases, stemming from their natural origins and proven clinical effectiveness. TCM compounds can exert therapeutic effects on respiratory diseases by regulating ferroptosis, which mainly involves modulation of pathways such as system Xc -GSH-GPX4,NCOA4-mediated ferritinophagy, Nrf2-GPX4, and Nrf2/HO-1. CONCLUSION: TCM compounds have demonstrated promising potential in improving respiratory diseases through the regulation of ferroptosis. The identification of specific TCM-related inducers and inhibitors of ferroptosis holds great significance in developing more effective strategies. However, current research remains confined to animal and cellular studies, emphasizing the imperative for further verifications through high-quality clinical data.
11Assessment of N-acetylcysteine as a therapy for phosgene-induced acute lung injury.PubMed
Rachel Rendell, Sarah Fairhall, Stuart Graham, et al.
The toxic industrial chemical (TIC) phosgene remains an important chemical intermediate in many industrial processes. Inhalation of phosgene can cause an acute lung injury (ALI) which, in severe cases may result in death. There are currently no effective pharmacological therapies or evidence-based treatment guidelines for managing exposed individuals. N-acetylcysteine (NAC) is a commercially available drug licensed in the UK and elsewhere for the treatment of paracetamol (acetaminophen) overdose. It has a number of mechanisms of action which may provide therapeutic benefit for the treatment of phosgene-induced ALI. It has previously been shown to provide therapeutic efficacy against the lung damaging effects of sulfur mustard vapour exposure, when given by the inhaled route, in the pig (Jugg et al., 2013). Our research objective was to determine whether inhaled NAC might also be therapeutic for other chemicals, in this case, phosgene. This study has demonstrated that multiple nebulised doses, administered from 30 min after exposure of terminally anaesthetised pigs to phosgene, is not an effective therapy when administered at the times and doses employed in this study. There remains no pharmacological treatment for phosgene-induced lung injury.
12Comparison of two fluid-management strategies in acute lung injury.PubMed
Herbert P Wiedemann, Arthur P Wheeler, et al.
BACKGROUND: Optimal fluid management in patients with acute lung injury is unknown. Diuresis or fluid restriction may improve lung function but could jeopardize extrapulmonary-organ perfusion. METHODS: In a randomized study, we compared a conservative and a liberal strategy of fluid management using explicit protocols applied for seven days in 1000 patients with acute lung injury. The primary end point was death at 60 days. Secondary end points included the number of ventilator-free days and organ-failure-free days and measures of lung physiology. RESULTS: The rate of death at 60 days was 25.5 percent in the conservative-strategy group and 28.4 percent in the liberal-strategy group (P=0.30; 95 percent confidence interval for the difference, -2.6 to 8.4 percent). The mean (+/-SE) cumulative fluid balance during the first seven days was -136+/-491 ml in the conservative-strategy group and 6992+/-502 ml in the liberal-strategy group (P<0.001). As compared with the liberal strategy, the conservative strategy improved the oxygenation index ([mean airway pressure x the ratio of the fraction of inspired oxygen to the partial pressure of arterial oxygen]x100) and the lung injury score and increased the number of ventilator-free days (14.6+/-0.5 vs. 12.1+/-0.5, P<0.001) and days not spent in the intensive care unit (13.4+/-0.4 vs. 11.2+/-0.4, P<0.001) during the first 28 days but did not increase the incidence or prevalence of shock during the study or the use of dialysis during the first 60 days (10 percent vs. 14 percent, P=0.06). CONCLUSIONS: Although there was no significant difference in the primary outcome of 60-day mortality, the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing nonpulmonary-organ failures. These results support the use of a conservative strategy of fluid management in patients with acute lung injury. (ClinicalTrials.gov number, NCT00281268 [ClinicalTrials.gov].).
13The immunosuppressive activity of artemisinin-type drugs towards inflammatory and autoimmune diseases.PubMed
Thomas Efferth, Franz Oesch
The sesquiterpene lactone artemisinin from Artemisia annua L. is well established for malaria therapy, but its bioactivity spectrum is much broader. In this review, we give a comprehensive and timely overview of the literature regarding the immunosuppressive activity of artemisinin-type compounds toward inflammatory and autoimmune diseases. Numerous receptor-coupled signaling pathways are inhibited by artemisinins, including the receptors for interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), β3-integrin, or RANKL, toll-like receptors and growth factor receptors. Among the receptor-coupled signal transducers are extracellular signal-regulated protein kinase (ERK), c-Jun N-terminal kinase (JNK), phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), AKT serine/threonine kinase (AKT), mitogen-activated protein kinase (MAPK)/extracellular signal regulated kinase (ERK) kinase (MEK), phospholipase C γ1 (PLCγ), and others. All these receptors and signal transduction molecules are known to contribute to the inhibition of the transcription factor nuclear factor κ B (NF-κB). Artemisinins may inhibit NF-κB by silencing these upstream pathways and/or by direct binding to NF-κB. Numerous NF-κB-regulated downstream genes are downregulated by artemisinin and its derivatives, for example, cytokines, chemokines, and immune receptors, which regulate immune cell differentiation, apoptosis genes, proliferation-regulating genes, signal transducers, and genes involved in antioxidant stress response. In addition to the prominent role of NF-κB, other transcription factors are also inhibited by artemisinins (mammalian target of rapamycin [mTOR], activating protein 1 [AP1]/FBJ murine osteosarcoma viral oncogene homologue [FOS]/JUN oncogenic transcription factor [JUN]), hypoxia-induced factor 1α (HIF-1α), nuclear factor of activated T cells c1 (NF-ATC1), Signal transducers and activators of transcription (STAT), NF E2-related factor-2 (NRF-2), retinoic-acid-receptor-related orphan nuclear receptor γ (ROR-γt), and forkhead box P-3 (FOXP-3). Many in vivo experiments in disease-relevant animal models demonstrate therapeutic efficacy of artemisinin-type drugs against rheumatic diseases (rheumatoid arthritis, osteoarthritis, lupus erythematosus, arthrosis, and gout), lung diseases (asthma, acute lung injury, and pulmonary fibrosis), neurological diseases (autoimmune encephalitis, Alzheimer's disease, and myasthenia gravis), skin diseases (dermatitis, rosacea, and psoriasis), inflammatory bowel disease, and other inflammatory and autoimmune diseases. Randomized clinical trials should be conducted in the future to translate the plethora of preclinical results into clinical practice.
14Dachengqi decoction alleviates acute lung injury by suppressing HIF-1α-mediated glycolysis.PubMed
Luorui Shang, Mengqi Zhang, Jinxiao Li, et al.
ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) is an aggressive inflammatory disease of the lungs characterized by a high mortality rate. More and more researchers have found that herbal medicines are highly effective in preventing and treating inflammatory lung diseases. Among them, Dachengqi Decoction (DCQD) is considered to be the representative prescription of "lung-intestine combined treatment" in traditional Chinese medicine, and its potential protective mechanism against ALI is worthy of further study. AIM OF THE STUDY: Based on the theory of "lung-intestine combined treatment", the protective effect and molecular mechanism of DCQD in alleviating ALI were verified by network pharmacology and experiments. MATERIALS AND METHODS: The active ingredients of DCQD were obtained by UPLC-MS. Network pharmacology and molecular docking techniques were used to screen the active ingredient-target pathway of DCQD for ALI treatment. Additionally, the ALI model was constructed and verified in vivo according to the predicted results. RESULTS: 34 active components and 570 potential targets of DCQD were selected by network pharmacological analysis. In addition, 950 target genes of ALI and 2095 target genes related to sepsis were obtained, and 570 interlinked target genes of the two were identified. We finally screened out 199 common target genes critical to DCQD treatment of ALI and sepsis, and then enriched them with GO and KEGG. In the ALI model, studies have found that DCQD alleviates the inflammatory response of ALI, possibly by inhibiting HIF-1α-mediated glycolysis. CONCLUSION: This study confirmed the preventive effect of DCQD on ALI, and found that DCQD can improve the protective mechanism of ALI by regulating the expression of HIF-1α, down-regulating glycolysis and reducing inflammation.
15Aprepitant alleviates acute lung injury in a rat model of hepatic ischemia-reperfusion via NLRP3/IL-1β signaling pathway.PubMed
Walaa Yehia Abdelzaher, Mina T Kelleni, Marly Nady Adly, et al.
Hepatic ischemia reperfusion (HIR) injury is a complication that complicates major liver surgeries and contributes to significant hepatic and remote organs damage. Aprepitant (Ap), a neurokinin-1 receptor (NK-1R) antagonists, is an antiemetic commonly used in preventing chemotherapy-induced nausea and vomiting. This study aimed to evaluate the potential protective effect of Ap against acute lung injury (ALI) associated with HIR, utilizing the Pringle maneuver to induce 30 min of hepatic ischemia followed by 1 h of reperfusion, while targeting the NLRP3/IL-1β signaling pathway. Serum alanine transaminase (ALT), aspartate transaminase (AST), Lung malondialdehyde (MDA), total antioxidant capacity (TAC), reduced glutathione (GSH), tumor necrosis factor-alpha (TNF-α), caspase-3 levels, NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, cleaved caspase-3 expressions were evaluated. Hepatic and lung specimens were evaluated histopathologically and an immunohistochemical study of lung interlukin 1beta (IL-1β) was also performed. HIR caused hepatic and lung damage as shown histopathologically and by an increase in serum ALT, AST and lung IL-1β. A significant increase in lung MDA, TNF-α, caspase-3 levels, NLRP3 and cleaved caspase-3 expressions and decrease in TAC and GSH parameters were detected. Ap significantly ameliorated the oxidative stress, inflammatory, and apoptotic parameters, and this was accompanied by a significant improvement in the histopathological findings with reduction in lung IL-1β. Targeting the NLRP3/IL-1β signaling pathway, as shown by Ap in our murine model, could reveal a promising therapeutic approach to protect against ALI during major liver surgeries.
16FGF1 alleviates LPS-induced acute lung injury via suppression of inflammation and oxidative stress.PubMed
Qhaweni Dhlamini, Wei Wang, Guifeng Feng, et al.
BACKGROUND: Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), are devastating clinical disorders with high mortality, and for which more effective therapies are urgently needed. FGF1, the prototype member of the FGF family, is shown to exert protective effects against injurious stimuli in multiple disease models. Here we aimed to evaluate whether FGF1 pretreatment is protective against LPS-induced ALI and elucidate the potential underlying mechanisms. METHODS: For drug-treated groups, C57B/6 mice received a single i.p. injection of FGF1 (1 mg/kg) 1 h before the LPS challenge or not. To induce the ALI model, the mice were treated by intratracheal instillation of LPS (5 mg/kg). Then, histopathological changes in lung tissues were assessed by hematoxylin and eosin staining and transmission electron microscopy. ELISA and qPCR assays were used to detect pro-inflammatory cytokine levels in BALF and lung tissues, respectively. The total number of inflammatory cells (neutrophils and macrophages) in BALF were counted using the Wright-Giemsa method. The expressions of reactive oxygen species (ROS) and malondialdehyde (MDA) were measured using their respective kits. Western blot and immunostaining were used to evaluate the expressions of antioxidants (Nrf-2, HO-1, SOD2, GPX4, and Catalase), as well as the inflammatory and/or apoptosis-related factors (TLR4, NF-κB, and Cleaved- caspase 3). RESULTS: FGF1 pretreatment significantly ameliorated the LPS-induced histopathological changes, reduced lung wet/dry ratios, ROS and MDA levels, total BALF protein, inflammatory cell infiltration, proinflammatory cytokine levels, and significantly increased the expression of antioxidant proteins (Nrf-2, HO-1, Catalase, and SOD2). In addition, FGF1 pretreatment significantly reduced the expression of TLR4 and cleaved- caspase 3, inhibited NF-κB activation, and reduced LPS-induced cell apoptosis. CONCLUSIONS: Altogether, our results suggest that FGF1 pretreatment is protective against LPS-induced ALI through mediating anti-inflammatory and antioxidant effects, which may be attributed to the downregulation of TLR4 expression and inhibition of NF-κB activation, as well as promotion of antioxidant defenses. Therefore, FGF1 administration may prove beneficial in preventative strategies for ALI/ARDS.
17Nanomedicine for acute respiratory distress syndrome: The latest application, targeting strategy, and rational design.PubMed
Qi Qiao, Xiong Liu, Ting Yang, et al.
Acute respiratory distress syndrome (ARDS) is characterized by the severe inflammation and destruction of the lung air-blood barrier, leading to irreversible and substantial respiratory function damage. Patients with coronavirus disease 2019 (COVID-19) have been encountered with a high risk of ARDS, underscoring the urgency for exploiting effective therapy. However, proper medications for ARDS are still lacking due to poor pharmacokinetics, non-specific side effects, inability to surmount pulmonary barrier, and inadequate management of heterogeneity. The increased lung permeability in the pathological environment of ARDS may contribute to nanoparticle-mediated passive targeting delivery. Nanomedicine has demonstrated unique advantages in solving the dilemma of ARDS drug therapy, which can address the shortcomings and limitations of traditional anti-inflammatory or antioxidant drug treatment. Through passive, active, or physicochemical targeting, nanocarriers can interact with lung epithelium/endothelium and inflammatory cells to reverse abnormal changes and restore homeostasis of the pulmonary environment, thereby showing good therapeutic activity and reduced toxicity. This article reviews the latest applications of nanomedicine in pre-clinical ARDS therapy, highlights the strategies for targeted treatment of lung inflammation, presents the innovative drug delivery systems, and provides inspiration for strengthening the therapeutic effect of nanomedicine-based treatment.
18Mechanisms underlying the therapeutic effects of Qingfeiyin in treating acute lung injury based on GEO datasets, network pharmacology and molecular docking.PubMed
Ying Wang, Yuan Yuan, Wenting Wang, et al.
BACKGROUND: Qingfeiyin (QFY) is a common Chinese herbal formula for the treatment of acute lung injury (ALI). However, its mechanisms of action are unclear. In this study, we systematically explored the effects and mechanism of action of QFY in ALI using network pharmacology and molecular docking. METHODS: Active compounds and targets of QFY were obtained from TCMSP and TCMID. ALI-related targets were retrieved from GEO datasets combined with GeneCards, OMIM, and TTD databases. A protein-protein interaction (PPI) network was built to screen the core targets. DAVID was used for GO and KEGG pathway enrichment analyses. The tissue and organ distribution of targets was evaluated. Interactions between potential targets and active compounds were assessed by molecular docking. A molecular dynamics simulation was conducted for the optimal core protein-compound complexes obtained by molecular docking. RESULTS: In total, 128 active compounds and 121 targets of QFY were identified. A topological analysis of the PPI network revealed 13 core targets. GO and KEGG pathway enrichment analyses indicated that the effects of QFY are mediated by genes related to inflammation, apoptosis, and oxidative stress as well as the MAPK and PI3K-Akt signaling pathways. Molecular docking and molecular dynamics simulations revealed good binding ability between the active compounds and screened targets. CONCLUSIONS: This study successfully predict the effective components and potential targets and pathways involved in the treatment of ALI for QFY. We provided a novel strategy for future research of molecular mechanisms of QFY in ALI treatment. Moreover, the potential active ingredients provide a reliable source for drug screening for ALI.
19Cryoprecipitate therapy.PubMed
B Nascimento, L T Goodnough, J H Levy
Cryoprecipitate, originally developed as a therapy for patients with antihaemophilic factor deficiency, or haemophilia A, has been in use for almost 50 yr. However, cryoprecipitate is no longer administered according to its original purpose, and is now most commonly used to replenish fibrinogen levels in patients with acquired coagulopathy, such as in clinical settings with haemorrhage including cardiac surgery, trauma, liver transplantation (LT), or obstetric haemorrhage. Cryoprecipitate is a pooled product that does not undergo pathogen inactivation, and its administration has been associated with a number of adverse events, particularly transmission of blood-borne pathogens and transfusion-related acute lung injury. As a result of these safety concerns, along with emerging availability of alternative fibrinogen preparations, cryoprecipitate has been withdrawn from use in a number of European countries. Compared with the plasma from which it is prepared, cryoprecipitate contains a high concentration of coagulation factor VIII, coagulation factor XIII, and fibrinogen. Cryoprecipitate is usually licensed by regulatory authorities for the treatment of hypofibrinogenaemia, and recommended for supplementation when plasma fibrinogen levels decrease below 1 g litre(-1); however, this threshold is empiric and is not based on solid clinical evidence. Consequently, there is uncertainty over the appropriate dosing and optimal administration of cryoprecipitate, with some guidelines from professional societies to guide clinical practice. Randomized, controlled trials are needed to determine the clinical efficacy of cryoprecipitate, compared with the efficacy of alternative preparations. These trials will allow the development of evidence-based guidelines in order to inform physicians and guide clinical practice.
20GSTP alleviates acute lung injury by S-glutathionylation of KEAP1 and subsequent activation of NRF2 pathway.PubMed
Xiaolin Sun, Chaorui Guo, Chunyan Huang, et al.
Oxidative stress plays an important role in the pathogenesis of acute lung injury (ALI). As a typical post-translational modification triggered by oxidative stress, protein S-glutathionylation (PSSG) is regulated by redox signaling pathways and plays diverse roles in oxidative stress conditions. In this study, we found that GSTP downregulation exacerbated LPS-induced injury in human lung epithelial cells and in mice ALI models, confirming the protective effect of GSTP against ALI both in vitro and in vivo. Additionally, a positive correlation was observed between total PSSG level and GSTP expression level in cells and mice lung tissues. Further results demonstrated that GSTP inhibited KEAP1-NRF2 interaction by promoting PSSG process of KEAP1. By the integration of protein mass spectrometry, molecular docking, and site-mutation validation assays, we identified C434 in KEAP1 as the key PSSG site catalyzed by GSTP, which promoted the dissociation of KEAP1-NRF2 complex and activated the subsequent anti-oxidant genes. In vivo experiments with AAV-GSTP mice confirmed that GSTP inhibited LPS-induced lung inflammation by promoting PSSG of KEAP1 and activating the NRF2 downstream antioxidant pathways. Collectively, this study revealed the novel regulatory mechanism of GSTP in the anti-inflammatory function of lungs by modulating PSSG of KEAP1 and the subsequent KEAP1/NRF2 pathway. Targeting at manipulation of GSTP level or activity might be a promising therapeutic strategy for oxidative stress-induced ALI progression.