Endotoxin-induced acute lung injury requires interaction with the liver

2005 ◽  
Vol 289 (5) ◽  
pp. L769-L776 ◽  
Author(s):  
Amsel M. Siore ◽  
Richard E. Parker ◽  
Arlene A. Stecenko ◽  
Chris Cuppels ◽  
Martha McKean ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Lung Tissue ◽  
Distress Syndrome ◽  
Laboratory Data ◽  
Lung Edema ◽  
Direct Effects ◽  
Tnf Α ◽  
Severe Lung

Clinical and laboratory data indicate that the liver plays an important role in the incidence, pathogenesis, and outcome of acute lung injury/acute respiratory distress syndrome. To distinguish direct effects of endotoxin on the lungs from liver-dependent effects during the early phase of the response to endotoxemia, we used an in situ perfused piglet preparation in which only the ventilated lung or both the lung and liver could be included in a blood perfused circuit. We monitored pulmonary vascular resistance, oxygenation, neutrophil count, lung edema as reflected by wet-dry weights of lung tissue, perfusate concentrations of TNF-α, IL-6, and 8-isoprostane (a marker of oxidative stress), and activation of the transcription factor (NF-κB) in lung tissue before and for 2 h after endotoxin. When only the lung was perfused, endotoxin caused pulmonary hypertension and neutropenia; but oxygenation was maintained; TNF-α, IL-6, and 8-isoprostane levels were minimally elevated; and there was no lung edema. When both the liver and lung were perfused, endotoxin caused marked hypoxemia, large increases in perfusate TNF-α, IL-6, and 8-isoprostane concentrations, and severe lung edema. NF-κB activation in the lung was greatest when the liver was in the perfusion circuit. We conclude that the direct effects of endotoxemia on the lungs include vasoconstriction and leukocyte sequestration, but not lung injury. Intense activation of the inflammatory response and oxidative injury that results in pulmonary edema and hypoxemia (acute lung injury) requires interaction of the lungs with the liver.

scholarly journals Reproduction of transfusion-related acute lung injury in an ex vivo lung model [see comments]

Blood ◽  
1990 ◽  
Vol 76 (7) ◽  
pp. 1438-1444 ◽  
Author(s):  
W Seeger ◽  
U Schneider ◽  
B Kreusler ◽  
E von Witzleben ◽  
D Walmrath ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Ex Vivo ◽  
Fold Increase ◽  
Vascular Leakage ◽  
Lung Model ◽  
Lung Edema ◽  
Rabbit Plasma ◽  
Transfusion Therapy ◽  
Severe Lung

Abstract Leukoagglutinins are implicated in transfusion-related acute lung injury (TRALI). In the present study, severe lung vascular leakage was reproduced by application of a leukoagglutinating antibody of anti-5b specificity in an ex vivo lung model. The antibody originated from a multiparous donor-plasma, observed to cause noncardiogenic edema during transfusion therapy. Heated full plasma (anti-5b-titer 1/128) or purified immunoglobulin G fraction was used for the studies. Ex vivo isolated rabbit lungs were perfused with albumin buffer, and human granulocytes (PMN) were admixed to the recirculating perfusate. In presence of anti-5b antibody plus 5b-positive PMN plus rabbit plasma as complement-source, severe lung edema occurred after a latent period of 3 to 6 hours. Pulmonary artery pressure was only transiently and moderately increased, and the leakage reaction could be traced back to a several-fold increase in lung vascular permeability. In contrast, no vascular leakage was noted in lungs perfused in the absence of anti-5b antibody, PMN, or rabbit plasma. Moreover, no permeability increase occurred on use of 5b-negative PMN. This reproduction of TRALI in an ex vivo lung model corroborates the role of leukoagglutinating antibodies in initiating PMN-dependent respiratory distress and suggests a contribution of concomitant complement activation.

scholarly journals Angelica Polysaccharide Ameliorates Sepsis-Induced Acute Lung Injury through Inhibiting NLRP3 and NF-κB Signaling Pathways in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Yan Zhu ◽  
Taocheng Meng ◽  
Aichen Sun ◽  
Jintao Li ◽  
Jinlai Li
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathways ◽  
Cecal Ligation ◽  
Weight Ratio ◽  
Receptor Protein ◽  
Lung Edema ◽  
Caspase 1 ◽  
Tnf Α

Objective. This study aimed to explore the role of angelica polysaccharide (AP) in sepsis-induced acute lung injury (ALI) and its underlying molecular mechanism. Methods. A sepsis model of cecal ligation and puncture (CLP) in male BALB/C mice was used. Then, 24 h after CLP, histopathological changes in lung tissue, lung wet/dry weight ratio, and inflammatory cell infiltration were analyzed. Next, levels of inflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, IL-6, and IL-18), as well as the activity of myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione (GSH), were measured to assess the role of AP. The protein expression of NF-κB p65, p-NF-κB p65, IκBα, p-IκBα, nucleotide-binding domain- (NOD-) like receptor protein 3 (NLRP3), ASC, and caspase-1 was detected by western blot. In addition, the expression of p-NF-κB p65 and NLRP3 was detected by immunohistochemistry. Results. AP treatment ameliorated CLP-induced lung injury and lung edema, as well as decreased the number of total cells, neutrophils, and macrophages in bronchoalveolar lavage fluid (BALF). AP reduced the levels of TNF-α, IL-1β, IL-6, and IL-18 in BALF, as well as in serum. Moreover, AP decreased MPO activity and MDA content, whereas increased SOD and GSH levels. AP inhibited the expression of p-NF-κB p65, p-IκBα, NLRP3, ASC, and caspase-1, while promoted IκBα expression. Conclusion. This study demonstrated that AP exhibits protective effects against sepsis-induced ALI by inhibiting NLRP3 and NF-κB signaling pathways in mice.

scholarly journals miR-20a attenuates acute lung injury in septic rats via targeting TLR4

2021 ◽  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Lung Tissue ◽  
Cecal Ligation ◽  
Normal Group ◽  
Lung Damage ◽  
Luciferase Reporter ◽  
Arterial Bleeding ◽  
Tnf Α

Background: Sepsis is most likely to cause lung damage in patients, and the detection rate and mortality rate are high. Here, we investigated the expression of miR-20a in sepsis-induced acute lung injury (ALI) rats and its effect on inflammatory response, and reveal its possible molecular mechanism. Method: The model of acute lung injury caused by sepsis in rats was established by cecal ligation and puncture. The expression of miR-20a in lung tissue was determined by RT-qPCR. Acute lung injury rats were injected with 5 nmol miR-20a agomir or agomir NC every day for 3 days. Rats were sacrificed by arterial bleeding and lung tissues were removed. Serum interleukin (IL) -1β, IL-6, and tumor necrosis factor alpha (TNF-α) were detected by ELISA. HE staining was used to observe the pathology of lung tissue and calculate the pathological score of lung injury. Western blot to determine the level of TLR4 and nuclear transcription factor κB p65 (NF-κB p65) protein in lung tissue. The luciferase reporter assay was used to verify the binding effect of miR-20a on the 3 non-coding TLR4. Results: We found that compared with that in Normal group, the expression of miR-20a in lung tissues of rats with ALI was decreased (p < 0.05). In miR-20a agomir group, the plasma level of IL-1β, IL-6, and TNF-α was significantly lower than that in agomir NC group and ALI group (p < 0.05), while higher than those in Normal group (p < 0.05). The HE staining results showed that the pathological score of lung injury in rats in miR-20a agomir group was lower than that of agomir NC group and ALI group (p < 0.05). Compared with agomir NC group and ALI group, the expression of TLR4 and NF-κB p65 in miR-20a agomir group was decreased (p < 0.01). The luciferase reporting experiment confirmed that TLR4 was a target gene of miR-20a. Conclusion: To sum up, miR-20a exerts a protective effect on sepsis-induced ALI rats through its anti-inflammatory effect. The targeting of TLR4 by miR-20a may be an effective method to reduce the inflammatory response in sepsis-induced ALI.

Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury

2000 ◽  
Vol 279 (6) ◽  
pp. L1137-L1145 ◽  
Author(s):  
Edward Abraham ◽  
Aaron Carmody ◽  
Robert Shenkar ◽  
John Arcaroli
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Responses ◽  
Nuclear Factor Κb ◽  
Lung Edema ◽  
Protein Levels ◽  
Inflammatory Protein ◽  
Transcriptional Regulatory ◽  
Tnf Α ◽  
Factor Α

Acute lung injury is characterized by accumulation of neutrophils in the lungs, accompanied by the development of interstitial edema and an intense inflammatory response. To assess the role of neutrophils as early immune effectors in hemorrhage- or endotoxemia-induced lung injury, mice were made neutropenic with cyclophosphamide or anti-neutrophil antibodies. Endotoxemia- or hemorrhage-induced lung edema was significantly reduced in neutropenic animals. Activation of the transcriptional regulatory factor nuclear factor-κB after hemorrhage or endotoxemia was diminished in the lungs of neutropenic mice compared with nonneutropenic controls. Hemorrhage or endotoxemia was followed by increases in pulmonary mRNA and protein levels for interleukin-1β (IL-1β), macrophage inflammatory protein-2 (MIP-2), and tumor necrosis factor-α (TNF-α). Endotoxin-induced increases in proinflammatory cytokine expression were greater than those found after hemorrhage. The amounts of mRNA or protein for IL-1β, MIP-2, and TNF-α were significantly lower after hemorrhage in the lungs of neutropenic versus nonneutropenic mice. Neutropenia was associated with significant reductions in IL-1β and MIP-2 but not in TNF-α expression in the lungs after endotoxemia. These experiments show that neutrophils play a centrol role in initiating acute inflammatory responses and causing injury in the lungs after hemorrhage or endotoxemia.

scholarly journals Diagnostic value of miR-155 for acute lung injury/acute respiratory distress syndrome in patients with sepsis

2020 ◽  
Vol 48 (7) ◽  
pp. 030006052094307
Author(s):  
Zhou-Feng Wang ◽  
Yu-Min Yang ◽  
Heng Fan
Keyword(s):  
Acute Respiratory Distress Syndrome ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Respiratory Distress Syndrome ◽  
Respiratory Distress ◽  
Distress Syndrome ◽  
Characteristic Curve ◽  
Diagnostic Value ◽  
Inflammatory Factors ◽  
Tnf Α

Objective We aimed to investigate the diagnostic value of microRNA-155 (miR-155) for acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) in patients with sepsis. Methods In this prospective study, we used Spearman correlation analysis to investigate relationships between miR-155 expression and inflammatory factors, oxygenation ratio (PaO2/FiO2), and ALI/ARDS score, and used area under the receiver operating characteristic curve (AU-ROC) to evaluate miR-155's diagnostic accuracy for ALI/ARDS in patients with sepsis. Results In total, 156 patients with sepsis were enrolled in our study, of which 41 had ALI and 32 had ARDS. miR-155 expression in plasma of patients with sepsis and ALI/ARDS was significantly higher than that of patients with sepsis but no ALI/ARDS. The miR-155 level in patients with sepsis and ALI/ARDS was positively correlated with interleukin (IL)-1β and tumor necrosis factor (TNF)-α levels and ALI/ARDS score, but negatively correlated with PaO2/FiO2. The AU-ROC of plasma miR-155 for diagnosis of sepsis with ALI/ARDS was 0.87, and plasma miR-155, IL-1β, and TNF-α had high sensitivity and specificity for the diagnosis of sepsis with ALI/ARDS. Conclusion miR-155 is highly expressed in plasma of patients with septic ALI/ARDS; it is positively correlated with lung function and can be used for early diagnosis.

scholarly journals Milonine Protects Against Acute Lung Injury By Modulating The Akt And NF-κB Signaling Pathway

2021 ◽  
Author(s):  
Larissa Rodrigues Bernardo ◽  
Laércia Karla Diega Paiva Ferreira ◽  
Larissa Adilis Maria Paiva Ferreira ◽  
Cosmo Isaías Duvirgens Vieira ◽  
João Batista de Oliveira ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Hydrophobic Interactions ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Lung Edema ◽  
Toll Like Receptor 4 ◽  
Downstream Signaling ◽  
Tnf Α ◽  
Anti Inflammatory

Abstract Acute lung injury (ALI) is an inflammation that triggers acute respiratory distress syndrome (ARDS) with perialveolar neutrophil infiltration, alveolar-capillary barrier damage, and lung edema. Activation of the toll-like receptor 4 complex and its downstream signaling pathways are responsible for the cytokine storm and cause alveolar damage on ARDS. Due to the complexity of inflammatory events on ALI, a defined pharmacotherapy has not been established. Thus, this study aimed to evaluate the anti-inflammatory potential of milonine, an alkaloid of Cissampelos sympodialis Eichl, in an ALI experimental model. BALB/c mice were lipopolysaccharide (LPS)-challenged and treated with milonine at 2.0 mg/kg. Twenty-four hours later, the bronchoalveolar lavage fluid (BALF), peripheral blood, and lungs were collected for cellular and molecular analysis. The milonine treatment decreased the inflammatory cell migration (principally neutrophils) to the alveolar cavity, the protein exudate, the pulmonary edema, and the level of pro-inflammatory cytokines (IL-1β, IL-6, TNF-α) into the BALF. The systemic level of IL-6 level was also reduced. In the lung tissue, milonine reduced the bronchoalveolar damage. The milonine docking analyzes demonstrated that the molecule formed hydrophobic interactions with the amino-acids Ile124 and Phe126 of the TLR4/MD2 groove. Indeed, the anti-inflammatory effect of milonine was due to the negative regulation of cytoplasmic kinase-Akt and NF-κB by interacting with the TLR4/MD2 complex. Therefore, milonine is an effective inflammatory modulator by blocking the interaction of the LPS-TLR4/MD2 complex and downregulating the intracellular inflammatory pathway axis being a potential molecule for the treatment of ALI.

scholarly journals STAT6 attenuated murine acute lung injury through NLRP3/p38 MAPK/NF-kappaB signaling in macrophages

2021 ◽  
Author(s):  
Lu Hu ◽  
Changzhou Shao ◽  
Linyue Pan ◽  
Zhilong Jiang
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
P38 Mapk ◽  
Flow Cytometry Analysis ◽  
Promising Therapeutic Approach ◽  
Tnf Α ◽  
Nf Kappab ◽  
Macrophage Subtypes ◽  
Pro Inflammatory Cytokines ◽  
Severe Lung

Abstract Signal transducer and activator of transcription 6 (STAT6) is an intracellular transcription factor, it remained unclear whether STAT6 affects murine acute lung injury (ALI) through modulation of macrophage subtypes and NLRP3/p38 MAPK/NF-kappaB signaling. We in this study, intratracheal treated wild-type (WT) and STAT6-/- mice with 5 mg/kg LPS. Lung tissues and bronchoalveolar lavage (BAL) were collected 2 days after the treatment. The results showed that lack of STAT6 in STAT6-/- mice caused more severe lung inflammation, neutrophil influx, and the expression of TNF-α, IL-6 and IL-1β in the inflamed lung tissues. Flow cytometry analysis showed Siglec F-CD206- biased polarization of M1 subtype macrophages in the LPS-treated STAT6-/- mice. In addition, lack of STAT6 increased the expression of NLRP3, p-p38 M APK, TNF-α, IL-1β and Calreticulin in the lung tissues of LPS-treated mice and STAT6-/- bone marrow-derived macrophages (BMDMs). However, Glibenclamide, PDTC and SB203580 effectively reversed the up-regulated pro-inflammatory cytokines in STAT6-/- BMDMs. Thereby, STAT6 defciency increased ALI severity, possibly through increasing polarization of M1 subtype macrophages and NLRP3/p38 MAPK/NF-kappaB signaling. NLRP3/p38 MAPK/NF-kappaB signaling may particiupate in the polarizatin of M1 subtype macrophages. Modulation of macrophages subtypes by molecular intervention of STAT6 signaling would be a promising therapeutic approach in the treatment of ALI.

scholarly journals An Experimental Model of Direct Acute Lung Injury in Rats Caused by Intratracheal Administration of Lipopolysaccharide from Salmonella enterica

Biomeditsina ◽  
2021 ◽  
Vol 17 (3) ◽  
pp. 84-89
Author(s):  
V. A. Pugach ◽  
M. A. Tyunin ◽  
N. S. Ilinskiy ◽  
E. V. Levchuk ◽  
E. I. Strokina ◽  
...  
Keyword(s):  
Body Weight ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Experimental Model ◽  
Lung Tissue ◽  
Salmonella Enterica ◽  
Distress Syndrome ◽  
Preclinical Research ◽  
Intratracheal Administration ◽  
Selection Of

An experimental model of direct acute lung injury was developed by intratracheal administration of lipopolysaccharide from Salmonella enterica (LD50 = 20 mg/kg). The dynamics of animal lethality, body weight, temperature and the severity of pathomorphological changes in the lung tissue were analyzed. It was found that the developed model is accompanied by a progressive decrease in body weight by 15%, persistent hypothermic reaction, pronounced edema and inflammatory reaction in the lung tissue within 4 days following lipopolysaccharide administration. The simplicity and reproducibility of the developed experimental model make it useful for preclinical research aimed at selection of candidate drugs for the prevention and treatment of acute respiratory distress syndrome.

scholarly journals Reproduction of transfusion-related acute lung injury in an ex vivo lung model [see comments]

Blood ◽  
1990 ◽  
Vol 76 (7) ◽  
pp. 1438-1444 ◽  
Author(s):  
W Seeger ◽  
U Schneider ◽  
B Kreusler ◽  
E von Witzleben ◽  
D Walmrath ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Ex Vivo ◽  
Fold Increase ◽  
Vascular Leakage ◽  
Lung Model ◽  
Lung Edema ◽  
Rabbit Plasma ◽  
Transfusion Therapy ◽  
Severe Lung

Leukoagglutinins are implicated in transfusion-related acute lung injury (TRALI). In the present study, severe lung vascular leakage was reproduced by application of a leukoagglutinating antibody of anti-5b specificity in an ex vivo lung model. The antibody originated from a multiparous donor-plasma, observed to cause noncardiogenic edema during transfusion therapy. Heated full plasma (anti-5b-titer 1/128) or purified immunoglobulin G fraction was used for the studies. Ex vivo isolated rabbit lungs were perfused with albumin buffer, and human granulocytes (PMN) were admixed to the recirculating perfusate. In presence of anti-5b antibody plus 5b-positive PMN plus rabbit plasma as complement-source, severe lung edema occurred after a latent period of 3 to 6 hours. Pulmonary artery pressure was only transiently and moderately increased, and the leakage reaction could be traced back to a several-fold increase in lung vascular permeability. In contrast, no vascular leakage was noted in lungs perfused in the absence of anti-5b antibody, PMN, or rabbit plasma. Moreover, no permeability increase occurred on use of 5b-negative PMN. This reproduction of TRALI in an ex vivo lung model corroborates the role of leukoagglutinating antibodies in initiating PMN-dependent respiratory distress and suggests a contribution of concomitant complement activation.

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