scholarly journals Impaired Glucocorticoid Receptor Signaling Aggravates Lung Injury after Hemorrhagic Shock

Cells ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 112
Author(s):  
Jonathan M. Preuss ◽  
Ute Burret ◽  
Michael Gröger ◽  
Sandra Kress ◽  
Angelika Scheuerle ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Lung Injury ◽  
Hemorrhagic Shock ◽  
Lung Tissue ◽  
Lung Inflammation ◽  
Lung Damage ◽  
Lung Mechanics ◽  
Cytokine Signaling ◽  
Pro Inflammatory Cytokines

We previously showed that attenuated lung injury after hemorrhagic shock (HS) coincided with enhanced levels of the glucocorticoid (GC) receptor (GR) in lung tissue of swine. Here, we investigated the effects of impaired GR signaling on the lung during resuscitated HS using a dysfunctional GR mouse model (GRdim/dim). In a mouse intensive care unit, HS led to impaired lung mechanics and aggravated lung inflammation in GRdim/dim mice compared to wildtype mice (GR+/+). After HS, high levels of the pro-inflammatory and pro-apoptotic transcription factor STAT1/pSTAT1 were found in lung samples from GRdim/dim mice. Lungs of GRdim/dim mice revealed apoptosis, most likely as consequence of reduced expression of the lung-protective Angpt1 compared to GR+/+ after HS. RNA-sequencing revealed increased expression of pro-apoptotic and cytokine-signaling associated genes in lung tissue of GRdim/dim mice. Furthermore, high levels of pro-inflammatory cytokines and iNOS were found in lungs of GRdim/dim mice. Our results indicate impaired repression of STAT1/pSTAT1 due to dysfunctional GR signaling in GRdim/dim mice, which leads to increased inflammation and apoptosis in the lungs. These data highlight the crucial role of functional GR signaling to attenuate HS-induced lung damage.

scholarly journals Surfactant Attenuates Air Embolism-Induced Lung Injury by Suppressing NKCC1 Expression and NF-κB Activation

Inflammation ◽  
2020 ◽  
Author(s):  
Chou-Chin Lan ◽  
Yao-Kuang Wu ◽  
Chung-Kan Peng ◽  
Kun-Lun Huang ◽  
Chin-Pyng Wu
Keyword(s):  
Lung Injury ◽  
Pulmonary Edema ◽  
Inflammatory Cytokines ◽  
Lung Inflammation ◽  
Inflammatory Responses ◽  
Air Embolism ◽  
Lower Surface ◽  
Beneficial Effects ◽  
Pro Inflammatory Cytokines

Abstract Excessive amounts of air can enter the lungs and cause air embolism (AE)-induced acute lung injury (ALI). Pulmonary AE can occur during diving, aviation, and iatrogenic invasive procedures. AE-induced lung injury presents with severe hypoxia, pulmonary hypertension, microvascular hyper-permeability, and severe inflammatory responses. Pulmonary AE-induced ALI is a serious complication resulting in significant morbidity and mortality. Surfactant is abundant in the lungs and its function is to lower surface tension. Earlier studies have explored the beneficial effects of surfactant in ALI; however, none have investigated the role of surfactant in pulmonary AE-induced ALI. Therefore, we conducted this study to determine the effects of surfactant in pulmonary AE-induced ALI. Isolated-perfused rat lungs were used as a model of pulmonary AE. The animals were divided into four groups (n = 6 per group): sham, air embolism (AE), AE + surfactant (0.5 mg/kg), and AE+ surfactant (1 mg/kg). Surfactant pretreatment was administered before the induction of pulmonary AE. Pulmonary AE was induced by the infusion of 0.7 cc air through a pulmonary artery catheter. After induction of air, pulmonary AE was presented with pulmonary edema, pulmonary microvascular hyper-permeability, and lung inflammation with neutrophilic sequestration. Activation of NF-κB was observed, along with increased expression of pro-inflammatory cytokines, and Na-K-Cl cotransporter isoform 1 (NKCC1). Surfactant suppressed the activation of NF-κB and decreased the expression of pro-inflammatory cytokines and NKCC1, thereby attenuating AE-induced lung injury. Therefore, AE-induced ALI presented with pulmonary edema, microvascular hyper-permeability, and lung inflammation. Surfactant suppressed the expressions of NF-κB, pro-inflammatory cytokines, and NKCC1, thereby attenuating AE-induced lung injury.

scholarly journals Macrophage micro-RNA-155 promotes lipopolysaccharide-induced acute lung injury in mice and rats

2016 ◽  
Vol 311 (2) ◽  
pp. L494-L506 ◽  
Author(s):  
Wen Wang ◽  
Zhi Liu ◽  
Jie Su ◽  
Wen-Sheng Chen ◽  
Xiao-Wu Wang ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Alveolar Macrophages ◽  
Lung Inflammation ◽  
Micro Rna ◽  
Pcr Analysis ◽  
Cytokine Signaling ◽  
Wild Type

Micro-RNA (miR)-155 is a novel gene regulator with important roles in inflammation. Herein, our study aimed to explore the role of miR-155 in LPS-induced acute lung injury(ALI). ALI in mice was induced by intratracheally delivered LPS. Loss-of-function experiments performed on miR-155 knockout mice showed that miR-155 gene inactivation protected mice from LPS-induced ALI, as manifested by preserved lung permeability and reduced lung inflammation compared with wild-type controls. Bone marrow transplantation experiments identified leukocytes, but not lung parenchymal-derived miR-155-promoted acute lung inflammation. Real-time PCR analysis showed that the expression of miR-155 in lung tissue was greatly elevated in wild-type mice after LPS stimulation. In situ hybridization showed that miR-155 was mainly expressed in alveolar macrophages. In vitro experiments performed in isolated alveolar macrophages and polarized bone marrow-derived macrophages confirmed that miR-155 expression in macrophages was increased in response to LPS stimulation. Conversely, miR-155 gain-of-function in alveolar macrophages remarkably exaggerated LPS-induced acute lung injury. Molecular studies identified the inflammation repressor suppressor of cytokine signaling (SOCS-1) as the downstream target of miR-155. By binding to the 3′-UTR of the SOCS-1 mRNA, miR-155 downregulated SOCS-1 expression, thus, permitting the inflammatory response during lung injury. Finally, we generated a novel miR-155 knockout rat strain and showed that the proinflammatory role of miR-155 was conserved in rats. Our study identified miR-155 as a proinflammatory factor after LPS stimulation, and alveolar macrophages-derived miR-155 has an important role in LPS-induced ALI.

scholarly journals Role of the C5a-C5a receptor axis in the inflammatory responses of the lungs after experimental polytrauma and hemorrhagic shock

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shinjini Chakraborty ◽  
Veronika Eva Winkelmann ◽  
Sonja Braumüller ◽  
Annette Palmer ◽  
Anke Schultze ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Inflammatory Responses ◽  
Experimental Models ◽  
Lung Damage ◽  
C5a Receptor ◽  
Cytokine Levels ◽  
Vitro Model

AbstractSingular blockade of C5a in experimental models of sepsis is known to confer protection by rescuing lethality and decreasing pro-inflammatory responses. However, the role of inhibiting C5a has not been evaluated in the context of sterile systemic inflammatory responses, like polytrauma and hemorrhagic shock (PT + HS). In our presented study, a novel and highly specific C5a L-aptamer, NoxD21, was used to block C5a activity in an experimental murine model of PT + HS. The aim of the study was to assess early modulation of inflammatory responses and lung damage 4 h after PT + HS induction. NoxD21-treated PT + HS mice displayed greater polymorphonuclear cell recruitment in the lung, increased pro-inflammatory cytokine levels in the bronchoalveolar lavage fluids (BALF) and reduced myeloperoxidase levels within the lung tissue. An in vitro model of the alveolar-capillary barrier was established to confirm these in vivo observations. Treatment with a polytrauma cocktail induced barrier damage only after 16 h, and NoxD21 treatment in vitro did not rescue this effect. Furthermore, to test the exact role of both the cognate receptors of C5a (C5aR1 and C5aR2), experimental PT + HS was induced in C5aR1 knockout (C5aR1 KO) and C5aR2 KO mice. Following 4 h of PT + HS, C5aR2 KO mice had significantly reduced IL-6 and IL-17 levels in the BALF without significant lung damage, and both, C5aR1 KO and C5aR2 KO PT + HS animals displayed reduced MPO levels within the lungs. In conclusion, the C5aR2 could be a putative driver of early local inflammatory responses in the lung after PT + HS.

scholarly journals Induction of acute lung inflammation in mice with hemorrhagic shock and resuscitation: role of HMGB1

2014 ◽  
Vol 11 (1) ◽  
Author(s):  
Raymond LC Kao ◽  
Xuemei Xu ◽  
Anargyros Xenocostas ◽  
Neil Parry ◽  
Tina Mele ◽  
...  
Keyword(s):  
Hemorrhagic Shock ◽  
Lung Inflammation ◽  
Acute Lung Inflammation

scholarly journals Selective Myeloid Depletion of Galectin-3 Offers Protection Against Acute and Chronic Lung Injury

2021 ◽  
Vol 12 ◽  
Author(s):  
Duncan C. Humphries ◽  
Ross Mills ◽  
Ross Dobie ◽  
Neil C. Henderson ◽  
Tariq Sethi ◽  
...  
Keyword(s):  
Pulmonary Fibrosis ◽  
Lung Injury ◽  
Lung Inflammation ◽  
Respir Crit ◽  
Pulmonary Inflammation ◽  
Myeloid Cell ◽  
Clinical Development ◽  
Galectin 3 ◽  
Direct Targeting

Rationale: Galectin-3 (Gal-3) is an immune regulator and an important driver of fibrosis in chronic lung injury, however, its role in acute lung injury (ALI) remains unknown. Previous work has shown that global deletion of galectin-3 reduces collagen deposition in a bleomycin-induced pulmonary fibrosis model (MacKinnon et al., Am. J. Respir. Crit. Care Med., 2012, 185, 537–46). An inhaled Gal-3 inhibitor, GB0139, is undergoing Phase II clinical development for idiopathic pulmonary fibrosis (IPF). This work aims to elucidate the role of Gal-3 in the myeloid and mesenchymal compartment on the development of acute and chronic lung injury.Methods:LgalS3fl/fl mice were generated and crossed with mice expressing the myeloid (LysM) and mesenchymal (Pdgfrb) cre drivers to yield LysM-cre+/-/LgalS3fl/fl and Pdgfrb-cre+/-/LgalS3fl/fl mice. The response to acute (bleomycin or LPS) or chronic (bleomycin) lung injury was compared to globally deficient Gal-3−/− mice.Results: Myeloid depletion of Gal-3 led to a significant reduction in Gal-3 expression in alveolar macrophages and neutrophils and a reduction in neutrophil recruitment into the interstitium but not into the alveolar space. The reduction in interstitial neutrophils corelated with decreased levels of pulmonary inflammation following acute bleomycin and LPS administration. In addition, myeloid deletion decreased Gal-3 levels in bronchoalveolar lavage (BAL) and reduced lung fibrosis induced by chronic bleomycin. In contrast, no differences in BAL Gal-3 levels or fibrosis were observed in Pdgfrb-cre+/-/LgalS3fl/flmice.Conclusions: Myeloid cell derived Galectin-3 drives acute and chronic lung inflammation and supports direct targeting of galectin-3 as an attractive new therapy for lung inflammation.

Role of proinflammatory activity contained in gastric juice from intensive care unit patients to induce lung injury in a rabbit aspiration model

2008 ◽  
Vol 36 (12) ◽  
pp. 3205-3212 ◽  
Author(s):  
Fabienne Brégeon ◽  
Laurent Papazian ◽  
Stéphane Delpierre ◽  
Osamu Kajikawa ◽  
Marie-José Payan ◽  
...  
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Lung Injury ◽  
Gastric Juice ◽  
Induce Lung Injury ◽  
Proinflammatory Activity

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.

scholarly journals NADPH Oxidase 4 Signaling in a Ventilator-induced Lung Injury Mouse Model

2021 ◽  
Author(s):  
Sang Hoon Lee ◽  
Mi Hwa Shin ◽  
Ah Young Leem ◽  
Su Hwan Lee ◽  
Kyung Soo Chung ◽  
...  
Keyword(s):  
Lung Injury ◽  
Lavage Fluid ◽  
Lung Damage ◽  
Control Group ◽  
Group 4 ◽  
Ventilator Induced Lung Injury ◽  
Cell Counts ◽  
Group 5 ◽  
Group 2

Abstract For patients with acute respiratory distress syndrome, a ventilator is essential to supply oxygen to tissues, but it may also cause lung damage. We investigated the role of NOX4 in a ventilator-induced lung injury (VILI) model.Wild-type (WT) male C57BL/6J mice and NOX4 knockout (KO) male mice were divided into five groups: (1) control group; (2) high tidal ventilation (HTV) group: WT mice + HTV; (3) NOX4 KO group; (4) NOX4 KO with HTV group; (5) NOX4 inhibitor group: WT mice + HTV + NOX4 inhibitor. In addition, the relationship between EphA2 (which is related to lung injury) and NOX4 was investigated using EphA2 KO mice, and NOX4 levels in the bronchoalveolar lavage fluid (BALF) of 38 patients with pneumonia were examined.In the NOX4 inhibitor group, cell counts and protein concentrations from BALF were significantly lower than those in the HTV group (both, p<0.001). In the NOX4 KO group and the NOX4 inhibitor group, EphA2 levels were significantly lower than those in the HTV group (p<0.001). NOX4 levels were significantly higher in patients with pneumonia and patients who received ventilator treatment in the ICU.In the VILI model, it may be possible to block VILI using NOX4 antibodies.

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