Gut-derived norepinephrine plays a critical role in producing hepatocellular dysfunction during early sepsis

2000 ◽  
Vol 279 (6) ◽  
pp. G1274-G1281 ◽  
Author(s):  
Shaolong Yang ◽  
Douglas J. Koo ◽  
Mian Zhou ◽  
Irshad H. Chaudry ◽  
Ping Wang
Keyword(s):  
Critical Role ◽  
Cecal Ligation ◽  
Plasma Norepinephrine ◽  
Novel Approach ◽  
Tnf Α ◽  
Liver Preparation ◽  
Icg Clearance ◽  
Early Sepsis ◽  
20 Nm

Although plasma norepinephrine (NE) increases and hepatocellular function is depressed during early sepsis, it is unknown whether gut is a significant source of NE and, if so, whether gut-derived NE helps produce hepatocellular dysfunction. We subjected rats to sepsis by cecal ligation and puncture (CLP), and 2 h later (i.e., early sepsis) portal and systemic blood samples were collected and plasma levels of NE were assayed. Other rats were enterectomized before CLP. Hepatocellular function was assessed with an in vivo indocyanine green (ICG) clearance technique, systemic levels of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were determined, and the effect of NE on hepatic ICG clearance capacity was assessed in an isolated, perfused liver preparation. Portal levels of NE were significantly higher than systemic levels at 2 h after CLP. Prior enterectomy reduced NE levels in septic animals. Thus gut appears to be the major source of NE release during sepsis. Enterectomy before sepsis also attenuated hepatocellular dysfunction and downregulated TNF-α, IL-1β, and IL-6. Perfusion of the isolated livers with 20 nM NE (similar to that observed in sepsis) significantly reduced ICG clearance capacity. These results suggest that gut-derived NE plays a significant role in hepatocellular dysfunction and upregulating inflammatory cytokines. Modulation of NE release and/or hepatic responsiveness to NE should provide a novel approach for maintaining hepatocellular function in sepsis.

Norepinephrine-induced hepatocellular dysfunction in early sepsis is mediated by activation of α2-adrenoceptors

2001 ◽  
Vol 281 (4) ◽  
pp. G1014-G1021 ◽  
Author(s):  
Shaolong Yang ◽  
Mian Zhou ◽  
Irshad H. Chaudry ◽  
Ping Wang
Keyword(s):  
Critical Role ◽  
Cecal Ligation ◽  
Perfused Liver ◽  
Male Adult ◽  
Isolated Perfused Liver ◽  
Adrenergic Antagonist ◽  
Tnf Α ◽  
Liver Preparation ◽  
Icg Clearance ◽  
Early Sepsis

Gut-derived norepinephrine (NE) has been shown to play a critical role in producing hepatocellular dysfunction in early sepsis, but it is not known whether α2-adrenoceptor activation mediates this dysfunction. We infused normal male adult rats with NE, NE plus the specific α2-adrenergic antagonist rauwolscine (RW), or vehicle (normal saline) for 2 h. Hepatocellular function was determined by in vivo indocyanine green (ICG) clearance. An isolated perfused liver preparation was also used to assess hepatocellular function by in vitro ICG clearance; NE alone or with RW was added to the perfusate. Rats were subjected to sepsis by cecal ligation and puncture (CLP). At 1 h after CLP, RW was infused for 15 min. At 5 h after CLP, we measured hepatocellular function and serum tumor necrosis factor-α (TNF-α) levels. Intraportal NE infusion in normal rats produced hepatocellular dysfunction, which was prevented by RW and NE infusion. This is confirmed by findings with the isolated perfused liver preparation. RW administration in early sepsis maintained hepatocellular function and downregulated TNF-α production at 5 h after CLP. These results suggest that NE-induced hepatocellular dysfunction in early sepsis is mediated by α2-adrenoceptor activation, which appears to upregulate TNF-α production. Modulation of hepatic responsiveness to NE by α2-adrenergic antagonists should provide a novel approach for maintaining cell and organ functions during sepsis.

scholarly journals Regulation of dendritic cell function improves survival in experimental sepsis through immune chaperone

2019 ◽  
Vol 25 (4) ◽  
pp. 235-243 ◽  
Author(s):  
Pengfei Li ◽  
Ran Zhao ◽  
Kevin Fan ◽  
Stephen Iwanowycz ◽  
Hongkuan Fan ◽  
...  
Keyword(s):  
Cell Function ◽  
Critical Role ◽  
Cecal Ligation ◽  
Experimental Sepsis ◽  
Adaptive Immune ◽  
Sepsis Model ◽  
Novel Approach ◽  
Tnf Α ◽  
Heat Shock Protein Gp96 ◽  
Dc Maturation

Dendritic cells (DCs) are professional Ag-presenting cells that play a critical role in both innate and adaptive immune responses. DCs recognize and respond to bacteria through multiple PRRs, including TLRs. Heat shock protein gp96/grp94 is a master essential chaperone for TLRs in the endoplasmic reticulum. We generated DC-specific gp96-knockout (KO) mice and showed that gp96 KO DCs were unable to respond to multiple TLR ligands. TLR-mediated hyperinflammatory response can lead to sepsis. However, the roles of neither DCs nor the DC-intrinsic gp96 in the process are completely understood. In a LPS-induced sepsis model, we hereby found that deletion of gp96 in DCs significantly reduced serum TNF-α levels and improved survival. Furthermore, using the well-defined polymicrobial sepsis model of cecal ligation and puncture, we found that DC-specific ablation of gp96 improved survival with significantly attenuated liver and renal injuries, decreased circulating inflammatory cytokines, altered DC maturation and activation, and increased serum Ig. Collectively, we demonstrate that deletion of gp96 in DCs is beneficial in protecting mice against sepsis induced by both endotoxemia and polymicrobial infections. We conclude that targeting gp96 in DCs may provide a potential novel approach for reducing the morbidity and mortality of sepsis.

scholarly journals Halofuginone functions as a therapeutic drug for chronic periodontitis in a mouse model

2020 ◽  
Vol 34 ◽  
pp. 205873842097489
Author(s):  
Jiang Wang ◽  
Bo Wang ◽  
Xin Lv ◽  
Yingjie Wang
Keyword(s):  
Alveolar Bone ◽  
Immune Cell ◽  
Critical Role ◽  
Therapeutic Drug ◽  
Mice Model ◽  
T Helper 17 ◽  
Th17 Cell Differentiation ◽  
Tnf Α

Periodontitis is an inflammatory disease caused by host immune response, resulting in a loss of periodontium and alveolar bone. Immune cells, such as T cells and macrophages, play a critical role in the periodontitis onset. Halofuginone, a natural quinazolinone alkaloid, has been shown to possess anti-fibrosis, anti-cancer, and immunomodulatory properties. However, the effect of halofuginone on periodontitis has never been reported. In this study, a ligature-induced mice model of periodontitis was applied to investigate the potential beneficial effect of halofuginone on periodontitis. We demonstrated that the administration of halofuginone significantly reduced the expression levels of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α) in vivo, and markedly suppressed immune cell infiltration into the infected sites. Furthermore, we also observed that halofuginone treatment blocked the T-helper 17 (Th17) cell differentiation in vivo and in vitro. We demonstrated for the first time that halofuginone alleviated the onset of periodontitis through reducing immune responses.

α2-Adrenoceptor agonist dexmedetomidine protects septic acute kidney injury through increasing BMP-7 and inhibiting HDAC2 and HDAC5

2012 ◽  
Vol 303 (10) ◽  
pp. F1443-F1453 ◽  
Author(s):  
Chung-Hsi Hsing ◽  
Chiou-Feng Lin ◽  
Edmund So ◽  
Ding-Ping Sun ◽  
Tai-Chi Chen ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Histone Deacetylases ◽  
Trichostatin A ◽  
Histone H3 ◽  
Cecal Ligation ◽  
Kidney Injury ◽  
Protective Effects ◽  
Tnf Α

Bone morphogenetic protein (BMP)-7 protects sepsis-induced acute kidney injury (AKI). Dexmedetomidine (DEX), an α2-adrenoceptor (α2-AR) agonist, has anti-inflammatory effects. We investigated the protective effects of DEX on sepsis-induced AKI and the expression of BMP-7 and histone deacetylases (HDACs). In vitro , the effects of DEX or trichostatin A (TSA, an HDAC inhibitor) on TNF-α, monocyte chemotactic protein (MCP-1), BMP-7, and HDAC mRNA expression in LPS-stimulated rat renal tubular epithelial NRK52E cells, was determined using real-time PCR. In vivo, mice were intraperitoneally injected with DEX (25 μg/kg) or saline immediately and 12 h after cecal ligation and puncture (CLP) surgery. Twenty-four hours after CLP, we examined kidney injury and renal TNF-α, MCP-1, BMP-7, and HDAC expression. Survival was monitored for 120 h. LPS increased HDAC2, HDAC5, TNF-α, and MCP-1 expression, but decreased BMP-7 expression in NRK52E cells. DEX treatment decreased the HDAC2, HDAC5, TNF-α, and MCP-1 expression, but increased BMP-7 and acetyl histone H3 expression, whose effects were blocked by yohimbine, an α2-AR antagonist. With DEX treatment, the LPS-induced TNF-α expression and cell death were attenuated in scRNAi-NRK52E but not BMP-7 RNAi-NRK52E cells. In CLP mice, DEX treatment increased survival and attenuated AKI. The expression of HDAC2, HDAC5, TNF-α, and MCP-1 mRNA in the kidneys of CLP mice was increased, but BMP-7 was decreased. However, DEX treatment reduced those changes. DEX reduces sepsis-induced AKI by decreasing TNF-α and MCP-1 and increasing BMP-7, which is associated with decreasing HDAC2 and HDAC5, as well as increasing acetyl histone H3.

scholarly journals BMX Represses Thrombin-PAR1–Mediated Endothelial Permeability and Vascular Leakage During Early Sepsis

2020 ◽  
Vol 126 (4) ◽  
pp. 471-485 ◽  
Author(s):  
Zhao Li ◽  
Mingzhu Yin ◽  
Haifeng Zhang ◽  
Weiming Ni ◽  
Richard W. Pierce ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Cecal Ligation ◽  
Endothelial Permeability ◽  
Vascular Leakage ◽  
Lung Epithelial Cells ◽  
Negative Regulator ◽  
Cecal Ligation And Puncture ◽  
Early Sepsis

Rationale: BMX (bone marrow kinase on the X chromosome) is highly expressed in the arterial endothelium from the embryonic stage to the adult stage in mice. It is also expressed in microvessels and the lymphatics in response to pathological stimuli. However, its role in endothelial permeability and sepsis remains unknown. Objective: We aimed to delineate the function of BMX in thrombin-mediated endothelial permeability and the vascular leakage that occurs with sepsis in cecal ligation and puncture models. Methods and Results: The cecal ligation and puncture model was applied to WT (wild type) and BMX-KO (BMX global knockout) mice to induce sepsis. Meanwhile, the electric cell-substrate impedance sensing assay was used to detect transendothelial electrical resistance in vitro and, the modified Miles assay was used to evaluate vascular leakage in vivo. We showed that BMX loss caused lung injury and inflammation in early cecal ligation and puncture–induced sepsis. Disruption of BMX increased thrombin-mediated permeability in mice and cultured endothelial cells by 2- to 3-fold. The expression of BMX in macrophages, neutrophils, platelets, and lung epithelial cells was undetectable compared with that in endothelial cells, indicating that endothelium dysfunction, rather than leukocyte and platelet dysfunction, was involved in vascular permeability and sepsis. Mechanistically, biochemical and cellular analyses demonstrated that BMX specifically repressed thrombin-PAR1 (protease-activated receptor-1) signaling in endothelial cells by directly phosphorylating PAR1 and promoting its internalization and deactivation. Importantly, pretreatment with the selective PAR1 antagonist SCH79797 rescued BMX loss-mediated endothelial permeability and pulmonary leakage in early cecal ligation and puncture–induced sepsis. Conclusions: Acting as a negative regulator of PAR1, BMX promotes PAR1 internalization and signal inactivation through PAR1 phosphorylation. Moreover, BMX-mediated PAR1 internalization attenuates endothelial permeability to protect vascular leakage during early sepsis.

ARV-330: Androgen receptor PROTAC degrader for prostate cancer.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 267-267 ◽  
Author(s):  
Taavi K Neklesa ◽  
Meizhong Jin ◽  
Andrew P Crew ◽  
AnnMarie K Rossi ◽  
Ryan R Willard ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Therapeutic Effects ◽  
Preclinical Development ◽  
Protein Levels ◽  
Novel Approach ◽  
Subsequent Degradation ◽  
20 Nm

267 Background: The transition from localized prostate cancer to metastatic disease often involves modulation of the Androgen Receptor (AR). During the disease progression, patients progressing on enzalutamide or abiraterone therapy exhibit amplified AR, increased intra-tumoral androgen production or AR mutations leading to promiscuity to other ligands. Therefore, AR is still the principal driver of the disease. Methods: A novel approach to block AR signaling is to specifically target AR for degradation. To this end, we have developed the PROteolysis TArgeting Chimera (PROTAC) technology that employs hetero-bifunctional small molecules that simultaneously bind VHL E3 ubiquitin ligase and a target of interest (e.g. AR). Due to induced proximity between VHL and AR, an AR PROTAC leads to ubiquitination and subsequent degradation of AR. Results: Our lead AR PROTAC, ARV-330, degrades 92-98% of total AR in all cell lines tested, with 50% degradation concentrations (DC50) < 1nM. AR degradation suppresses the AR-target gene PSA expression, inhibits proliferation, and induces potent apoptosis in VCaP cells with maximal apoptosis observed at 20 nM. While enzalutamide loses its activity in the presence of > 0.5 nM R1881, ARV-330 maintains its activity. In cells containing the ARF876L mutation, enzalutamide is an agonist; however, ARV-330 remains effective. In fact, ARV-330 is able to degrade all clinically relevant AR mutations. ARV-330 exhibits good pharmacokinetic properties, with t1/2 values of several hours and bioavailability of > 80% after sc injection. Treatment of mice with ARV-330, at doses ranging from 0.3 to 10 mg/kg, results in reduction of AR protein levels. The in vitro potency translates into in vivo efficacy, as ARV-330 demonstrates prostate involution in intact mice. In castrated mice implanted with VCaP tumors, ARV-330 shows robust reduction of plasma PSA and blockade of tumor growth. Conclusions: In summary, the AR PROTAC ARV-330 removes AR from prostate cancer cells in a potent manner and produces therapeutic effects as a result. This cellular efficacy has translated into biomarker activity and efficacy in animal models, and ARV-330 is now in preclinical development.

ESL-1 Is a Major Physiological Leukocyte Ligand for E-Selectin That Cooperates with PSGL-1 and CD44, and Together Mediate All Binding Activity to Endothelial Selectins In Vivo.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1787-1787
Author(s):  
Andres Hidalgo ◽  
Anna J. Peired ◽  
Paul S. Frenette
Keyword(s):  
Affinity Purification ◽  
Critical Role ◽  
Binding Activity ◽  
Wild Type ◽  
Selectin Ligands ◽  
Tnf Α ◽  
Polarized Cells ◽  
Selectin Ligand ◽  
Soluble E Selectin

Abstract Endothelial selectins mediate leukocyte (WBC) rolling on activated endothelium. ESL-1 was isolated by affinity purification more than 10 years ago but whether it is a physiological ligand for E-selectin remains unclear. Recent studies suggest that PSGL-1 and CD44 are physiological E-selectin ligands on neutrophils (PMNs)(J. Exp. Med. 2005 201:1183). To analyze the contribution of ESL-1, PSGL-1 and CD44, we knocked down ESL-1 expression using lentiviral transfer of short hairpin (sh) RNA into wild-type (WT), PSGL-1- or/and CD44-deficient bone marrow lineage-negative (Lin-) cells. Sorted GFP+ cells from mice transplanted with Lin- cells transduced with the shESL-1 exhibited >90% reduction in total ESL-1 levels by Q-PCR and Western blot analyses, and complete absence of ESL-1 on the PMN surface. shESL-1 transduced Lin- cells engrafted recipients mice with the same efficiency as control vector. Downregulation of ESL-1 slightly affected (~33%) the binding of soluble E-selectin to PMNs, but did not alter WBC rolling numbers in TNF-α-stimulated cremasteric venules. Absence of ESL-1 or CD44, but not PSGL-1, resulted in significant increases in mean rolling velocities (4.7 ± 0.4 μm/s for WT; 8.3 ± 0.4 μm/s for shESL-1*; 7.2 ± 0.2 μm/s for CD44−/−* and 5.4 ± 0.4 μm/s for PSGL-1−/−; *p<0.001). Moreover, WBCs lacking ESL-1 exhibited a characteristic “skipping” rolling motion, suggesting that ESL-1 plays a critical role in stabilizing WBC rolling. Remarkably, ESL-1 downregulation in the absence of PSGL-1 led to dramatic reductions in WBC binding to soluble E-selectin (~99%), and rolling (~93%) on TNF-α-stimulated venules. To determine the contribution of these 3 glycoproteins in WBC recruitment, mice transplanted with WT, PSGL-1- and/or CD44-deficient Lin- cells that were transduced with the shESL-1 or control vectors, were injected i.p. with thioglycollate and the number of peritoneal GFP+ PMNs determined. Only the absence of all 3 glycoproteins compromised PMN recruitment to the levels observed in P- and E-selectin double-deficient mice (82% reduction compared to WT; p<0.001), suggesting that ESL-1, PSGL-1 and CD44 comprise all endothelial selectin ligand activity on PMNs in vivo. To assess the role of E-selectin ligands in WBC activation, we monitored in vivo L-selectin clustering on the surface of over 4,000 rolling WBCs using high-speed multichannel fluorescence videomicroscopy. The majority of wild-type rolling WBCs exhibited polarization of L-selectin 150 to 230 min after TNF-α. L-selectin clustering was greatly reduced in E-selectin−/− mice (58 ± 4% polarized cells in WT vs 23.5 ± 1% in E-selectin−/− mice; p<0.001). To determine which E-selectin ligand(s) mediated L-selectin clustering in vivo, we evaluated L-selectin distribution on rolling WBCs deficient in ESL-1, CD44 or PSGL-1. Absence of CD44, but not ESL-1 or PSGL-1, reduced L-selectin redistribution to levels found in E-selectin−/− mice (20 ± 2% polarized cells), indicating that CD44 is the signalling E-selectin ligand required for L-selectin clustering. In addition, E-selectin-mediated CD44 signalling was p38-dependent, as assessed in WT mice treated with the p38 inhibitor SB203580 (77% reduction; p<0.001). Our results indicate that ESL-1, PSGL-1 and CD44 comprise all selectin ligand binding activity on WBCs, and suggest specialized contributions for each ligand where PSGL-1 mediates the initial tethering, ESL-1 is critical for the conversion into steady slow rolling, and CD44 is required for E-selectin-mediated signals contributing to WBC activation.

scholarly journals Beneficial effect of STAT3 decoy oligodeoxynucleotide transfection on organ injury and mortality in mice with cecal ligation and puncture-induced sepsis

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Samar Imbaby ◽  
Naoyuki Matsuda ◽  
Kengo Tomita ◽  
Kohshi Hattori ◽  
Sailesh Palikhe ◽  
...  
Keyword(s):  
Critical Role ◽  
Cecal Ligation ◽  
High Mobility ◽  
Organ Injury ◽  
Cecal Ligation And Puncture ◽  
Signal Transducers ◽  
Significant Survival ◽  
Upstream Kinase ◽  
Stat3 Decoy

Abstract Sepsis is a major clinical challenge with unacceptably high mortality. The signal transducers and activators of transcription (STAT) family of transcription factors is known to activate critical mediators of cytokine responses, and, among this family, STAT3 is implicated to be a key transcription factor in both immunity and inflammatory pathways. We investigated whether in vivo introduction of synthetic double-stranded STAT3 decoy oligodeoxynucleotides (ODNs) can provide benefits for reducing organ injury and mortality in mice with cecal ligation and puncture (CLP)-induced polymicrobial sepsis. We found that STAT3 was rapidly activated in major end-organ tissues following CLP, which was accompanied by activation of the upstream kinase JAK2. Transfection of STAT3 decoy ODNs downregulated pro-inflammatory cytokine/chemokine overproduction in CLP mice. Moreover, STAT3 decoy ODN transfection significantly reduced the increases in tissue mRNAs and proteins of high mobility group box 1 (HMGB1) and strongly suppressed the excessive elevation in serum HMGB1 levels in CLP mice. Finally, STAT3 decoy ODN administration minimized the development of sepsis-driven major end-organ injury and led to a significant survival advantage in mice after CLP. Our results suggest a critical role of STAT3 in the sepsis pathophysiology and the potential usefulness of STAT3 decoy ODNs for sepsis gene therapy.

scholarly journals Platelet Toll-like receptor expression modulates lipopolysaccharide-induced thrombocytopenia and tumor necrosis factor-α production in vivo

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 637-641 ◽  
Author(s):  
Rukhsana Aslam ◽  
Edwin R. Speck ◽  
Michael Kim ◽  
Andrew R. Crow ◽  
K. W. Annie Bang ◽  
...  
Keyword(s):  
Innate Immunity ◽  
Critical Role ◽  
Receptor Expression ◽  
Tlr4 Expression ◽  
Antiplatelet Antibody ◽  
Tnf Α ◽  
Intracellular Compartments ◽  
Thrombin Activation ◽  
Factor Α

AbstractToll-like receptors (TLRs) play a critical role in stimulating innate immunity by recognizing pathogen-associated molecular patterns (PAMPs) on invading microorganisms. Platelets also play a role in innate immunity, and we studied whether they express TLR. Results show that human and murine platelets variably expressed TLR2, TLR4, and TLR9 by flow cytometry and Western blotting. TLR4 expression was confirmed by demonstrating murine platelet binding to lipopolysaccharide (LPS). Thrombin activation of the platelets significantly enhanced the expression of TLR9, suggesting that at least some TLRs may derive from intracellular compartments. When LPS was administered to LPS-sensitive C3H/HeN and LPS-resistant C3H/HeJ mice, functional TLR4 expression in vivo was shown to be responsible for LPS-induced thrombocytopenia. However, when the C3H/HeN mice were first rendered thrombocytopenic by an antiplatelet antibody and then administered LPS, a significant reduction occurred in their ability to produce TNF-α. The decreased cytokine production in the thrombocytopenic mice was restored with platelet transfusion. These results suggest that platelets express various TLRs and that the functional significance of one of these, TLR4, appears to be a role in the modulation of LPS-induced thrombocytopenia and TNF-α production. This work implicates platelets as important mediators of innate immune responses against invading microorganisms.

scholarly journals Exosomes from adipose-derived mesenchymal stem cells alleviate sepsis-induced lung injury in mice by inhibiting the secretion of IL-27 in macrophages

2022 ◽  
Vol 8 (1) ◽  
Author(s):  
Xiaoyan Wang ◽  
Danyong Liu ◽  
XiHe Zhang ◽  
LiuMing Yang ◽  
Zhengyuan Xia ◽  
...  
Keyword(s):  
Lung Injury ◽  
Pulmonary Edema ◽  
Tissue Injury ◽  
Cecal Ligation ◽  
Wild Type Mouse ◽  
Vascular Leakage ◽  
Inflammatory Disorder ◽  
Tnf Α

AbstractAcute lung injury (ALI) represents a frequent sepsis-induced inflammatory disorder. Mesenchymal stromal cells (MSCs) elicit anti-inflammatory effects in sepsis. This study investigated the mechanism of exosomes from adipose-derived MSCs (ADMSCs) in sepsis-induced ALI. The IL-27r−/− (WSX-1 knockout) or wild-type mouse model of sepsis was established by cecal ligation and puncture (CLP). The model mice and lipopolysaccharide (LPS)-induced macrophages were treated with ADMSC-exosomes. The content of Dil-labeled exosomes in pulmonary macrophages, macrophages CD68+ F4/80+ in whole lung tissues, and IL-27 content in macrophages were detected. The mRNA expression and protein level of IL27 subunits P28 and EBI3 in lung tissue and the levels of IL-6, TNF-α, and IL-1β were measured. The pulmonary edema, tissue injury, and pulmonary vascular leakage were measured. In vitro, macrophages internalized ADMSC-exosomes, and ADMSC-exosomes inhibited IL-27 secretion in LPS-induced macrophages. In vivo, IL-27 knockout attenuated CLP-induced ALI. ADMSC-exosomes suppressed macrophage aggregation in lung tissues and inhibited IL-27 secretion. ADMSC-exosomes decreased the contents of IL-6, TNF-α, and IL-1β, reduced pulmonary edema and pulmonary vascular leakage, and improved the survival rate of mice. Injection of recombinant IL-27 reversed the protective effect of ADMSC-exosomes on sepsis mice. Collectively, ADMSC-exosomes inhibited IL-27 secretion in macrophages and alleviated sepsis-induced ALI in mice.

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