Upregulation of PGC-1α expression by pioglitazone mediates prevention of sepsis-induced acute lung injury

Abstract The imbalance between pro-inflammatory M1 and anti-inflammatory M2 macrophages plays a critical role in the pathogenesis of sepsis-induced acute lung injury (ALI). Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) may modulate macrophage polarization toward the M2 phenotype by altering mitochondrial activity. This study aimed to investigate the role of the PGC-1α agonist pioglitazone (PGZ) in modulating sepsis-induced ALI. A mouse model of sepsis-induced ALI was established using cecal ligation and puncture (CLP). An in vitro model was created by stimulating MH-S cells with lipopolysaccharide (LPS). qRT-PCR was used to measure mRNA levels of M1 markers iNOS and MHC-II and M2 markers Arg1 and CD206 to evaluate macrophage polarization. Western blotting detected expression of peroxisome proliferator-activated receptor gamma (PPARγ) PGC-1α, and mitochondrial biogenesis proteins NRF1, NRF2, and mtTFA. To assess mitochondrial content and function, reactive oxygen species levels were detected by dihydroethidium staining, and mitochondrial DNA copy number was measured by qRT-PCR. In the CLP-induced ALI mouse model, lung tissues exhibited reduced PGC-1α expression. PGZ treatment rescued PGC-1α expression and alleviated lung injury, as evidenced by decreased lung wet-to-dry weight ratio, pro-inflammatory cytokine secretion (tumor necrosis factor-α, interleukin-1β, interleukin-6), and enhanced M2 macrophage polarization. Mechanistic investigations revealed that PGZ activated the PPARγ/PGC-1α/mitochondrial protection pathway to prevent sepsis-induced ALI by inhibiting M1 macrophage polarization. These results may provide new insights and evidence for developing PGZ as a potential ALI therapy.

Edema pulmonar por reexpansión. Reporte de Caso / Pulmonary edema due to re-expansion. Case Report

Introducción. El edema pulmonar por reexpansión es una complicación poco frecuente, secundaria a una rápida reexpansión pulmonar posterior al drenaje por toracentesis o toracostomía cerrada. Al día de hoy, se ha descrito una incidencia menor al 1 % tras toracostomía cerrada, con mayor prevalencia en la segunda y tercera década de la vida. Su mecanismo fisiopatológico exacto es desconocido; se ha planteado un proceso multifactorial de daño intersticial pulmonar asociado con un desequilibrio de las fuerzas hidrostáticas. Caso clínico. Presentamos el caso de un paciente que desarrolló edema pulmonar por reexpansión posterior a toracostomía cerrada. Se hizo una revisión de la literatura sobre esta complicación. Resultados. Aunque la clínica sugiere el diagnóstico, la secuencia de imágenes desempeña un papel fundamental. En la mayoría de los casos suele ser autolimitado, por lo que su manejo es principalmente de soporte; sin embargo, se han reportado tasas de mortalidad que alcanzan hasta el 20 %, por tanto, es importante conocer los factores de riesgo y las medidas preventivas. Conclusión. El edema pulmonar de reexpansión posterior a toracostomía es una complicación rara en los casos con neumotórax, aunque es una complicación que se puede presentar en la práctica diaria, por lo cual debe tenerse en mente para poder hacer el diagnóstico y un manejo adecuado.

Introduction. Re-expansion pulmonary edema is a rare complication secondary to rapid pulmonary re-expansion after drainage by thoracentesis and/or closed thoracostomy. As of today, an incidence of less than 1% has been described after closed thoracostomy, with a higher prevalence in the second and third decades of life. Its exact pathophysiological mechanism is unknown; a multifactorial process of lung interstitial damage associated with an imbalance of hydrostatic forces has been proposed. Clinical case. We present the case of a patient who developed pulmonary edema due to re-expansion after closed thoracostomy, conducting a review of the literature on this complication. Results. Although the clinic suggests the diagnosis, the sequence of images plays a fundamental role. In most cases, it tends to be a self-limited disease, so its management is mainly supportive. However, mortality rates of up to 20% have been recorded. Therefore, it is important to identify patients with major risk factors and initiate preventive measures in these patients. Conclusions. Re-expansion pulmonary edema after thoracostomy is a rare complication in cases with pneumothorax; however, it is a complication that can occur in daily practice. Therefore, it must be kept in mind to be able to make the diagnosis and an adequate management.

Protective Effects of Danmu Extract Syrup on Acute Lung Injury Induced by Lipopolysaccharide in Mice through Endothelial Barrier Repair / 中国结合医学杂志

OBJECTIVE@#To investigate the effects of Danmu Extract Syrup (DMS) on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice and explore the mechanism.@*METHODS@#Seventy-two male Balb/C mice were randomly divided into 6 groups according to a random number table (n=12), including control (normal saline), LPS (5 mg/kg), LPS+DMS 2.5 mL/kg, LPS+DMS 5 mL/kg, LPS+DMS 10 mL/kg, and LPS+Dexamethasone (DXM, 5 mg/kg) groups. After pretreatment with DMS and DXM, the ALI mice model was induced by LPS, and the bronchoalveolar lavage fluid (BALF) were collected to determine protein concentration, cell counts and inflammatory cytokines. The lung tissues of mice were stained with hematoxylin-eosin, and the wet/dry weight ratio (W/D) of lung tissue was calculated. The levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1 β in BALF of mice were detected by enzyme linked immunosorbent assay. The expression levels of Claudin-5, vascular endothelial (VE)-cadherin, vascular endothelial growth factor (VEGF), phospho-protein kinase B (p-Akt) and Akt were detected by Western blot analysis.@*RESULTS@#DMS pre-treatment significantly ameliorated lung histopathological changes. Compared with the LPS group, the W/D ratio and protein contents in BALF were obviously reduced after DMS pretreatment (P<0.05 or P<0.01). The number of cells in BALF and myeloperoxidase (MPO) activity decreased significantly after DMS pretreatment (P<0.05 or P<0.01). DMS pre-treatment decreased the levels of TNF-α, IL-6 and IL-1 β (P<0.01). Meanwhile, DMS activated the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway and reversed the expressions of Claudin-5, VE-cadherin and VEGF (P<0.01).@*CONCLUSIONS@#DMS attenuated LPS-induced ALI in mice through repairing endothelial barrier. It might be a potential therapeutic drug for LPS-induced lung injury.

Protective Effect of Zingiberis Rhizoma Recens on LPS-induced Acute Lung Injury in Mice Through TLR4/NF-κB Signaling Pathway / 中国实验方剂学杂志

ObjectiveTo explore the protective effect and mechanism of Zingiberis Rhizoma Recens alcohol extract on lipopolysaccharide （LPS）-induced acute lung injury in mice. MethodBalb/c mice were randomly divided into normal group， model group， dexamethasone group， and low- and high-dose Zingiberis Rhizoma Recens groups. Mice in the normal group were instilled with normal saline through the nose， and the other groups were instilled with normal saline containing LPS （50 μg）. After 30 minutes of modeling， the dexamethasone group was gavaged with 5 mg·kg-1 of dexamethasone acetate solution， the low- and high-dose Zingiberis Rhizoma Recens groups were gavaged with different doses of （7， 14 g·kg-1） of Zingiberis Rhizoma Recens alcohol extract， and the normal group and the model group were gavaged with the same volume of water. After 24 hours of modeling， the total number of white blood cells in bronchoalceolar lavage fluid （BALF） was detected by cell counter， and the levels of the inflammatory factors including tumor necrosis factor （TNF）-α， interleukin （IL）-1β， IL-6， and superoxide dismutase （SOD）， and myeloperoxidase （MPO） was detected by enzyme-linked immunosorbent assay （ELISA）. Haematoxylin-eosin （HE） staining method was used to observe the pathological changes of lung tissue in each group， and the Western blot was used to detect the protein expression of nuclear transcription factor （NF）-κB p65， phosphorylation （p）-NF-κB p65， and Toll-like receptor 4 （TLR4） in lung tissue. ResultCompared with the normal group， the white blood cell count in BALF and the levels of TNF-α， IL-1β， IL-6， and MPO in the model group was increased （P<0.01）， and the level of SOD was decreased （P<0.05）. Pathological damage of lung tissue was obvious， and the protein expression of NF-κB p65， p-NF-κB p65， and TLR4 in lung tissue was increased （P<0.01）. Compared with the model group， the white blood cell count in BALF and the levels of TNF-α， IL-1β， IL-6， and MPO in the treatment group was decreased （P<0.05，P<0.01）， and the level of SOD was increased （P<0.05，P<0.01）. Pathological damage of lung tissue was alleviated， and the protein expression of NF-κB p65， p-NF-κB p65， and TLR4 in lung tissue was decreased （P<0.01）. ConclusionZingiberis Rhizoma Recens alcohol extract may play a protective role in LPS-induced acute lung injury in mice by inhibiting the TLR4/NF-κB signaling pathway.

Xuebijing improves inflammation and pyroptosis of acute lung injury by up-regulating miR-181d-5p-mediated SPP1 inactivation

Abstract Background Xuebijing (XBJ) is widely applied in the treatment of Acute Lung Injury (ALI). This study focused on the potential mechanism of XBJ in Lipopolysaccharide (LPS)-induced ALI. Methods The rat ALI model was established by injection of LPS (10 mg/kg) and pretreated with XBJ (4 mL/kg) three days before LPS injection. BEAS-2B cell line was stimulated with LPS (1 μg/mL) and ATP (5 mM) to induce pyroptosis, and XBJ (2 g/L) was pretreated 24h before induction. The improvement effects of XBJ on pulmonary edema, morphological changes, and apoptosis in ALI lung tissue were evaluated by lung wet/dry weight ratio, HE-staining, and TUNEL staining. Inflammatory cytokines in lung tissue and cell supernatant were determined by ELISA. pyroptosis was detected by flow cytometry. Meanwhile, the expressions of miR-181d-5p, SPP1, p-p65, NLRP3, ASC, caspase-1, p20, and GSDMD-N in tissues and cells were assessed by RT-qPCR and immunoblotting. The relationship between miR-181d-5p and SPP1 in experimental inflammation was reported by dual luciferase assay. Results XBJ could improve inflammation and pyroptosis of ALI by inhibiting contents of inflammatory cytokines, and levels of inflammation- and pyroptosis-related proteins. Mechanistically, XBJ could up-regulate miR-181d-5p and inhibit SPP1 in ALI. miR-181d-5p can target the regulation of SPP1. Depressing miR-181d-5p compensated for the ameliorative effect of XBJ on ALI, and overexpressing SPP1 suppressed the attenuating effect of XBJ on LPS-induced inflammation and pyroptosis. Conclusion XBJ can regulate the miR-181d-5p/SPP1 axis to improve inflammatory response and pyroptosis in ALI.

Lesión pulmonar aguda producida por transfusión (TRALI): Reporte de caso

Introducción: La lesión pulmonar aguda (TRALI) y la sobrecarga circulatoria (TACO) son las principales causas de morbilidad y mortalidad relacionadas con la transfusión. La TRALI se presenta durante o después de las transfusiones de plasma y sus derivados, o por inmunoglobulinas en alta concentración intravenosa; se asocia a procesos sépticos, cirugías y transfusiones masivas. La TACO es la exacerbación de manifestaciones respiratorias en las primeras 6 horas postransfusión. Reporte caso: Paciente de sexo masculino de 38 días de vida, ingresó al servicio de urgencias con un cuadro clínico de 8 días de evolución, caracterizado por dificultad respiratoria dado por retracciones subcostales y aleteo nasal sin otro síntoma asociado, con antecedentes de importancia de prematuridad y bajo peso al nacer. El reporte de hemograma arrojó cifras compatibles con anemia severa, por lo que requirió transfusión de glóbulos rojos empaquetados desleucocitados. El paciente presentó un cuadro respiratorio alterado en un periodo menor a 6 horas, por lo que se descartaron causas infecciosas y finalmente se consideró cuadro compatible con TRALI. Conclusiones: Se debe considerar una lesión pulmonar aguda relacionada con una transfusión de sangre si se produce una insuficiencia respiratoria aguda durante o inmediatamente después de la infusión de hemoderivados que contienen plasma.

Introduction: Acute lung injury (TRALI) and circulatory overload (TACO) are the main causes of transfusion-related morbidity and mortality. TRALI occurs during or after transfusions of plasma or its derivatives, or by immunoglobulins in high intravenous concentration; it is associated with septic processes, surgeries, and massive transfusions. TACO is the exacerbation of respiratory manifestations in the first 6 hours post transfusion. Case report: A 38-day-old male was admitted to the emergency department with clinical symptoms experienced over the course of 8 days and characterized by respiratory distress due to subcostal retractions and nasal flaring with no other associated symptoms. Important antecedents included prematurity and low birth weight. The hemogram report showed figures compatible with anemia, which benefited from transfusion of packed red blood cells without leukocytes. In a period of less than 6 hours, the patient presented altered respiratory symptoms, practitioners ruled out infectious causes and finally considered clinical signs compatible with TRALI. Conclusion: Acute lung injury related to blood transfusion should be considered if acute respiratory failure occurs during or immediately after infusion of plasma-containing blood products.

Ischemic Postconditioning Attenuates Myocardial Ischemia-Reperfusion-Induced Acute Lung Injury by Regulating Endoplasmic Reticulum Stress-Mediated Apoptosis

ABSTRACT Objective: To explore the effect of ischemic postconditioning on myocardial ischemia-reperfusion-induced acute lung injury (ALI). Methods: Forty adult male C57BL/6 mice were randomly divided into sham operation group (SO group), myocardial ischemia-reperfusion group (IR group), ischemic preconditioning group (IPRE group) and ischemic postconditioning group (IPOST group) (10 mice in each group). Anterior descending coronary artery was blocked for 60 min and then reperfused for 15 min to induce myocardial IR. For the IPRE group, 3 consecutive cycles of 5 min of occlusion and 5 minutes of reperfusion of the coronary arteries were performed before ischemia. For the IPOST group, 3 consecutive cycles of 5 min reperfusion and 5 minutes of occlusion of the coronary arteries were performed before reperfusion. Pathological changes of lung tissue, lung wet-to-dry (W/D) weight ratio, inflammatory factors, oxidative stress indicators, apoptosis of lung cells and endoplasmic reticulum stress (ERS) protein were used to evaluate lung injury. Results: After myocardial IR, lung injury worsened significantly, manifested by alveolar congestion, hemorrhage, structural destruction of alveolar septal thickening, and interstitial neutrophil infiltration. In addition, lung W/D ratio was increased, plasma inflammatory factors, including interleukin (IL)-6, tumor necrosis factor (TNF)-α, and IL-17A, were increased, malondialdehyde (MDA) activity of lung tissue was increased, and superoxide dismutase (SOD) activity was decreased after myocardial IR. It was accompanied by the increased protein expression levels of ERS-related protein glucose regulatory protein 78 (GRP78), CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP), and caspase-12, and the increased apoptotic indices of lung tissues. Conclusion: IPOST can effectively improve myocardial IR-induced ALI by inhibiting ERS-induced apoptosis of alveolar epithelial cells.

Mechanism of NLRP3 Inflammasome Mediated Pyroptosis in Acute Pancreatitis - related Lung Injury / 胃肠病学

Background: Pyroptosis is involved in the occurrence of acute pancreatitis, but its role in remote organ injury remains unclear. Aims: To investigate the role and mechanism of NLRP3 inflammasome-dependent pyroptosis in acute pancreatitis- related lung injury. Methods: Thirty-two male Sprague-Dawley rats were randomly divided into four groups: control group, severe acute pancreatitis (SAP) group, Z-WEHD-FMK (caspase-1 inhibitor) group and disulfiram (GSDMD inhibitor) group. Experimental SAP was constructed by using 5% sodium taurocholate in the latter 3 groups. Serum levels of amylase, lipase, procalcitonin, and the myeloperoxidase (MPO) activity were determined; the severity of pancreatic and lung injuries was assessed by histopathology and lung wet/dry weight ratio; serum levels of pyroptosis-related inflammatory cytokines and the expressions of proteins involved in pyroptosis pathway in lung tissue were measured by ELISA method and immunohisto- chemistry and Western blotting, respectively. Results: Compared with the control group, the serum biochemical indices, MPO activity, and interleukin (IL)-1β, IL-18 levels in SAP group were significantly increased with aggravated pancreatic and lung tissue injuries; meanwhile, the expressions of NLRP3, caspase-1 and GSDMD in lung tissue were significantly up- regulated (all P<0.05). Pretreatment with caspase-1 or GSDMD inhibitors reduced the severity of pancreatic and lung tissue injuries, improved the serum biochemical indices and MPO activity, and ameliorated the increased pyroptosis - related inflammatory cytokines and pyroptosis pathway - related proteins (all P<0.05). Conclusions: NLRP3/caspase - 1/GSDMD pathway mediated pyroptosis plays an important role in acute pancreatitis-related lung injury, and inhibition of pyroptosis pathways might be a new direction for its treatment.

Silencing ZKSCAN3 gene expression aggravates lung injury induced by LPS in mice / 中国临床药理学与治疗学

AIM: To explore the role of ZKSCAN3 in acute lung injury (ALI) induced by lipopolysaccharide (LPS). METHODS: After verifying the efficacy of ZKSCAN3 siRNA, male C57BL/6 mice were randomly divided into 4 groups (n = 8): control group(group A), LPS group (group B), scrambled siRNA group (group C) and ZKSCAN3 siRNA group (group D). Mice in groups A and B were given 1 mL of PBS via tail vein; mice in groups C were given corresponding doses of PBS containing scrambled siRNA; and mice in group D were given corresponding doses of RNase-free PBS containing ZKSCAN3 siRNA (50 μg). After 24 hours, mice in groups B, C, and D were instilled with LPS solution (5 mg/kg) through tracheal intubation to create an ALI model; group A was given the corresponding dose of PBS (20 ΜL). The samples were collected and tested 24 hours after the modeling administration. RESULTS: Compared with group B, silencing ZKSCAN3 gene expression reduced SOD activity and Bcl-2 level; while MDA, Bax and caspase-3 increased; correspondingly, the content of protein and cells in BAL, the apoptosis rate of lung tissue and the pathological score significantly increased (P < 0.05).CONCLUSION: Silencing ZKSCAN3 gene expression aggravates the lung injury caused by LPS, which may aggravate the pathological damage of lung tissue in mice by weakening the antioxidant function and aggravating tissue necrosis.

Research status of dialectical prevention and treatment of acute lung injury based on the theory of "Wei qi and Ying Xue" / 中国临床药理学与治疗学

Acute lung injury (ALI) is a common clinical critical respiratory disease. At present, the mechanism of the disease has not been fully elucidated, there is a lack of specific drugs in clinical practice and the mortality rate is high, which is a difficult problem in the medical field. In recent years, traditional Chinese medicine has exerted its unique advantages and efficacy in the prevention and treatment of ALI, which has aroused the attention of domestic and foreign scholars. Based on the theory of "Wei Qi Ying Xue", this paper discusses the current research status of prevention and treatment of ALI by traditional Chinese medicine, and analyzes its pathogenesis, clinical manifestations and corresponding analysis with TCM syndrome. According to the angle of "Wei Qi Ying Xue", the progress of syndrome differentiation and treatment is highly consistent with immune response, inflammatory response, oxidative stress and apoptosis, in order to find new ideas and medication for the prevention and treatment of ALI with integrated traditional Chinese and Western medicine.

Role of FoxO1/p38MAPK signaling pathway in acute lung injury induced by LPS / 中国药理学通报

Aim To investigate the effect of forkhead transcription factors of O classl (FoxO1) on lipopolysaccharide (LPS) -induced acute lung injury and its regulatory mechanism. Methods The model of acute lung injury (ALI) was simulated by LPS. HE staining was used to observe the pathological changes of lung tissues. The contents of tumor necrosis factor a (TNF-a) and interleukin-6 (IL-6) in lung tissues were determined by ELISA. The expression of FoxOl in mouse lung tissues was observed by immunohistochemical staining. The phosphorylation levels of FoxOl, DNA methyltransferase and p38 MAPK were detected by Western blot. The mRNA levels of FoxOl, IL-6, TNF-a and DNA methyltransferase were detected by qRT-PCR. DNA methylation in FoxOl promoter region in lung tissues was detected by nested methylation specific PCR (nMS-PCR). Pulmonary vascular endothelial cells (PVECs) were cultured and transfected with FoxOl siRNA, and the phosphorylation of p38 MAPK was detected by Western blot. The correlation between FoxOl methylation level and inflammatory factors was analyzed by Pearson method. Results Compared with control group, alveolar inflammatory cells increased significantly in LPS group, and pulmonary edema and hyperemia were obvious. TNF-α and IL-6 levels increased by 52. 2% and 150. 4% (P < 0. 05), respectively. The phosphorylation level of p38 MAPK and FoxOl expression increased by 134. 1% and 61. 8% (P < 0. 05), respectively, while the DNA methylation level of Fox0l promoter region decreased by 17. 2% (P < 0. 05). After transfection of FoxOl siRNA in vitro, the phosphorylation level of p38 decreased. Pearson analysis showed that FoxOl methylation level was negatively correlated with inflammatory factors. Conclusion The regulation of FoxOl/p3 8 MAPK signaling pathway by hypomethylation of FoxOl promoter is an important mechanism of LPS-induced acute lung injury.

Effect of phillygenin on inflammatory response of A549 cells induced by lipopolysaccharide and normal human plasma / 中国药理学通报

Aim To investigate the effect of phillygenin ( PHI) on lipopolysacchride ( LPS) and normal human plasma ( NHP) induced inflammatory injury on alveolar type II epithelial A549 cells and the related mechanism. Methods A549 cells were exposured to 1 mg • L

Research progress of HDACs and associated inhibitors on regulation of acute lung injury / 中国药理学通报

Acute lung injury ( ALI) and its most extreme form a-cute respiratory distress syndrome ( ARDS) are lung diseases with high morbidity and mortality. There is no effective therapeutic intervention until now for its complicated pathophysiologi-cal processes and sophisticated regulatory mechanism. Histone deacetylases (HDACs) are a family of proteins with deacetylase activity. Studies have shown that HDACs are involved in the pathophysiological processes of ALI/ARDS, including inflammatory responses,endothelial permeability,oxidative stresses,alveolar fluid clearance and lung tissue repairment. Simultaneously, the use of HDACs inhibitors (HDACIs) can interfere with ALI/ ARDS progression. In this review we describe and summarize the pathophysiological processes and the underlying mechanisms in ALI/ARDS regulated by HDACs and HDACIs in detail, in order to provide the basis for the clinical application of HDACs-targe- ted agents and indicate directions for future study.

ACT001 exerts anti-inflammatory and antioxidative activity to alleviate sepsis-induced acute lung injury through STAT1/CIITA/MHC- II pathway / 中国药理学通报

Aim This study aimed to assess the therapeutic potential of ACT001, a micheliolide derivative, in the treatment of acute lung injury ( ALI) induced by sepsis and investigate its pharmacological mechanisms. Methods At the animal level, an ALI model was established in mice through intraperitoneal injection of li-popolysaccharide (LPS). Subsequently, ACT001 was administered to the ALI-afflicted mice. The therapeutic effects of ACT001 were assessed by evaluating factors such as individual survival rate, lung inflammation, and pulmonary edema. At the cellular level, RAW264. 7 cells were stimulated with LPS to explore the pharmacological mechanism of ACT001. The study examined inflammatory response and oxidative stress levels, and proteomics analysis was conducted to investigate the underlying molecular mechanisms. Results At the animal level, ACT001 can improve the survival of mice with ALI, reduce lung inflammation, and reduce the levels of inflammatory cytokines in serum. At the cellular level, ACT001 promotes the polarization of RAW264. 7 cells toward an anti-inflammatory pheno-type by inhibiting MHC-II related pathways, inhibiting the production of NO and related inflammatory cytokines while increasing SOD content and scavenging ROS. Conclusions ACT001 exhibited the potential to alleviate ALI via its anti-inflammatory and antioxidative activity, mainly by inhibiting the STAT1/ CIITA/ MHC-II pathway. ACT001 holds promise as a novel therapeutic candidate for the treatment of ALI induced by sepsis.

Pulmonary endothelium-targeted nanoassembly of indomethacin and superoxide dismutase relieves lung inflammation

Lung inflammation is an essential inducer of various diseases and is closely related to pulmonary-endothelium dysfunction. Herein, we propose a pulmonary endothelium-targeted codelivery system of anti-inflammatory indomethacin (IND) and antioxidant superoxide dismutase (SOD) by assembling the biopharmaceutical SOD onto the "vector" of rod-like pure IND crystals, followed by coating with anti-ICAM-1 antibody (Ab) for targeting endothelial cells. The codelivery system has a 237 nm diameter in length and extremely high drug loading of 39% IND and 2.3% SOD. Pharmacokinetics and biodistribution studies demonstrate the extended blood circulation and the strong pulmonary accumulation of the system after intravenous injection in the lipopolysaccharide (LPS)-induced inflammatory murine model. Particularly, the system allows a robust capacity to target pulmonary endothelium mostly due to the rod-shape and Ab coating effect. In vitro, the preparation shows the synergistic anti-inflammatory and antioxidant effects in LPS-activated endothelial cells. In vivo, the preparation exhibits superior pharmacodynamic efficacy revealed by significantly downregulating the inflammatory/oxidative stress markers, such as TNF-α, IL-6, COX-2, and reactive oxygen species (ROS), in the lungs. In conclusion, the codelivery system based on rod-like pure crystals could well target the pulmonary endothelium and effectively alleviate lung inflammation. The study offers a promising approach to combat pulmonary endothelium-associated diseases.

Xuebijing alleviates LPS-induced acute lung injury by downregulating pro-inflammatory cytokine production and inhibiting gasdermin-E-mediated pyroptosis of alveolar epithelial cells / 中国天然药物

Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is characterized by diffuse alveolar injury primarily caused by an excessive inflammatory response. Regrettably, the lack of effective pharmacotherapy currently available contributes to the high mortality rate in patients with this condition. Xuebijing (XBJ), a traditional Chinese medicine recognized for its potent anti-inflammatory properties, exhibits promise as a potential therapeutic agent for ALI/ARDS. This study aimed to explore the preventive effects of XBJ on ALI and its underlying mechanism. To this end, we established an LPS-induced ALI model and treated ALI mice with XBJ. Our results demonstrated that pre-treatment with XBJ significantly alleviated lung inflammation and increased the survival rate of ALI mice by 37.5%. Moreover, XBJ substantially suppressed the production of TNF-α, IL-6, and IL-1β in the lung tissue. Subsequently, we performed a network pharmacology analysis and identified identified 109 potential target genes of XBJ that were mainly involved in multiple signaling pathways related to programmed cell death and anti-inflammatory responses. Furthermore, we found that XBJ exerted its inhibitory effect on gasdermin-E-mediated pyroptosis of lung cells by suppressing TNF-α production. Therefore, this study not only establishes the preventive efficacy of XBJ in ALI but also reveals its role in protecting alveolar epithelial cells against gasdermin-E-mediated pyroptosis by reducing TNF-α release.

Comparison on anti-inflammatory activity of Gynostemma pentaphyllum processed with different methods / 中国中药杂志

The aim of this study is to investigate the effects of Gynostemma pentaphyllum dried with two different methods(air drying and heating) on inflammation in acute lung injury(ALI) mice in vivo and in vitro. Lipopolysaccharide(LPS) was sprayed into the airway of wild type C57BL/6J male mice to establish the model, and the drug was injected into the tail vein 24 h after modeling. Lung function, lung tissue wet/dry weight(W/D) ratio, the total protein concentration, interleukin 6(IL-6), IL-1β, and tumor necrosis factor-α(TNF-α) in the bronchoalveolar lavage fluid(BALF), and pathological changes of the lung tissue were used to evaluate the effects of different gypenosides on ALI mice. The results showed that total gypenosides(YGGPs) and the gypenosides substituted with one or two glycosyl(GPs_(1-2)) in the air-dried sample improved the lung function, significantly lowered the levels of IL-1β and TNF-α in BALF, and alleviated the lung inflammation of ALI mice. Moreover, GPs_(1-2) had a more significant effect on inhibiting NO release in RAW264.7 cells. This study showed that different drying methods affected the anti-inflammatory activity of G. pentaphyllum, and the rare saponins in the air-dried sample without heating had better anti-inflammatory activity.

Mechanism of Qilongtian Capsules in treatment of acute lung injury based on network pharmacology prediction and experimental validation / 中国中药杂志

This study aimed to explore the mechanism of Qilongtian Capsules in treating acute lung injury(ALI) based on network pharmacology prediction and in vitro experimental validation. Firstly, UPLC-Q-TOF-MS/MS was used to analyze the main chemical components of Qilongtian Capsules, and related databases were used to obtain its action targets and ALI disease targets. STRING database was used to build a protein-protein interaction(PPI) network. Metascape database was used to conduct enrichment analysis of Gene Ontology(GO) and Kyoto Encyclopedia of Genes and Genomes(KEGG). AutoDock software was used to perform molecular docking verification on the main active components and key targets. Then, the RAW264.7 cells were stimulated with lipopolysaccharide(LPS) for in vitro experiments. Cell viability was measured by MTT and ROS level was measured by DCFH-DA. NO content was measured by Griess assay, and IL-1β, IL-6, and TNF-α mRNA expression was detected by RT-PCR. The predicted targets were preliminarily verified by investigating the effect of Qilongtian Capsules on downstream cytokines. Eighty-four compounds were identified by UPLC-Q-TOF-MS/MS. Through database retrieval, 44 active components with 589 target genes were screened out. There were 560 ALI disease targets, and 65 intersection targets. PPI network topology analysis revealed 10 core targets related to ALI, including STAT3, JUN, VEGFA, CASP3, and MMP9. KEGG enrichment analysis showed that Qilongtian Capsules mainly exerted an anti-ALI effect by regulating cancer pathway, AGE-RAGE, MAPK, and JAK-STAT signaling pathways. The results of molecular docking showed that the main active components in Qilongtian Capsules, including crenulatin, ginsenoside F_1, ginsenoside Rb_1, ginsenoside Rd, ginsenoside Rg_1, ginsenoside Rg_3, notoginsenoside Fe, notoginsenoside G, notoginsenoside R_1, notoginsenoside R_2, and notoginsenoside R_3, had good binding affinities with the corresponding protein targets STAT3, JUN, VEGFA, CASP3, and MMP9. Cellular experiments showed that Qilongtian Capsules at 0.1, 0.25, and 0.5 mg·mL~(-1) reduced the release of NO, while Qilongtian Capsules at 0.25 and 0.5 mg·mL~(-1) reduced ROS production, down-regulated mRNA expression of IL-1β, IL-6, TNF-α, and inhibited the inflammatory cascade. In summary, Qilongtian Capsules may exert therapeutic effects on ALI through multiple components and targets.

Study on Mechanism of Linggan Wuwei Jiangxintang in Treating Acute Lung Injury / 中国实验方剂学杂志

ObjectiveTo explore the action mechanism of Linggan Wuwei Jiangxintang on the treatment of lipopolysaccharide （LPS）-induced acute lung injury （ALI） in mice. MethodTraditional Chinese Medicine Systems Pharmacology Database and Analysis Platform （TCMSP）， GeneCards， DisGeNET， and Herb databases were combined with clinical data from Gene Expression Omnibus （GEO） to screen the key targets of Linggan Wuwei Jiangxintang in the treatment of ALI. The protein-protein interaction （PPI） network was constructed to screen the core targets， and gene ontology （GO） and Kyoto encyclopedia of genes and genomes （KEGG） pathway enrichment analyses were performed. The mouse ALI model was established by LPS induction to verify the effect and key targets of Linggan Wuwei Jiangxintang on the treatment of ALI. The expression levels of Toll-like receptor 4 （TLR4）， nuclear transcription factor-κB p65 （NF-κB p65）， and phosphorylated NF-κB p65 （NF-κB p-p65） in lung tissue were detected by Western blot. ResultThe analysis showed that the treatment of ALI with Linggan Wuwei Jiangxintang was related to 10 core targets such as interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， and JUN， involving TNF signaling pathway， Toll-like receptor signaling pathway， NF-κB signaling pathway， etc. The animal experimental results show that Linggan Wuwei Jiangxintang can reduce lung injury， improve the pathological state of ALI mice， significantly reduce the expression of TNF-α and IL-6 in serum， increase the activity of total superoxide dismutase （T-SOD） and catalase （CAT） in lung tissue， and reduce the expression levels of JUN， TLR4， NF-κB p65， and NF-κB p-p65 proteins in lung tissue. ConclusionLinggan Wuwei Jiangxintang can inhibit LPS-induced inflammation and oxidative damage in ALI mice， and its mechanism may be related to the inhibition of TLR4/NF-κB signaling pathway and the reduction of inflammatory factors such as TNF-α and IL-6.

Evaluation of Animal Models of Acute Lung Injury Caused by Non-physical Factors Based on Data Mining / 中国实验方剂学杂志

ObjectiveTo study the characteristics of animal models of acute lung injury caused by non-physical factors， so as to provide a reference for the standardization of the preparation of such animal models and lay a foundation for the research on the pathogenesis and the diagnosis and treatment of acute lung injury. MethodThe articles about the animal experiments of acute lung injury published in the last decade were retrieved from China National Knowledge Infrastructure （CNKI）， Wanfang， SinoMed， VIP， and PubMed with the theme terms of "acute lung injury" and "animal model". The animal species， drugs used in modeling， modeling period， methods used in molding， model standards， and model evaluation indicators were summarized， and Excel was used for the frequency analysis. ResultA total of 338 articles were included in this study. The results of the frequency analysis showed that SD rats/C57BL/6 mice were mainly used to establish the animal models of acute lung injury. Male mice were mostly used for modeling， and the commonly used modeling agent was lipopolysaccharides （LPS）. In most cases， the modeling lasted for 6 h after drug administration. Hematoxylin-eosin staining was mainly used for the observation of histological changes in the lungs， which were taken as the criteria for modeling. The established models were mainly evaluated based on lung dry/wet weight ratio， lung index， morphological changes in the lung tissue， myeloperoxidase （MPO）， superoxide dismutase （SOD）， and levels of inflammatory cytokines in the serum and bronchoalveolar lavage fluid （BALF）. ConclusionThe models of acute lung injury were mostly prepared by intraperitoneal injection of LPS （5 mg·kg-1） in SD rats and tracheal instillation of LPS （5 mg·kg-1） in C57BL/6 mice， which were praised for the simple operation， high success rate， and consistent with the pathogenesis of acute lung injury. This study provides a reference for the basic research on acute lung injury by animal experiments.