scholarly journals Histone neutralization in a rat model of acute lung injury induced by double-hit lipopolysaccharide

2021 ◽  
Author(s):  
yangyang ge ◽  
Chenchen wang ◽  
Yuduo Zhen ◽  
Junjie Luo ◽  
jiayi chen ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Rat Model ◽  
Lung Edema ◽  
High Dose ◽  
High Morbidity ◽  
Therapeutic Effects ◽  
Edema Formation ◽  
Double Hit ◽  
The Impact

Background: Acute respiratory distress syndrome (ARDS) remains a challenge because of its high morbidity and mortality. Circulation histones levels in ARDS patients were correlated to disease severity and mortality. This study examined the impact of histone neutralization in a rat model of acute lung injury (ALI) induced by a lipopolysaccharide (LPS) double-hit. Methods: Sixty-eight male Sprague-Dawley rats were randomized to sham (N=8, received saline only) or LPS (N=60). The LPS double-hit consisted of a 0.8 mg/kg intraperitoneal injection followed after 16 hours by 5 mg/kg intra-tracheal nebulized LPS. The LPS group was then randomized into five groups: LPS only (N=12); LPS + 5, 25, or 100 mg/kg intravenous STC3141 every 8 hours (LPS+L, LPS+M, LPS+H, respectively, each N=12); or LPS + intraperitoneal dexamethasone 2.5 mg/kg every 24 hours for 56 hours (LPS+D, N=12) The animals were observed for 72 hours. Results: LPS animals developed ALI as suggested by lower oxygenation, lung edema formation, and histological changes compared to the sham animals. Compared to the LPS group, LPS+H and +D animals had significantly lower circulating histone levels; only the LPS+D group had significantly lower bronchoalveolar lavage fluid (BALF) histone concentrations. The LPS+L, +M, +H and +D groups had improved oxygenation compared to the LPS group and the LPS+H and +D groups had a lower lung wet-to-dry ratio. All animals survived. Conclusion: Neutralization of histone using STC3141, especially at high dose, had similar therapeutic effects to dexamethasone in this LPS double-hit rat ALI model, with significantly decreased circulating histone concentration, improved oxygenation, and decreased lung edema formation. Keywords: ALI, ARDS, histone, histone neutralization, STC3141, rat LPS model

scholarly journals Emodin alleviates LPS-induced inflammatory response in lung injury rat by affecting the function of neutrophils

2020 ◽  
Author(s):  
Hongxia Mei ◽  
Ying Tao ◽  
Tianhao Zhang ◽  
Feng Qi
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Rat Model ◽  
Neutrophil Function ◽  
Life Threatening ◽  
Pulmonary Inflammatory Response ◽  
Anti Inflammatory ◽  
Factor Α ◽  
The Impact

Abstract Background: Acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS) are critical life-threatening syndromes characterized by the infiltration of a large number of neutrophils that lead to an excessive inflammatory response. Emodin (Emo) is a naturally occurring anthraquinone derivative and an active ingredient of Chinese medicine. It is believed to have anti-inflammatory effects. In this study, we examined the impact of Emo on the pulmonary inflammatory response and the neutrophil function in a rat model of lipopolysaccharide (LPS)-induced ALI.Results: Treatment with Emo protected rat against LPS-induced ALI. Compared to untreated rat, Emo-treated rat exhibited significantly ameliorated lung pathological changes and decreased tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). However, Emo has no protective effect on the rat model of acute lung injury with neutrophil deficiency. In addition, treatment with Emo enhanced the bactericidal capacity of LPS-induced neutrophils via the up-regulation of the ability of neutrophils to phagocytize bacteria and generate neutrophil extracellular traps (NETs). Emo also downregulated the neutrophil respiratory burst and the expression of reactive oxygen species (ROS) in LPS-stimulated neutrophils, alleviating the damage of neutrophils to surrounding tissues. Finally, Emo can accelerate the resolution of inflammation by promoting apoptosis of neutrophils. Conclusion: Our results provide the evidence that Emo could ameliorates LPS-induced ALI via its anti-inflammatory action by modulating the function of neutrophils. Emo may be a promising preventive and therapeutic agent in the treatment of ALI.

scholarly journals Double-hit mouse model of cigarette smoke priming for acute lung injury

2017 ◽  
Vol 312 (1) ◽  
pp. L56-L67 ◽  
Author(s):  
Pavlo Sakhatskyy ◽  
Zhengke Wang ◽  
Diana Borgas ◽  
Joanne Lomas-Neira ◽  
Yaping Chen ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Strain Difference ◽  
Intratracheal Instillation ◽  
Epidemiological Studies ◽  
Lung Edema ◽  
Key Features ◽  
Double Hit ◽  
Akr Mice

Epidemiological studies indicate that cigarette smoking (CS) increases the risk and severity of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS). The mechanism is not understood, at least in part because of lack of animal models that reproduce the key features of the CS priming process. In this study, using two strains of mice, we characterized a double-hit mouse model of ALI induced by CS priming of injury caused by lipopolysaccharide (LPS). C57BL/6 and AKR mice were preexposed to CS briefly (3 h) or subacutely (3 wk) before intratracheal instillation of LPS and ALI was assessed 18 h after LPS administration by measuring lung static compliance, lung edema, vascular permeability, inflammation, and alveolar apoptosis. We found that as little as 3 h of exposure to CS enhanced LPS-induced ALI in both strains of mice. Similar exacerbating effects were observed after 3 wk of preexposure to CS. However, there was a strain difference in susceptibility to CS priming for ALI, with a greater effect in AKR mice. The key features we observed suggest that 3 wk of CS preexposure of AKR mice is a reproducible, clinically relevant animal model that is useful for studying mechanisms and treatment of CS priming for a second-hit-induced ALI. Our data also support the concept that increased susceptibility to ALI/ARDS is an important adverse health consequence of CS exposure that needs to be taken into consideration when treating critically ill individuals.

scholarly journals Panaxydol attenuates ferroptosis against LPS-induced acute lung injury in mice by Keap1-Nrf2/HO-1 pathway

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jiucui Li ◽  
Kongmiao Lu ◽  
Fenglan Sun ◽  
Shanjuan Tan ◽  
Xiao Zhang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Molecular Mechanisms ◽  
Pulmonary Inflammation ◽  
Epithelial Cell Line ◽  
High Morbidity ◽  
Regulated Necrosis ◽  
The Impact

Abstract Background Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) induces uncontrolled and self-amplified pulmonary inflammation, and has high morbidity and mortality rates in critically ill patients. In recent years, many bioactive ingredients extracted from herbs have been reported to effectively ameliorate ALI/ARDS via different mechanisms. Ferroptosis, categorized as regulated necrosis, is more immunogenic than apoptosis and contributes to the progression of ALI. In this study, we examined the impact of panaxydol (PX), isolated from the roots of Panax ginseng, on lipopolysaccharide (LPS)-induced ALI in mice. Methods In vivo, the role of PX on LPS-induced ALI in mice was tested by determination of LPS-induced pulmonary inflammation, pulmonary edema and ferroptosis. In vitro, BEAS-2B cells were used to investigate the molecular mechanisms by which PX functions via determination of inflammation, ferroptosis and their relationship. Results Administration of PX protected mice against LPS-induced ALI, including significantly ameliorated lung pathological changes, and decreased the extent of lung edema, inflammation, and ferroptosis. In vitro, PX inhibited LPS-induced ferroptosis and inflammation in bronchial epithelial cell line BEAS-2B cells. The relationship between ferroptosis and inflammation was investigated. The results showed that ferroptosis mediated inflammation in LPS-treated BEAS-2B cells, and PX might ameliorate LPS-induced inflammation via inhibiting ferroptosis. Meanwhile, PX could upregulate Keap1-Nrf2/HO-1 pathway, and selective inhibition of Keap1-Nrf2/HO-1 pathway significantly abolished the anti-ferroptotic and anti-inflammatory functions of PX in LPS-treated cells. Conclusion PX attenuates ferroptosis against LPS-induced ALI via Keap1-Nrf2/HO-1 pathway, and is a promising novel therapeutic candidate for ALI.

scholarly journals Emodin alleviates LPS-induced inflammatory response in lung injury rat by affecting the function of neutrophils

2020 ◽  
Author(s):  
Hongxia Mei ◽  
Ying Tao ◽  
Tianhao Zhang ◽  
Feng Qi
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Response ◽  
Rat Model ◽  
Neutrophil Function ◽  
Life Threatening ◽  
Pulmonary Inflammatory Response ◽  
Anti Inflammatory ◽  
Factor Α ◽  
The Impact

Abstract Background: Acute lung injury (ALI) and/or acute respiratory distress syndrome (ARDS) are critical life-threatening syndromes characterized by the infiltration of a large number of neutrophils that lead to an excessive inflammatory response. Emodin (Emo) is a naturally occurring anthraquinone derivative and an active ingredient of Chinese medicine. It is believed to have anti-inflammatory effects. In this study, we examined the impact of Emo on the pulmonary inflammatory response and the neutrophil function in a rat model of lipopolysaccharide (LPS)-induced ALI.Results: Treatment with Emo protected rat against LPS-induced ALI. Compared to untreated rat, Emo-treated rat exhibited significantly ameliorated lung pathological changes and decreased tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). However, Emo has no protective effect on the rat model of acute lung injury with neutrophil deficiency. In addition, treatment with Emo enhanced the bactericidal capacity of LPS-induced neutrophils via the up-regulation of the ability of neutrophils to phagocytize bacteria and generate neutrophil extracellular traps (NETs). Emo also downregulated the neutrophil respiratory burst and the expression of reactive oxygen species (ROS) in LPS-stimulated neutrophils, alleviating the damage of neutrophils to surrounding tissues. Finally, Emo can accelerate the resolution of inflammation by promoting apoptosis of neutrophils. Conclusion: Our results provide the evidence that Emo could ameliorates LPS-induced ALI via its anti-inflammatory action by modulating the function of neutrophils. Emo may be a promising preventive and therapeutic agent in the treatment of ALI.

scholarly journals Intravenous Dexamethasone Attenuated Inflammation and Influenced Apoptosis of Lung Cells in an Experimental Model of Acute Lung Injury

2016 ◽  
pp. S663-S672 ◽  
Author(s):  
P. KOSUTOVA ◽  
P. MIKOLKA ◽  
S. BALENTOVA ◽  
M. ADAMKOV ◽  
M. KOLOMAZNIK ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Caspase 3 ◽  
Diffuse Alveolar Damage ◽  
Weight Ratio ◽  
Dry Weight ◽  
Inflammatory Cells ◽  
Lavage Fluid ◽  
Lung Edema ◽  
Edema Formation

Acute lung injury (ALI) is characterized by diffuse alveolar damage, inflammation, and transmigration and activation of inflammatory cells. This study evaluated if intravenous dexamethasone can influence lung inflammation and apoptosis in lavage-induced ALI. ALI was induced in rabbits by repetitive saline lung lavage (30 ml/kg, 9±3-times). Animals were divided into 3 groups: ALI without therapy (ALI), ALI treated with dexamethasone i.v. (0.5 mg/kg, Dexamed; ALI+DEX), and healthy non-ventilated controls (Control). After following 5 h of ventilation, ALI animals were overdosed by anesthetics. Total and differential counts of cells in bronchoalveolar lavage fluid (BAL) were estimated. Lung edema was expressed as wet/dry weight ratio. Concentrations of IL-1ß, IL-8, esRAGE, S1PR3 in the lung were analyzed by ELISA methods. In right lung, apoptotic cells were evaluated by TUNEL assay and caspase-3 immunohistochemically. Dexamethasone showed a trend to improve lung functions and histopathological changes, reduced leak of neutrophils (P<0.001) into the lung, decreased concentrations of pro-inflammatory IL-1β (P<0.05) and marker of lung injury esRAGE (P<0.05), lung edema formation (P<0.05), and lung apoptotic index (P<0.01), but increased immunoreactivity of caspase-3 in the lung (P<0.001). Considering the action of dexamethasone on respiratory parameters and lung injury, the results indicate potential of this therapy in ALI.

scholarly journals Effects of Roflumilast, a Phosphodiesterase-4 Inhibitor, on the Lung Functions in a Saline Lavage-Induced Model of Acute Lung Injury

2017 ◽  
pp. S237-S245 ◽  
Author(s):  
P. KOSUTOVA ◽  
P. MIKOLKA ◽  
M. KOLOMAZNIK ◽  
S. REZAKOVA ◽  
A. CALKOVSKA ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Weight Ratio ◽  
Lung Compliance ◽  
Pde4 Inhibitor ◽  
Lung Edema ◽  
Lung Weight ◽  
Edema Formation ◽  
Phosphodiesterase 4 ◽  
Respiratory Parameters

Acute lung injury (ALI) is associated with deterioration of alveolar-capillary lining and transmigration and activation of inflammatory cells. Whereas a selective phosphodiesterase-4 (PDE4) inhibitor roflumilast has exerted potent anti-inflammatory properties, this study evaluated if its intravenous delivery can influence inflammation, edema formation, and respiratory parameters in rabbits with a lavage-induced model of ALI. ALI was induced by repetitive saline lung lavage (30 ml/kg). Animals were divided into 3 groups: ALI without therapy (ALI), ALI treated with roflumilast i.v. (1 mg/kg; ALI+Rofl), and healthy ventilated controls (Control), and were ventilated for following 4 h. Respiratory parameters (blood gases, ventilatory pressures, lung compliance, oxygenation indexes etc.) were measured and calculated regularly. At the end of experiment, animals were overdosed by anesthetics. Total and differential counts of cells in bronchoalveolar lavage fluid (BAL) were estimated microscopically. Lung edema was expressed as wet/dry lung weight ratio. Treatment with roflumilast reduced leak of cells (P<0.01), particularly of neutrophils (P<0.001), into the lung, decreased lung edema formation (P<0.01), and improved respiratory parameters. Concluding, the results indicate a future potential of PDE4 inhibitors also in the therapy of ALI.

scholarly journals Dopamine inhibits pulmonary edema through the VEGF-VEGFR2 axis in a murine model of acute lung injury

2012 ◽  
Vol 302 (2) ◽  
pp. L185-L192 ◽  
Author(s):  
Pawan K. Vohra ◽  
Luke H. Hoeppner ◽  
Gunisha Sagar ◽  
Shamit K. Dutta ◽  
Sanjay Misra ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Vascular Permeability ◽  
Murine Model ◽  
Therapeutic Effects ◽  
Myeloperoxidase Activity ◽  
Protective Effects ◽  
Vascular Permeability Factor ◽  
Edema Formation

The neurotransmitter dopamine and its dopamine receptor D2 (D2DR) agonists are known to inhibit vascular permeability factor/vascular endothelial growth factor (VEGF)-mediated angiogenesis and vascular permeability. Lung injury is a clinical syndrome associated with increased microvascular permeability. However, the effects of dopamine on pulmonary edema, a phenomenon critical to the pathophysiology of both acute and chronic lung injuries, have yet to be established. Therefore, we sought to determine the potential therapeutic effects of dopamine in a murine model of lipopolysaccharide (LPS)-induced acute lung injury (ALI). Compared with sham-treated controls, pretreatment with dopamine (50 mg/kg body wt) ameliorated LPS-mediated edema formation and lowered myeloperoxidase activity, a measure of neutrophil infiltration. Moreover, dopamine significantly increased survival rates of LPS-treated mice, from 0–75%. Mechanistically, we found that dopamine acts through the VEGF-VEGFR2 axis to reduce pulmonary edema, as dopamine pretreatment in LPS-treated mice resulted in decreased serum VEGF, VEGFR2 phosphorylation, and endothelial nitric oxide synthase phosphorylation. We used D2DR knockout mice to confirm that dopamine acts through D2DR to block vascular permeability in our lung injury model. As expected, a D2DR agonist failed to reduce pulmonary edema in D2DR−/− mice. Taken together, our results suggest that dopamine acts through D2DR to inhibit pulmonary edema-associated vascular permeability, which is mediated through VEGF-VEGFR2 signaling and conveys protective effects in an ALI model.

scholarly journals Effect of different doses of dexmedetomidine on lung function and tissue cell apoptosis in a rat model of hyperoxic acute lung injury

2020 ◽  
Vol 19 (5) ◽  
pp. 1093-1098
Author(s):  
Yan Yang ◽  
Xian Qin ◽  
Chuangang Han ◽  
Yan Huang ◽  
Lei Jin ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Function ◽  
Lung Injury ◽  
Rat Model ◽  
Cell Apoptosis ◽  
Tissue Cell ◽  
High Dose ◽  
Apoptosis Index ◽  
Tnf Α ◽  
Different Doses

Purpose: To study the effect of different doses of dexmedetomidine on lung function and lung tissue cell apoptosis in a rat model of hyperoxic acute lung injury. Methods: Five groups of healthy male Sprague-Dawley rats were used: normal rats, untreated hyperoxic rats, and hyperoxic rats given 3 different doses of dexmedetomidine, with 20 rats in each group. The levels of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) were determined usingenzyme-linked immunosorbent assay (ELISA). Parietal paraffin cuts were taken from the right upper lobe for measurement of apoptosis using in situ terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and the apoptosis index was calculated. Results: At 24 and 48 h, the levels of IL-6 and TNF-α in the hyperoxia model group were significantly higher than those in the normal control group, and their levels in the middle- and high-dose groups were markedly lowered, relative to untreated hyperoxia rats (p < 0.05). Apoptosis index in the hyperoxia model rats significantly increased, relative to normal rats (p < 0.05). The apoptosis index in the mediumand high-dose groups decreased significantly (p < 0.05). Conclusion: Dexmedetomidine inhibits inflammatory responses caused by high concentration of oxygen inhalation, minimizes lung injury, improves lung function and inhibits lung apoptosis. Keywords: Dexmedetomidine, Hyperoxia, Acute lung injury, Lung function, Apoptosis

scholarly journals Reduction of Lung Inflammation, Oxidative Stress and Apoptosis by the PDE4 Inhibitor Roflumilast in Experimental Model of Acute Lung Injury

2018 ◽  
pp. S645-S654 ◽  
Author(s):  
P. KOSUTOVA ◽  
P. MIKOLKA ◽  
M. KOLOMAZNIK ◽  
S. BALENTOVA ◽  
M. ADAMKOV ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Cell Apoptosis ◽  
White Blood Cells ◽  
Thiobarbituric Acid ◽  
Lavage Fluid ◽  
Pde4 Inhibitor ◽  
Lung Edema ◽  
Edema Formation ◽  
Differential Counts

Damage of alveolar-capillary barrier, inflammation, oxidative injury, and lung cell apoptosis represent the key features of acute lung injury (ALI). This study evaluated if selective phosphodiesterase (PDE)-4 inhibitor roflumilast can reduce the mentioned changes in lavage-induced model of ALI. Rabbits with ALI were divided into 2 groups: ALI without therapy (A group) and ALI treated with roflumilast i.v. (1 mg/kg; A+R group). One group of healthy animals without ALI served as ventilated controls (C group). All animals were oxygen-ventilated for further 4 h. At the end of experiment, total and differential counts of cells in bronchoalveolar lavage fluid (BALF) and total and differential counts of white blood cells were estimated. Lung edema formation was assessed from determination of protein content in BALF. Pro-inflammatory cytokines (TNFα, IL-6 and IL-8) and markers of oxidation (3-nitrotyrosine, thiobarbituric-acid reactive substances) were detected in the lung tissue and plasma. Apoptosis of lung cells was investigated immunohistochemically. Treatment with roflumilast reduced leak of cells, particularly of neutrophils, into the lung, decreased concentrations of cytokines and oxidative products in the lung and plasma, and reduced lung cell apoptosis and edema formation. Concluding, PDE4 inhibitor roflumilast showed potent anti-inflammatory actions in this model of ALI.

scholarly journals Estradiol attenuates LPS-induced acute lung injury via induction of aquaporins AQP1 and AQP5

2021 ◽  
Vol 19 ◽  
pp. 205873922110491
Author(s):  
Xiaobo Wang ◽  
Xiuyun Zhou ◽  
Xiumei Xia ◽  
Yili Zhang
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Weight Ratio ◽  
Lung Edema ◽  
Therapeutic Effects ◽  
Lps Challenge ◽  
And Oxidative Stress

Background Acute lung injury (ALI) is associated with increased inflammation and oxidative stress. Estradiol is produced by the ovaries and is the most active hormone of estrogen. Our aim was to investigate whether estradiol contributes to protect against lipopolysaccharide (LPS)-induced ALI via induction of aquaporins AQP1 and AQP5 and the underlying mechanisms. Methods and results For induction of ALI, LPS was applied once by intraperitoneal injection in SD rats 14 days after oophorectomy. To assess the therapeutic effects of estradiol on LPS-induced ALI, estradiol was subcutaneously injected for 1 h prior to LPS challenge. Estradiol can significantly attenuate the lung edema reflected by decreasing wet-to-dry weight ratio and permeability of lung and total protein concentration of bronchial lavage fluid (BALF). Results of histological detection showed that estradiol attenuated the lung injury reflected by reducing edema, congestion, and thickening pulmonary septal of lung tissues. In addition, estradiol attenuated TNF-α, IL-1β, and IL-6 and oxidative stress in lung tissues. Estradiol was more effective than estradiol associated with ERα antagonist or ERβ antagonist in protecting against LPS-induced ALI in rats. Mechanistically, we investigate whether estradiol regulates the expression of AQP1 and AQP5 in lung tissues. Of interest, estradiol upregulates AQP1 and AQP5 mRNA and protein expression. Taken together, these results demonstrate that estradiol can increase the expression of AQP1 and AQP5, which plays a critical role in ameliorating oxidative stress and downregulating inflammatory responses induced by LPS.Conclusion Therefore, these findings strongly suggest that AQP1 and AQP5 mediate the anti-inflammatory and antioxidant effects of estradiol.

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