Isoflurane attenuates sepsis-associated lung injury.
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SUBMITTER: Koutsogiannaki S
PROVIDER: S-EPMC8892593 | biostudies-literature | 2022 Apr
REPOSITORIES: biostudies-literature
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Isoflurane attenuates sepsis-associated lung injury.
Koutsogiannaki Sophia S Okuno Toshiaki T Kobayashi Yuichi Y Ogawa Narihito N Yuki Koichi K
Biochemical and biophysical research communications 20220213
Acute lung injury is one of major complications associated with sepsis, responsible for morbidity and mortality. Patients who suffer from acute lung injury often require respiratory support under sedations, and it would be important to know the role of sedatives in lung injury. We examined volatile anesthetic isoflurane, which is commonly used in surgical setting, but also used as an alternative sedative in intensive care settings in European countries and Canada. We found that isoflurane exposu ...[more]
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Project description:BackgroundNeonatal sepsis represents a unique therapeutic challenge owing to an immature immune system. Necroptosis is a form of programmed cell death that has been identified as an important mechanism of inflammation-induced cell death. Receptor-interacting protein kinase 1 plays a key role in mediating this process. We hypothesized that pharmacologic blockade of receptor-interacting protein kinase 1 activity would be protective in neonatal sepsis.MethodsSepsis was induced in C57BL/6 mouse pups (5-7 days old) by intraperitoneal injection of adult cecal slurry. At 1 hour after cecal slurry injection, the receptor-interacting protein kinase 1 inhibitor necrostatin-1 (10 µg/g body weight) or vehicle (5% dimethyl sulfoxide in phosphate buffered saline) was administered via retro-orbital injection. At 20 hours after cecal slurry injection, blood and lung tissues were collected for various analyses.ResultsAt 20 hours after sepsis induction, vehicle-treated pups showed a marked increase in serum levels of interleukin 6, interleukin 1-beta, and interleukin 18 compared to sham. With necrostatin-1 treatment, serum levels of interleukin 6, interleukin 1-beta, and interleukin 18 were decreased by 77%, 81%, and 63%, respectively, compared to vehicle. In the lungs, sepsis induction resulted in a 232-, 10-, and 2.8-fold increase in interleukin 6, interleukin 1-beta, and interleukin 18 mRNA levels compared to sham, while necrostatin-1 treatment decreased these levels to 40-, 4-, and 0.8-fold, respectively. Expressions of the neutrophil chemokines keratinocyte chemoattractant and macrophage-inflammatory-protein-2 were also increased in the lungs in sepsis, while necrostatin-1 treatment decreased these levels by 81% and 61%, respectively, compared to vehicle. In addition, necrostatin-1 treatment significantly improved the lung histologic injury score and decreased lung apoptosis in septic pups. Finally, treatment with necrostatin-1 increased the 7-day survival rate from 0% in the vehicle-treated septic pups to 29% (P = .11).ConclusionInhibition of receptor-interacting protein kinase 1 by necrostatin-1 decreases systemic and pulmonary inflammation, decreases lung injury, and increases survival in neonatal mice with sepsis. Targeting the necroptosis pathway might represent a new therapeutic strategy for neonatal sepsis.
| S-EPMC6204110 | biostudies-literature
Project description:IntroductionSepsis refers to severe systemic inflammation leading to acute lung injury (ALI) and death. Introducing novel therapies can reduce the mortality in ALI. Osteopontin (OPN), a secretory glycoprotein produced by immune reactive cells, plays a deleterious role in various inflammatory diseases. However, its role in ALI caused by sepsis remains unexplored. We hypothesize that treatment with an OPN-neutralizing antibody (anti-OPN Ab) protects mice against ALI during sepsis.MethodsSepsis was induced in 8-week-old male C57BL/6 mice by cecal ligation and puncture (CLP). Anti-OPN Ab or non-immunized IgG as control, at a dose of 50 μg/mouse, was intravenously injected at the time of CLP. After 20 hours, the expression of OPN and proinflammatory cytokines in tissues and plasma was examined by real-time PCR, Western blot, and ELISA. Plasma levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) and the lung myeloperoxidase (MPO) levels were determined by colorimetric assays. Lung damage and neutrophil infiltrations were determined by histological H&E and Gr-1 staining, respectively. The effect of recombinant mouse OPN (rmOPN) on human neutrophil-like cell (HL-60) migration was performed by Boyden chamber assays and the involvement of intracellular signaling molecules in HL-60 cells was revealed by Western blot.ResultsAfter 20 hours of sepsis, mRNA and protein levels of OPN were significantly induced in lungs, spleen, and plasma. Treatment with an anti-OPN Ab in septic mice significantly reduced the plasma levels of ALT, AST, and LDH, and the proinflammatory cytokines IL-6, IL-1β and the chemokine MIP-2, compared with the vehicle group. Similarly, the lung mRNA and protein expressions of proinflammatory cytokines and chemokine were greatly reduced in anti-OPN Ab-treated animals. The lung histological architecture, MPO and neutrophil infiltration were significantly improved in anti-OPN Ab-treated mice compared with the vehicle animals. Treatment of rmOPN in HL-60 cells significantly increased their migration, in vitro. The neutrophils treated with rmOPN remarkably increased the levels of phospho focal adhesion kinase (pFAK), phospho extracellular signal-regulated kinase (pERK) and phospho p38.ConclusionsOur findings clearly demonstrate the beneficial outcomes of anti-OPN Ab treatment in protecting against ALI, implicating a novel therapeutic strategy in sepsis.
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Project description:Background and Objective: Lung-protective mechanical ventilation is known to attenuate ventilator-associated lung injury (VALI), but often at the expense of hypoventilation and hypercapnia. It remains unclear whether the main mechanism by which VALI is attenuated is a product of limiting mechanical forces to the lung during ventilation, or a direct biological effect of hypercapnia. Methods: Acute lung injury (ALI) was induced in 60 anesthetized rats by the instillation of 1.25 M HCl into the lungs via tracheostomy. Ten rats each were randomly assigned to one of six experimental groups and ventilated for 4 h with: 1) Conventional HighV E Normocapnia (high VT, high minute ventilation, normocapnia), 2) Conventional Normocapnia (high VT, normocapnia), 3) Protective Normocapnia (VT 8 ml/kg, high RR), 4) Conventional iCO 2 Hypercapnia (high VT, low RR, inhaled CO2), 5) Protective iCO 2 Hypercapnia (VT 8 ml/kg, high RR, added CO2), 6) Protective endogenous Hypercapnia (VT 8 ml/kg, low RR). Blood gasses, broncho-alveolar lavage fluid (BALF), and tissue specimens were collected and analyzed for histologic and biologic lung injury assessment. Results: Mild ALI was achieved in all groups characterized by a decreased mean PaO2/FiO2 ratio from 428 to 242 mmHg (p < 0.05), and an increased mean elastance from 2.46 to 4.32 cmH2O/L (p < 0.0001). There were no differences in gas exchange among groups. Wet-to-dry ratios and formation of hyaline membranes were significantly lower in low VT groups compared to conventional tidal volumes. Hypercapnia reduced diffuse alveolar damage and IL-6 levels in the BALF, which was also true when CO2 was added to conventional VT. In low VT groups, hypercapnia did not induce any further protective effect except increasing pulmonary IL-10 in the BALF. No differences in lung injury were observed when hypercapnia was induced by adding CO2 or decreasing minute ventilation, although permissive hypercapnia decreased the pH significantly and decreased liver histologic injury. Conclusion: Our findings suggest that low tidal volume ventilation likely attenuates VALI by limiting mechanical damage to the lung, while hypercapnia attenuates VALI by limiting pro-inflammatory and biochemical mechanisms of injury. When combined, both lung-protective ventilation and hypercapnia have the potential to exert an synergistic effect for the prevention of VALI.
| S-EPMC9068936 | biostudies-literature
Project description:The aim of the current study was to investigate the effects of glucosamine (GlcN) on septic lethality and sepsis-induced inflammation using animal models of mice and zebrafish. GlcN pretreatment improved survival in the cecal ligation and puncture (CLP)-induced sepsis mouse model and attenuated lipopolysaccharide (LPS)-induced septic lung injury and systemic inflammation. GlcN suppressed LPS-induced M1-specific but not M2-specific gene expression. Furthermore, increased expressions of inflammatory genes in visceral tissue of LPS-injected zebrafish were suppressed by GlcN. GlcN suppressed LPS-induced activation of mitogen-activated protein kinase (MAPK) and NF-κB in lung tissue. LPS triggered a reduction in O-GlcNAc levels in nucleocytoplasmic proteins of lung, liver, and spleen after 1 day, which returned to normal levels at day 3. GlcN inhibited LPS-induced O-GlcNAc down-regulation in mouse lung and visceral tissue of zebrafish. Furthermore, the O-GlcNAcase (OGA) level was increased by LPS, which were suppressed by GlcN in mouse and zebrafish. OGA inhibitors suppressed LPS-induced expression of inflammatory genes in RAW264.7 cells and the visceral tissue of zebrafish. Stable knockdown of Oga via short hairpin RNA led to increased inducible nitric oxide synthase (iNOS) expression in response to LPS with or without GlcN in RAW264.7 cells. Overall, our results demonstrate a protective effect of GlcN on sepsis potentially through modulation of O-GlcNAcylation of nucleocytoplasmic proteins.
| S-EPMC6333887 | biostudies-literature
Project description:ObjectiveTo investigate the mechanism of Tocilizumab (TCZ) in attenuating acute lung injury in rats with sepsis by regulating the S100A12/NLRP3 axis.MethodsA rat model of sepsis was constructed using cecal ligation and puncture (CLP). Rats were treated with TCZ, and their lung tissue was collected. H&E staining was used to detect pathologic damage to lung tissue, and lung wet/dry (W/D) weight ratio was measured to assess pulmonary edema. Lipid oxidation assay and superoxide dismutase (SOD) activity assay kits were used to measure malondialdehyde (MDA) and SOD levels. Primary rat pulmonary microvascular endothelial cells (MPVECs) were treated with lipopolysaccharide (LPS) to construct a rat model of sepsis, which was then treated with TCZ. The mRNA and protein expressions of S100A12/NLRP3 were detected by qRT-PCR and western blot, respectively. S100A12 knockdown and overexpression plasmids, and NLRP3 knockdown plasmids were constructed and transfected into sepsis cells to intervene in the levels of S100A12/NLRP3. The apoptosis rate was detected by apoptosis assay. The levels of IL-6, TNF-α, and IL-10 in cells and tissues were analyzed by ELISA.ResultsCompared to the Sham group, the CLP group had increased W/D weight ratio of lung tissue, IL-6, TNF-α, and MDA levels, lowered IL-10 and SOD levels, and more severe tissue damage (all P<0.05). After TCZ treatment, the above indicators were improved. The expressions of S100A12/NLRP3 cells were increased in LPS-induced MPVECs, but decreased after TCZ treatment. LPS induced apoptosis, but TCZ reduced the apoptosis, weakened the secretion levels of IL-6 and TNF-α, and enhanced IL-10 secretion levels. Transfection to cause the overexpression of S100A12 or NLRP3 plasmid partially counteracted the effect of TCZ. Knockdown of S100A12 was transfected on the basis of overexpression of NLRP3, which weakened the countervailing effect of overexpressed NLRP3 on TCZ.ConclusionTCZ has a therapeutic effect on lung injury in rats with sepsis by reducing the expressions of S100A12/NLRP3.
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Project description:During sepsis, systemic inflammation is observed and is associated with multiple organ failure. Activation of NF-κB is crucial for inducing inflammation, which is controlled by degradation of inhibitor molecules (IκB). The ubiquitination proteasome pathway is responsible for the regulation of protein turnover. In this study, we hypothesized that administration of 4[4-(5-nitro-furan-2-ylmethylene)-3, -dioxo-pyrazolidin-1-yl]-benzoic acid ethyl ester (PYR-41), an inhibitor of ubiquitination, could reduce inflammation and organ injury in septic mice. PYR-41 prevented the reduction of IκB protein levels and inhibited release of tumor necrosis factor (TNF)-α in mouse macrophage RAW264.7 cells at 4 h after lipopolysaccharide stimulation dose-dependently. Male C57BL/6 mice were subjected to cecal ligation and puncture (CLP) to induce sepsis. PYR-41 (5 mg/kg) or dimethyl sulfoxide in saline (vehicle) was injected intravenously immediately after CLP. At 20 h after CLP, PYR-41 treatment significantly decreased serum levels of proinflammatory cytokines (TNF-α, interleukin [IL]-1β, and IL-6) and organ injury markers (aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase). PYR-41 significantly improved microscopic structure, and reduced myeloperoxidase activity, number of apoptotic cells and caspase-3 degradation in the lungs of septic mice. The reduced protein levels of IκB in the lungs after CLP were restored by PYR-41 treatment. PYR-41 inhibited the expression of cytokines (IL-1β and IL-6), chemokines (keratinocyte-derived chemokine and macrophage inflammatory protein 2), and inflammatory mediators (cyclooxygenase-2 and inducible nitric oxide synthase) in the lungs of septic mice. Importantly, PYR-41 significantly increased 10-day survival in septic mice from 42% to 83%. Therefore, targeting ubiquitination by PYR-41 to inhibit NF-κB activation may represent a potential strategy of sepsis therapeutics.
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Project description:Sepsis is an acute inflammatory condition that can result in multiple organ failure and acute lung injury. Growth arrest-specific protein 6 (Gas6) is a broad regulator of the innate immune response involved with the nuclear factor ?B signaling pathway. We hypothesized that Gas6 could have a protective role in attenuating the severity of acute lung injury and sepsis. Male mice were subjected to sepsis by cecal ligation and puncture (CLP) after which recombinant murine Gas6 (rmGas6; 5 ?g/mouse) or normal saline (vehicle) was administered intravenously. Blood and lung tissues were collected at 20 h after CLP for various measurements. Treatment with rmGas6 significantly reduced serum levels of the injury markers aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase, as well as proinflammatory cytokines interleukin 6 (IL-6) and IL-17, compared with the vehicle group (P < 0.05). The parenchyma of the lungs damaged by CLP was attenuated by rmGas6 treatment. Lung mRNA levels of tumor necrosis factor ?, IL-1?, IL-6, IL-17, and macrophage inflammatory protein 2 (MIP-2) were decreased by 60%, 86%, 82%, 93%, and 82%, respectively, with rmGas6 treatment as determined by real-time reverse transcriptase-polymerase chain reaction (P < 0.05). The degradation of I?B-? induced by CLP in the lungs was inhibited by rmGas6 treatment. The number of neutrophils and myeloperoxidase activity in the lungs were significantly reduced in the rmGas6 group. Moreover, rmGas6 reduced the in vitro migration of differentiated human promyelocytic HL60 cells by 64%. Finally, the 10-day survival rate of mice subjected to CLP was increased from 31% in the vehicle group to 67% in the rmGas6 group (P < 0.05). Thus, Gas6 has potential to be developed as a novel therapeutic agent to treat patients with sepsis and acute lung injury.
| S-EPMC3834042 | biostudies-literature
Project description:BackgroundSevere sepsis and its subsequent complications cause high morbidity and mortality rates worldwide. The lung is one of the most vulnerable organs sensitive to the sepsis-associated inflammatory storm and usually develops into acute respiratory distress syndrome (ARDS)/acute lung injury (ALI). The pathogenesis of sepsis-associated ALI is accompanied by coordinated transmembrane signal transduction and subsequent programmed cell death; however, the underlying mechanism remains largely unclear.ResultsHere we find that the expression of serine incorporator 2 (Serinc2), a protein involved in phosphatidylserine synthesis and membrane incorporation, is upregulated in cecal ligation and puncture (CLP)-induced ALI. Furthermore, the Serinc2-knockout (KO) mouse line is generated by the CRISPR-cas9 approach. Compared with wild-type mice, the Serinc2-KO mice exhibit exacerbated ALI-related pathologies after CLP. The expressions of pro-inflammatory factors, including IL1β, IL6, TNFα, and MCP1, are significantly enhanced by Serinc2 deficiency, concurrent with over-activation of STAT3, p38 and ERK pathways. Conversely, Serinc2 overexpression in RAW264.7 cells significantly suppresses the inflammatory responses induced by lipopolysaccharide (LPS). Serinc2 KO aggravates CLP-induced apoptosis as evidenced by increases in TUNEL-positive staining, Bax expression, and cleaved caspase-3 and decreases in BCL-2 expression and Akt phosphorylation, whereas these changes are suppressed by Serinc2 overexpression in LPS-treated RAW264.7 cells. Moreover, the administration of AKTin, an inhibitor of Akt, abolishes the protective effects of Serinc2 overexpression against inflammation and apoptosis.ConclusionsOur findings demonstrate a protective role of Serinc2 in the lung through activating the Akt pathway, and provide novel insight into the pathogenesis of sepsis-induced ALI.
| S-EPMC9260995 | biostudies-literature
Project description:Although the accumulation of amyloidogenic proteins in neuroinflammatory conditions is generally considered pathologic, in a murine model of multiple sclerosis, amyloid-forming fibrils, comprised of hexapeptides, are anti-inflammatory. Whether these molecules modulate systemic inflammatory conditions remains unknown. We hypothesized that an amylin hexapeptide that forms fibrils can attenuate the systemic inflammatory response in a murine model of sepsis. To test this hypothesis, mice were pre-treated with either vehicle or amylin hexapeptide (20 μg) at 12 hours and 6 hours prior to intraperitoneal (i.p.) lipopolysaccharide (LPS, 20 mg/kg) administration. Illness severity and survival were monitored every 6 hours for 3 days. Levels of pro- (IL-6, TNF-α, IFN-γ) and anti-inflammatory (IL-10) cytokines were measured via ELISA at 1, 3, 6, 12, and 24 hours after LPS (i.p.). As a metric of lung injury, pulmonary artery endothelial cell (PAEC) barrier function was tested 24 hours after LPS administration by comparing lung wet-to-dry ratios, Evan's blue dye (EBD) extravasation, lung histology and caspase-3 activity. Compared to controls, pretreatment with amylin hexapeptide significantly reduced mortality (p<0.05 at 72 h), illness severity (p<0.05), and pro-inflammatory cytokine levels, while IL-10 levels were elevated (p<0.05). Amylin pretreatment attenuated LPS-induced lung injury, as demonstrated by decreased lung water and caspase-3 activity (p<0.05, versus PBS). Hence, in a murine model of systemic inflammation, pretreatment with amylin hexapeptide reduced mortality, disease severity, and preserved lung barrier function. Amylin hexapeptide may represent a novel therapeutic tool to mitigate sepsis severity and lung injury.
| S-EPMC6039005 | biostudies-literature
Project description:BackgroundIn sepsis, the lung is one of the worst affected organs, often leading to acute lung injury (ALI). More and more evidence suggests that macrophages are also involved in the pathogenesis of ALI. In our previous study, we successfully synthesized Iron-capsaicin-based nanoparticles (Fe-CAP NPs) and found that it could inhibit the secretion of inflammatory cytokines to alleviate ALI. Here, we further explore the anti-inflammatory mechanism of Fe-CAP NPs.MethodsBone marrow-derived macrophages (BMDM) and C57 mice were divided into four groups: control group, lipopolysaccharide (LPS) group, CAP + LPS group and Fe-CAP + LPS group. Western blot and Immunofluorescence were used to detect the expression of macrophage phenotypic markers CD86 and CD206 in BMDM and lung tissue. Fluorescence microbeads, Transwell and ROS kit were used to detect the phagocytosis, migration and ROS clearing capability of BMDM. Western blot was used to detect the expression of JAK2/STAT3 pathway and apoptosis proteins in BMDM. TUNEL kit and H&E staining were used to evaluate apoptosis and pathological changes in lung tissue.ResultsIn vitro, CD86 expression was increased in LPS, but decreased after Fe-CAP pretreatment. CD206 expression was the opposite. Fe-CAP reduced phagocytosis, migration and scavenged ROS in LPS-treated BMDM. Fe-CAP inhibited P-JAK2 and P-STAT3 expression and reduced apoptosis. In vivo, Fe-CAP improved lung histopathology and reduced apoptosis in lung tissue of LPS group. CD86 expression was increased in lung tissue of LPS group, but decreased in Fe-CAP preconditioning, and CD206 expression was reversed.ConclusionFe-CAP NPs could alleviate sepsis-induced ALI by regulating the polarization and function of macrophages, reducing ROS level and apoptosis.
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