Lung cancer is one of the most prevalent and lethal malignant tumors worldwide. In recent years, immune checkpoint inhibitors have significantly improved the survival outcomes of some patients with advanced non-small cell lung cancer; however, primary and acquired resistance remain important barriers limiting their clinical efficacy. Research has revealed that structural remodeling of the tumor microenvironment (TME) is one of the key factors involved in immunotherapy resistance. Efferocytosis is an important process by which tumor-associated macrophages clear apoptotic cells. In the lung cancer TME, the high apoptotic cell burden can lead to persistent activation of efferocytosis. Studies have shown that sustained efferocytosis is not merely a process of cellular debris clearance, but can also induce metabolic reprogramming in macrophages, including dysregulated lipid metabolism and enhanced glycolysis, and promote the secretion of immunosuppressive and tissue-repair-related factors. These changes further promote pathological angiogenesis, activation of cancer-associated fibroblasts, and excessive extracellular matrix deposition, thereby driving structural remodeling of the TME and forming an immune-excluded microenvironment characterized by vascular abnormalities and stromal fibrosis. This process restricts effector T-cell infiltration and impairs the efficacy of immune checkpoint inhibitors. This review describes the molecular mechanisms of macrophage efferocytosis in the lung cancer TME, focusing on its regulatory roles in metabolic reprogramming, pathological angiogenesis, and stromal fibrosis, and discusses potential therapeutic strategies targeting efferocytosis-related signaling pathways and TME structural remodeling, aiming to provide new insights into overcoming immunotherapy resistance in lung cancer.

Cognitive dysfunction, characterized by memory impairment, attentional deficits, and executive dysfunction, represents a critical clinical manifestation in post-acute sequelae of COVID-19 that significantly compromises patients' quality of life. The lung-brain axis, as a bidirectional regulatory network connecting the respiratory system to the central nervous system, interacts through neural circuits, humoral pathways, and microbial pathways, and may play a central role in the cognitive impairments occurring in long COVID (LC). This paper systematically reviews the multidimensional pathways of the lung-brain axis and their pathological mechanisms in the cognitive impairment of LC, including direct viral neuroinvasion during the acute phase, chronic injury triggered by viral persistence, immune homeostasis dysregulation, hypoxaemia, microbiome disruption, and renin- angiotensin system imbalance. It then explores clinical intervention strategies based on the lungbrain axis, integrating supportive treatments, such as oxygen therapy, exercise therapy, and cognitive training, with treatments targeting the lung-brain axis, including antiviral drugs, immunomodulation, probiotics, and neuromodulation techniques. It is also suggested that future research should favour the integration of multi-omics technologies and the development of individualised therapeutic targets.

Objectives Large language models (LLMs) are increasingly studied for clinical decision support, but high-risk cardiology exposes persistent weaknesses in hallucination control, guideline adherence, and medication-safety reasoning. Heart failure with reduced ejection fraction (HFrEF) is a demanding test case because safe care requires structured guideline-directed therapy, comorbidity-aware monitoring, and reliable risk warnings. Methods We developed a dynamic alignment framework using 1087 retrospective HFrEF cases from Affiliated Zhongshan Hospital of Dalian University. An open-source LLaMA-3.1 backbone was optimized through four sequential stages: continual pre-training for heart-failure domain adaptation, supervised fine-tuning for structured clinical responses, reinforcement policy optimization for safety-oriented alignment, and retrieval-augmented generation for guideline grounding. Models were assessed with dual-track clinical and linguistic metrics. Results LLaMA-3.1 was the strongest supervised baseline, but supervised fine-tuning alone did not fully resolve guideline-adherence limitations. Staged alignment produced a measurable Alignment Tax: the final retrieval-grounded variant improved the Clinical Score from 0.716 to 0.864 and reached a Guideline Score of 0.881, while BLEU-4 decreased from 0.371 to 0.272. The decline in surface overlap coincided with stronger risk safety, stricter structure, and more guideline-directed outputs. Conclusions Dynamic alignment shifted the model from linguistic mimicry toward clinically constrained HFrEF decision support. These findings suggest that staged optimization with policy alignment and retrieval grounding can improve evidence-based recommendations, while conventional language-overlap metrics may underestimate clinically safer generation.

Obstructive sleep apnea syndrome (OSAS) is a prevalent sleep-related breathing disorder characterized by intermittent hypoxia (IH). Myocardial injury is a common complication associated with OSAS. Alpha-lipoic acid (LA), a potent antioxidant, has been utilized in various disease contexts and has demonstrated significant protective effects in myocardial infarction models. Given the limited treatment options available for OSAS-related myocardial injury, this study aimed to demonstrate the potential therapeutic effects of LA and to investigate the underlying mechanisms. IH is a widely employed method to simulate the pathophysiological conditions associated with OSAS. In vivo experiments were conducted using mice placed in a specialized hypoxic chamber to replicate IH conditions. Echocardiography indicated that exposure to IH severely impaired cardiac function. Treatment with LA activated the Nrf2 pathway and autophagy, which contributed to the improvement of cardiac function in mice with OSAS. Additionally, in vitro studies demonstrated that IH induced apoptosis and decreased cell viability in H9C2 cardiomyocytes. LA enhanced Nrf2 nuclear translocation and its downstream signaling pathways, thereby promoting autophagy, inhibiting apoptosis, and alleviating injury in H9C2 cardiomyocytes. Furthermore, in vitro inhibition of Nrf2 using ML385 reduced autophagy levels and attenuated the protective effects of LA against apoptosis in H9C2 cardiomyocytes. These findings suggest that LA may provide a promising therapeutic strategy for myocardial injury associated with OSAS. By elucidating these findings, new insights into the protective mechanisms of LA against IH-induced myocardial injury are provided, highlighting its potential as a therapeutic agent for diseases associated with OSAS.

OBJECTIVE:To investigate the anti-apoptosis and anti-ferroptosis effects of dl-3-n-butylphthalide (dl-NBP) on cerebral ischemia-reperfusion injury (CIRI) in rats, and the potential involvement of cysteine-X-cysteine chemokine receptor 4 (CXCR4). METHODS:The differentially expressed genes between healthy people and stroke patients were screened by GEO database. A transient middle cerebral artery occlusion rat model was used to induce CIRI in vivo. Rats were randomly divided into sham group, tMCAO group, and dl-NBP + tMCAO group. The therapeutic effect of dl-NBP in vivo and its effect on apoptosis and ferroptosis in brain tissues were evaluated. An in vitro oxygen-glucose deprivation/reperfusion (OGD/R) model was established to simulate CIRI in cultured PC12 cells, and the effects of dl-NBP on apoptosis and ferroptosis were examined. In this model, CXCR4 expression was assessed by western blotting and its involvement in dl-NBP-mediated protection assessed by inhibition with AMD3100. RESULTS:In the stroke-related GSE22255 and GSE66724 datasets, a total of six genes with increased co-expression were found, including CXCR4. Dl-NBP treatment significantly reduced both the volume of cerebral infarction and the degree of cerebral edema, and improved neurological function in rats. dl-NBP reduced the degree of apoptosis and ferroptosis and alleviated CIRI both in vivo and in vitro. The pro-survival effects of dl-NBP were significantly reversed after CXCR4 inhibition with AMD3100. CONCLUSION:Dl-NBP has anti-apoptotic and anti-ferroptotic effects on CIRI both in vivo and in vitro, and this effect is mediated by CXCR4.

Obstructive sleep apnoea hypopnea syndrome (OSAHS) is a sleep disorder associated with significant cardiovascular complications, characterized by intermittent hypoxia (IH). IH causes endothelial dysfunction, an early event in cardiovascular disease. We investigated the role of dual-specificity phosphatase 8 (DUSP8), a key negative regulator of the mitogen-activated protein kinase (MAPK) signalling pathway, in IH-induced endothelial cell damage, and the therapeutic effects of N-acetylcysteine (NAC) by establishing IH models in human umbilical vein endothelial cells and C57BL/6 mice. DUSP8 and MAPK signalling pathway-related proteins were analysed by western blotting, and DUSP8 mRNA and miR-21-5p expression was assessed by RT-qPCR. Inflammatory cytokines were detected by an enzyme-linked immunosorbent assay, apoptosis-related proteins were analysed by western blotting, and apoptosis was assessed using flow cytometry. IH stimulation induced inflammation and apoptosis in endothelial cells, downregulated DUSP8 expression, and upregulated the phosphorylation of key molecules involved in the MAPK signalling pathway. However, DUSP8 overexpression alleviated IH-induced inflammation and apoptosis in endothelial cells and reduced the phosphorylation of key molecules in the MAPK signalling pathway. Bioinformatic analysis and dual-luciferase reporter assays confirmed that DUSP8 is a direct target of miR-21-5p. DUSP8 overexpression effectively reversed the damage caused by miR-21-5p upregulation under IH conditions. Furthermore, in cell and animal models of IH, NAC demonstrated protective effects against inflammation, apoptosis, and oxidative stress through a mechanism linked to the miR-21-5p/DUSP8/MAPK signalling pathway. Overall, this study elucidated the protective role of DUSP8 against IH-induced endothelial injury and confirmed the potential of NAC as a therapeutic agent for OSAHS-related diseases.

Acute myocardial infarction (MI) is among the diseases with the highest incidences and seriously threatens public health worldwide, with the present clinical treatment methods presenting considerable risks. Ferroptosis, characterized by iron dependence and intracellular oxidative accumulation, is a type of programmed cell death that has opened new avenues for treating MI. Muscone is one of the major active monomers of musk, which can improve ventricular remodeling after MI and myocardial ischemia-reperfusion injury. However, the ferroptosis mechanism underlying muscone-mediated MI treatment remains unelucidated. Therefore, this study aimed to investigate the mechanisms of action of muscone in MI management both in vivo and in vitro. Notably, muscone could attenuate MI injury, increase myocardial angiogenesis, and inhibit myocardial ferroptosis in the in vivo rat model. Furthermore, in vitro experiment results in rat cardiomyocytes H9c2 cells showed that muscone could inhibit hypoxia-induced cell damage, improve cell viability, and inhibit cell apoptosis and ferroptosis. Mechanistically, muscone-mediated ferroptosis inhibition was regulated by the nuclear factor erythroid 2-related factor 2 (Nrf2)/System Xc-/glutathione peroxidase 4 (GPX4) signaling pathway to treat MI. Altogether, the results of this study show the therapeutic potential of muscone in MI treatment. These findings provide notable insights regarding the development of therapeutic approaches targeted at the Nrf2/System Xc- /GPX4 signaling pathway.

Objective(s): Proliferation and migration of pulmonary artery smooth muscle cells (PASMCs) contribute to hypoxia-induced pulmonary hypertension (HPH). The transcription factor Cbp/p300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 2 (Cited2) has been implicated in the control of tumor cells and mesenchymal stem cell (MSC) and cardiomyocyte growth or migration. Whether Cited2 is involved in the proliferation and migration of PASMCs and the underlying mechanisms deserve to be explored. Materials and Methods: Cited2 expression was detected in rat PASMCs under hypoxia conditions and HPH rat models. The effect of Cited2 on the proliferation and migration of PASMC was detected by overexpression or knockdown of the Cited2 gene. After PAMSCs were treated with recombinant TGF-β1 and the lentivirus vector overexpressing Cited2, expression of peroxisome proliferator-activated receptor gamma (PPARγ) was examined by western blotting.Results: We revealed that hypoxia down-regulated the expression of Cited2 in PASMCs and rat pulmonary arteries. Cited2 overexpression inhibited the proliferation and migration of PASMCs under hypoxia, while Cited2 knockdown induced the proliferation and migration of PASMCs. Cited2 inhibits the negative regulation of the TGF-β1 pathway on PPARγ to inhibit the proliferation and migration of PASMCs.Conclusion: These findings suggest that increased Cited2 expression contributes to the inhibition of PASMCs proliferation and migration by regulating TGF-β1-mediated target gene expression in HPH and provides a new target for molecular therapy of HPH.

Obstructive Sleep Apnea-Hypopnea Syndrome (OSAHS) is a common disorder that disrupts breathing during sleep, with known links to several heart-related conditions.Investigating the underlying mechanisms can guide the creation of new treatments.We focused on the role of specific genetic regulators, known as long non-coding RNAs (lncRNAs), which recent evidence suggests may play a part in heart disease resulting from OSAHS.Our study explored how a simulated OSAHS condition, Cyclic Intermittent Hypoxia (CIH), affects heart cells.We found that CIH increases levels of the lncRNA GAS5 and an enzyme called TRIM11, while reducing the levels of Bcl-2, a molecule that prevents cell death, thus leading to increased heart cell apoptosis.We also demonstrated that a microRNA, miR-205-5p, is a key player in this process, as it can modify the effect of GAS5 on TRIM11.Introducing miR-205-5p mimics lessened the impact of GAS5 on TRIM11.Our findings reveal a novel lncRNA GAS5/miR-205-5p/TRIM11 pathway by which OSAHS may cause heart damage.This research offers fresh insights into the molecular dynamics of heart injury induced by OSAHS and may inform future therapeutic strategies.

The objective of this study was to explore the molecular basis through which Curcumin (Cur) mitigates neuronal damage caused by obstructive sleep apnea (OSA). HT22 was used to simulate intermittent hypoxia (IH) injury and explore the effect of Cur on these cells. We evaluated the cell viability, cytotoxicity, apoptosis, proliferation, and Wnt/β-catenin (WβC) pathway. IWR-1 was used to block the pathway and investigate the protective mechanism of Cur. We constructed an in vivo model of IH to validate the results of the cellular experiments. IH accelerated apoptosis and cytotoxicity, suppressed proliferation, and decreased the activity of the WβC pathway. Cur can significantly improve cell viability, reduce apoptosis rate and cell toxicity, promote cell proliferation, and up-regulate the WβC. After blocking the WβC pathway, the proliferative effect of Cur was observably weakened. In vivo, IH caused hippocampal damage and inhibited WβC pathway activity in mice, which was ameliorated by Cur treatment. This implies that Cur could be a novel treatment option for neurological impairment brought on by OSA.

Obstructive sleep apnea (OSA) is a common clinical condition linked to cognitive impairment, mainly characterized by chronic intermittent hypoxia (CIH). GLP-1 receptor agonist, known for promoting insulin secretion and reducing glucose levels, has demonstrated neuroprotective effects in various experimental models such as stroke, Alzheimer’s disease, and Parkinson’s disease. This study aims to investigate the potential role and mechanisms of the GLP-1 receptor agonist liraglutide in ameliorating OSA-induced cognitive deficits. CIH exposure, a well-established and mature OSA pathological model, was used both in vitro and in vivo. In vitro, CIH significantly activated oxidative stress, inflammation, and apoptosis in SH-SY5Y cells. Liraglutide enhanced the nuclear translocation of Nrf2, activating its downstream pathways, thereby mitigating CIH-induced injury in SH-SY5Y cells. Additionally, liraglutide modulated the MAPK/NF-κB signaling pathway, reducing the expression of inflammatory factors and proteins. In vivo, we subjected mice to an intermittent hypoxia incubator to mimic the pathogenesis of human OSA. The Morris water maze test revealed that CIH exposure substantially impaired spatial memory. Subsequent western blot analyses and histopathological examinations indicated that liraglutide could activate the Nrf2/HO-1 axis and inhibit the MAPK/NF-κB signaling pathway, thereby alleviating OSA-associated cognitive dysfunction in mice. These findings suggest that GLP-1 receptor agonists may offer a promising preventive strategy for OSA-associated cognitive impairment. By refining these findings, we provide new insights into GLP-1’s protective mechanisms in combating cognitive deficits associated with CIH, underscoring its potential as a therapeutic agent for conditions linked to OSA.

Obstructive sleep apnea (OSA) is a common respiratory disorder. Multiple organs, especially the central nervous system (CNS), are damaged, and dysfunctional when intermittent hypoxia (IH) occurs during sleep for a long time. The quality of life of individuals with OSA is significantly impacted by cognitive decline, which also escalates the financial strain on their families. Consequently, the development of novel therapies becomes imperative. IH induces oxidative stress, endoplasmic reticulum stress, iron deposition, and neuroinflammation in neurons. Synaptic dysfunction, reactive gliosis, apoptosis, neuroinflammation, and inhibition of neurogenesis can lead to learning and long-term memory impairment. In addition to nerve injury, the role of IH in neuroprotection was also explored. While causing neuron damage, IH activates the neuronal self-repairing mechanism by regulating antioxidant capacity and preventing toxic protein deposition. By stimulating the proliferation and differentiation of neural stem cells (NSCs), IH has the potential to enhance the ratio of neonatal neurons and counteract the decline in neuron numbers. This review emphasizes the perspectives and opportunities for the neuroprotective effects of IH and informs novel insights and therapeutic strategies in OSA.

The purpose of this work was to investigate how curcumin (Cur) might enhance cognitive function and to gain a better understanding of the molecular mechanisms behind Cur's impacts on neurogenesis deficits brought on by intermittent hypoxia (IH). Using network pharmacology, we explored possible targets for Cur's obstructive sleep apnea (OSA) therapy. We established an IH model using C57BL/6 mice and c17.2 cells, and we assessed the influence of Cur on treatment outcomes as well as the effect of IH on cognitive function. Hippocampal damage and neurogenesis, as well as expression of core targets, were then examined. Network pharmacology analysis revealed that Cur has the potential for multi-target, multi-pathway therapy, with CTNNB1 and MYC as core target genes. The Morris water maze test showed that Cur (100 mg/kg, intragastrically) significantly improved cognitive dysfunction induced by IH. The hematoxylin and eosin (H&E) and Nissl staining indicated that Cur could alleviate damage to the hippocampus caused by IH. Immunohistochemistry, immunofluorescence, and western blotting results showed that Cur might promote neurogenesis and upregulate the expression of β-catenin and c-myc. In vitro, Cur (0.5 μM) has a protective effect on IH-induced neural stem cells (NSCs) injury and apoptosis and can restore the Wnt/β-catenin. Cur significantly increased the neurogenesis via the Wnt/β-catenin pathway, providing the scientific groundwork for the development of new treatment strategies for neurological damage linked to OSA.

BackgroundTrastuzumab therapy for HER2-positive cancers is associated with cardiotoxicity. This umbrella review synthesizes evidence from systematic reviews and meta-analyses on cardioprotective interventions during trastuzumab treatment.MethodsA comprehensive search was conducted in PubMed, Embase, Cochrane Library, and Web of Science. Systematic reviews and meta-analyses examining cardioprotective interventions in patients receiving trastuzumab were included. The methodological quality was assessed using the AMSTAR-2 tool. Data on cardiac events, treatment interruptions, left ventricular ejection fraction (LVEF) changes, and exercise interventions were synthesized.ResultsTen systematic reviews met the inclusion criteria. Statins demonstrated the strongest cardioprotective effect (RR = 0.47, 95% CI: 0.26–0.84), potentially preventing more than half of cardiac events during trastuzumab therapy, followed by beta-blockers (RR = 0.61, 95% CI: 0.39–0.93). Beta-blockers and ACEIs effectively reduced treatment interruptions, enabling approximately 40% more patients to maintain treatment continuity (RR = 0.63, 95% CI: 0.47–0.86). Among non-pharmacological interventions, structured exercise programs showed significant benefits in preserving cardiac function, demonstrating meaningful improvements in resting LVEF (WMD = −3.27%, 95% CI: −5.86 to −0.68).DiscussionThis review demonstrates that cardioprotective interventions, particularly statins and beta-blockers, significantly reduce the risk of cardiac complications during trastuzumab therapy. The positive impact on cardiac events and treatment interruptions suggests these interventions may enhance overall treatment efficacy by allowing more patients to complete their prescribed course.ConclusionEvidence strongly supports the systematic implementation of cardioprotective strategies in clinical practice, particularly statins and beta-blockers, as part of routine care protocols for patients receiving trastuzumab therapy. These interventions demonstrate significant potential in preventing cardiac complications and maintaining treatment continuity. Further research should focus on optimizing personalized approaches and evaluating long-term outcomes.

Idiopathic pulmonary fibrosis (IPF) is a progressive respiratory disease with no known cause. It is characterized by widespread inflammation and structural abnormalities in the alveoli of the lungs, ultimately leading to the development of pulmonary fibrosis. Triptolide (TP), an epoxy-diterpene lactone compound known for its potent anti-inflammatory and antifibrotic effects, was limited clinical use due to poor water solubility and side effects. Two soluble TP prodrugs (PG490-88 and Minnelide) have entered clinical research. However, their activities are based on enzyme metabolism, which is influenced by species-specific differences. In this study, we present water-soluble TP derivatives synthesized by introducing ethylenediamine carbamate groups (TP-DEAs) at the 14-hydroxy position. The introduced groups were found to spontaneously convert into the parent drug through enzyme-independent metabolic conversion. The water solubility and stability of the compounds were examined in vitro. Notably, TP-DEA2 exhibited high water solubility (30.8 mg/mL), exceeding TP solubility by more than 1181-fold. In vitro, TP-DEA2 converted to TP autonomously without the involvement of enzymes. In addition, TP-DEA2 can inhibit the expression of a disintegrin and metalloproteinase 10 (ADAM 10) induced by TGF-β1 and reduce the secretion of a-SMA in fibroblasts. In vivo, TP-DEA2 transformed into TP, effectively inhibiting fibrosis in the bleomycin group without observed toxicity. Importantly, positive outcomes when administering TP-DEA2 at a later stage post-bleomycin exposure suggest its potential role in treating IPF.

Objective(s): Paraquat (PQ), a highly effective and rapidly non-selective herbicide, mainly targets the lungs and causes acute lung injury (ALI). So far, the scarcity of effective drug candidates against PQ-induced ALI remains a big challenge. Andrographolide (Andro), with its anti-inflammatory and antioxidant activities, has been demonstrated to alleviate ALI. Nevertheless, whether Andro could alleviate the PQ-mediated ALI remains unknown. Therefore, this study will explore the effects as well as the possible mechanism of Andro against ALI caused by PQ. Materials and Methods: C57BL/6J mice were injected with 20 mg/kg PQ intraperitoneally to establish an ALI model. PQ-treated MLE-12 cells were applied to a vitro model. Nuclear factor erythroid like-2 (Nrf2) was knocked out to explore the specific effects of the Nrf2/ Heme oxygenase-1 (OH-1) pathway in the protection of Andro against ALI caused by PQ. Results: Andro significantly reduced lung damage and the ratio of Wet/Dry (W/D) weight, decreased MDA, IL-6, IL-1β, and TNF-ɑ levels, reversed the decrease of CAT and SOD levels, and inhibited apoptosis caused by PQ. Andro obviously increased the ratio of Bcl-2/Bax while reducing caspase-3 and cleaved caspase-3 levels. Furthermore, Andro dramatically elevated the antioxidant proteins Nrf2, NQO-1, and HO-1 levels compared with the PQ group. This experiment demonstrated that Andro reduced ROS and inhibited apoptosis, induced by PQ in MLE-12 cells, by inducing Nrf2/HO-1 pathway activation. Conclusion: Andro effectively ameliorates oxidant stress and apoptosis in ALI caused by PQ, possibly through inducing Nrf2/HO-1 pathway activation.

Objectives This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of tenofovir versus entecavir in children and adults with chronic hepatitis B.

Type 2 diabetes mellitus (T2DM) has caused a huge clinical and economic burden worldwide. The management strategy of T2DM has been mentioned in many guidelines. However, controversy still exists in the recommendation of anti-hyperglycemic agents. To this end, this protocol has been written according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P). We will make an overview of systematic reviews based-on network meta-analysis firstly that report on safety and efficacy of different category of anti-hyperglycemic agents for T2DM patients. We will identify network meta-analysis by applying a robust and standardized search strategy within Embase, PubMed, Web of Science, and Cochrane Database of Systematic Reviews. Hemoglobin A1c (HbA1c) and fasting plasma glucose (FPG) will be defined as the primary outcomes. We will assess the methodological quality of included reviews by applying the A MeaSurement Tool to Assess Systematic Reviews (AMSTAR-2) tool, and quality of evidence for all outcomes will be judged by using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). This will provide an accessible narrative synthesis to clinicians, patients, policy makers, and developers of clinical guidelines based on published high-quality network meta-analysis. We will submit our results for peer-review publication and presentation at domestic and international conferences. We will also disseminate our results through established clinical networks and consumer networks, using pamphlet where appropriate. Ethics approval is not required for this overview as we will analysis published network meta-analysis only.Trial registration number:INPLASY202070118.

目的:探究依达拉奉对慢性间歇缺氧导致大鼠肾脏损伤的保护作用及其对Caspase-1介导的细胞焦亡信号通路的影响.方法:24只SPF级雄性SD大鼠随机分为正常对照(NC)组、间歇缺氧(IH)组、间歇缺氧+生理盐水(IH+NS)组、间歇缺氧+依达拉奉(IH+EDA)组,每组6只.将4组大鼠放置在密闭式饲养舱内造模,NC组舱内氧气浓度维持在21％ 左右,IH组、IH+NS组、IH+EDA组定时输入纯氧气、纯氮气、压缩空气,使舱内形成缺氧-复氧循环(60 s低氧期+60 s复氧期),低氧期舱内氧浓度降至6％～7％,每日造模8 h(10:00-18:00),同时IH+EDA组大鼠每天造模前按照5 mg/kg剂量标准予以腹腔注射依达拉奉,IH+NS组大鼠按照同等剂量标准腹腔注射生理盐水.造模8周后采集大鼠血液标本及肾脏组织标本,测定各组大鼠血肌酐(Crea)、尿素(Ure-a)水平;HE、Masson染色后光镜下观察肾脏病理形态变化、纤维化程度;化学法测定丙二醛(MDA)含量、超氧化物歧化酶(SOD)活力;免疫组织化学染色法测定肾组织NLRP3、Caspase-1、IL-1β蛋白表达水平;Western blot法测定肾组织Caspase-1、IL-1β蛋白表达水平;RT-PCR法测定消皮素D(gasdermin D,GSDMD)、IL-18 mRNA扩增水平.结果:间歇缺氧暴露后,大鼠血清Crea、U-rea明显升高(P<0.01),肾小管发生病理损害、肾单位球囊间隙出现胶原纤维沉积,MDA含量增加、SOD活力降低(P<0.01),Caspase-1、NLRP3、IL-1β蛋白表达增加(P<0.01或P<0.05)、GSDMD mRNA、IL-18 mRNA扩增增加(P<0.01);而经过依达拉奉干预后,上述指标呈现出与间歇低氧暴露后相反的变化趋势,肾脏病理损害减轻(P<0.01或P<0.05).结论:慢性间歇缺氧可能通过氧化应激活化Caspase-1参与的细胞焦亡信号通路介导肾脏损伤过程,而依达拉奉可能通过清除氧自由基、下调机体氧化应激水平,抑制焦亡通路的活化,起到保护肾脏的作用.