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 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.

YiQiFuMai Lyophilized Injection Attenuates Sepsis-Induced Acute Lung Injury via TLR4/Src/VE-cadherin/p120-catenin Signaling Pathway

2020 ◽  
Author(s):  
Xue-wei Pan ◽  
Li-xuan Xue ◽  
Qian-liu Zhou ◽  
Jia-zhi Zhang ◽  
Yu-jie Dai ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Therapeutic Potential ◽  
Cecal Ligation ◽  
Inflammatory Cells ◽  
Underlying Mechanism ◽  
Lavage Fluid ◽  
Lung Edema ◽  
P120 Catenin

Abstract Background: Sepsis is a severe disorder leading to a clinically critical syndrome of multiple organ dysfunction syndrome. Most patients with sepsis will be associated with acute lung injury (ALI), which is an independent risk factors of organ failure and death in patients with sepsis at the same time. YiQiFuMai Lyophilized Injection (YQFM) is a modern traditional Chinese prescription preparation, which could ameliorate ALI induced by lipopolysaccharide (LPS) or fine particulate matter. The current study aimed to investigate the effect of YQFM on sepsis-induced ALI and the underlying mechanism.Methods: Male C57BL/6J mice were treated with cecal ligation and puncture (CLP) after tail intravenous injected with YQFM (1, 2 and 4 g/kg). The measurements of lung edema, evans blue leakage, myeloperoxidase content, inflammatory cells in bronchoalveolar lavage fluid, histopathological assay and expression of associated proteins were performed at 18 h after CLP.Results: The results illustrated that YQFM inhibited pulmonary edema and inflammatory response, thus ameliorated ALI in sepsis mice. Furthermore, the expression of TLR4 and phosphorylated Src was down-regulated, and the expression of p120-catenin and VE-cadherin was restored by YQFM administration.Conclusion: Our study suggested the therapeutic potential of YQFM on treating sepsis-induced ALI via regulating TLR4/Src/VE-cadherin/p120-catenin signaling pathway.

scholarly journals Inhibition of Lipopolysaccharide E. coli-induced acute lung injury by extracted Antidesma bunius (L.) Spreng fruits as compared to Fluticasone Propionate, a corticosteroid

2021 ◽  
Author(s):  
Maria Nilda Muñoz ◽  
Jennifer Lucero ◽  
Kimberly Stacy Hope Benzon ◽  
Jerica Isabel L. Reyes ◽  
Charina de Silva ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Fluticasone Propionate ◽  
Lung Injury ◽  
Murine Model ◽  
Lavage Fluid ◽  
Vehicle Control ◽  
Control Group ◽  
Lung Edema ◽  
Blue Dye ◽  
E Coli

The hallmark of Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is inflammation-induced alveolar-vascular barrier destruction and neutrophilic infiltration that leads to the formation of cytokines and oxygen radicals. The objective of the study is to investigate the protective and toxicological effects of Antidesma bunius (L.) Spreng [Bignay] in murine model of Lipopolysaccharide E. coli (LPS)-induced ALI and compared with Fluticasone Propionate (FP), a synthetic corticosteroid. We showed that extracted Bignay fruits have high amount of phenols, steroids and flavonoids but insignificant amount of heavy metals and aflatoxins. BALB/c mice of either sex were divided into 4 groups in the ALI mouse model; Group 1: vehicle control; Group 2: LPS alone; Group 3: Bignay + LPS; and Group 4: FP + LPS. Bignay and FP were administered via intraperitoneal injection while LPS was given intra-tracheally. Biomarkers of ALI such as total lung inflammatory cell count, total lung protein content, lung edema and interleukin-6  (IL-6) secretion were measured 24 hrs after vehicle control or LPS treatment. Compared to vehicle controls, LPS caused significant increased in all measured biomarkers of ALI in samples collected from bronchoalveolar lavage fluid and were significantly attenuated by Bignay fruit extract or FP. Pulmonary vascular leakage caused by LPS was also evaluated after injection with Evans blue dye, an indication of lung injury. Extracted Bignay fruits or FP when given to mice 2 hrs after LPS administration substantially decreased the pulmonary vascular leak. Our findings are the first evidence demonstrating the preventive and non-toxic effects of extracted Bignay fruits in a murine model of LPS-induced ALI. The results could be attributed to the presence of active secondary metabolites such as flavonoids, phenols and steroids. It is also evident that extracted Bignay fruits are as effective as FP, well-established steroid, in blocking the biomarkers of ALI caused by LPS.

scholarly journals Lung protective effect of Punicalagin on LPS-induced acute lung injury in mice

2022 ◽  
Author(s):  
Yibin Zeng ◽  
Hongying Zhao ◽  
Tong Zhang ◽  
Chao Zhang ◽  
Yanni He ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Protective Effect ◽  
Lung Tissue ◽  
White Blood Cells ◽  
Weight Ratio ◽  
Dry Weight ◽  
Lavage Fluid ◽  
Protein Levels ◽  
Anti Inflammation

Background: Punicalagin (Pun) is one of the main bioactive compounds in pomegranate peel, it possesses many properties, including antioxidant, anti-inflammation, and immunosuppressive activities. The study was aimed to investigate the protective effect and mechanisms of Pun on lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice. Methods and Results: Forty-eight BALB/c male mice were used to establish ALI by intratracheal-instilled 2.4 mg/kg LPS, the mice were randomly divided into model and Pun (10, 20, 40 mg/kg) groups. The other twelve mice were intratracheal-instilled same volume of water as control. After 2 h of receiving LPS, mice were administrated drug through intraperitoneal injection. Lung index, histopathological changes, white blood cells and biomarkers in bronchoalveolar lavage fluid (BALF) were analyzed. The protein expression of total and phosphor p65, IκBα, ERK1/2, JNK and p38 in lung tissue was detected. The result showed that Pun could reduce the lung index and wet/dry weight ratio, improve lung histopathological injury. In addition, Pun decreased the inflammation cells and regulated the biomarkers in BALF. Furthermore, Pun dose-dependently reduced the phosphor protein levels of p65, IκBα, ERK1/2, JNK and p38 in lung tissue, which exhibited that the effect of Pun related to MAPKs pathway. More importantly, there is no toxicity was observed in the acute toxicity study of Pun. Conclusion: Pun improves LPS-induced ALI mainly through its anti-inflammatory properties, which is associated with NF-κB and MAPKs signaling pathways. The study implied that Pun maybe a potent agent against ALI in future clinic.

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 A Peptide Inhibitor of Peroxiredoxin 6 Phospholipase A2 Activity Significantly Protects against Lung Injury in a Mouse Model of Ventilator Induced Lung Injury (VILI)

Antioxidants ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 925
Author(s):  
Aron B. Fisher ◽  
Chandra Dodia ◽  
Shampa Chatterjee
Keyword(s):  
Lung Injury ◽  
Tidal Volume ◽  
Thiobarbituric Acid ◽  
Lavage Fluid ◽  
Lung Damage ◽  
Protein Carbonyls ◽  
Lung Edema ◽  
Peroxiredoxin 6 ◽  
Ventilator Induced Lung Injury ◽  
Volume Ventilation

Ventilator induced lung injury (VILI) is a lung injury syndrome associated with mechanical ventilation, most frequently for treatment of Acute Lung Injury (ALI), and generally secondary to the use of greater than physiologic tidal volumes. To reproduce this syndrome experimentally, C57Bl/6 mice were intubated and ventilated with low (4 mL/Kg body weight) or high (12 mL/Kg) tidal volume for 6 h. Lung parameters with low volume ventilation were unchanged from non-ventilated (control) mice. High tidal volume ventilation resulted in marked lung injury with increased neutrophils in the bronchoalveolar lavage fluid (BALF) indicating lung inflammation, increase in both protein in BALF and lung dry/wet weight indicating lung edema, increased lung thiobarbituric acid reactive substances (TBARS), and 8-isoprostanes indicating lung lipid peroxidation, and increased lung protein carbonyls indicating protein oxidation. Either intratracheal or intravenous pretreatment of mice with a 9 amino acid peptide called peroxiredoxin 6 inhibitor peptide-2 (PIP-2) significantly reduced all parameters of lung injury by ~50–80%. PIP-2 inhibits NADPH oxidase type 2 (NOX2) activation. We propose that PIP-2 does not affect the mechanically induced lung damage component of VILI but does significantly reduce the secondary inflammatory component.

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 Anti-inflammatory Role of Trilobatin on Lipopolysaccharide-induced Acute Lung Injury through Activation of AMPK/GSK3β-Nrf2 Pathway

2020 ◽  
Keyword(s):  
Oxidative Stress ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Interleukin 1 ◽  
Dry Weight ◽  
Lavage Fluid ◽  
Pathological Process ◽  
Lung Edema ◽  
Necrosis Factor Alpha ◽  
Induce Lung Injury

Inflammation is essential for the pathological process of acute lung injury (ALI). Trilo-batin, a glycosylated dihydrochalcone can show anti-oxidative and anti-inflammation properties. This study aimed to explore whether trilobatin could suppress inflammation in lipopolysaccharide (LPS)-induced ALI. Firstly, mice were injected with trilobatin intraperitoneally, and then LPS was administered intranasally to induce lung injury. Data from analysis of lung edema and pathologic histology of lung tissues indicated that pretreatment with trilobatin alleviated LPS-induced histopathological changes and decreased wet-to-dry weight (W/D) ratio. Moreover, LPS-induced lung injury was attenuated post trilobatin treatment with reduced protein concentration, cell numbers, neutrophils and macrophages in BALF (bronchoalveolar lavage fluid). Secondly, trilobatin treatment decreased the protein level of tumor necrosis factor alpha (TNF-α) and interleukin-1 beta (IL-1β) thereby suppressing LPS-induced inflammation. LPS-induced oxidative stress was ameliorated following trilobatin treatment with decreased malondialdehyde (MDA) and increased glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT). Lastly, trilobatin decreased NF-κB phosphorylation and increased Nrf2 through up-regulation of AMPK and GSK3β phosphorylation. In conclusion, trilobatin repressed oxidative stress and inflammatory damage by ameliorating LPS-induced ALI through activation of AMPK/GSK3β-Nrf2 and inhibition of NF-κB.

scholarly journals Effects of Conventional Mechanical Ventilation Performed by Two Neonatal Ventilators on the Lung Functions of Rabbits with Meconium-Induced Acute Lung Injury

2016 ◽  
Vol 16 (3) ◽  
pp. 5-13
Author(s):  
D Mokra ◽  
P Mikolka ◽  
P Kosutova ◽  
M Kolomaznik ◽  
M Jurcek ◽  
...  
Keyword(s):  
Mechanical Ventilation ◽  
Acute Lung Injury ◽  
Gas Exchange ◽  
Lung Injury ◽  
Small Volume ◽  
Left Lung ◽  
Conventional Mechanical Ventilation ◽  
Lung Edema ◽  
Edema Formation ◽  
Lung Functions

AbstractSevere meconium aspiration syndrome (MAS) in the neonates often requires a ventilatory support. As a method of choice, a conventional mechanical ventilation with small tidal volumes (VT<6 ml/kg) and appropriate ventilatory pressures is used. The purpose of this study was to assess the short-term effects of the small-volume CMV performed by two neonatal ventilators: Aura V (Chirana Stara Tura a.s., Slovakia) and SLE5000 (SLE Ltd., UK) on the lung functions of rabbits with experimentally-induced MAS and to estimate whether the newly developed neonatal version of the ventilator Aura V is suitable for ventilation of the animals with MAS.In the young rabbits, a model of MAS was induced by an intratracheal instillation of a suspension of neonatal meconium (4 ml/kg, 25 mg/ml). After creating the model of MAS, the animals were ventilated with small-volume CMV (frequency 50/min, VT<6 ml/kg, inspiration time 50 %, fraction of inspired oxygen 1.0, positive end-expiratory pressure 0.5 kPa, mean airway pressure 1.1 kPa) performed by ventilator Aura V (Aura group, n=7) or ventilator SLE5000 (SLE group, n=7) for additional 4 hours. One group of animals served as healthy non-ventilated controls (n=6). Blood gases, oxygenation indexes, ventilatory pressures, lung compliance, oxygen saturation and total and differential white blood cell (WBC) count were regularly determined. After euthanizing the animals, a left lung was saline-lavaged and total and differential counts of cells in the bronchoalveolar lavage (BAL) fluid were determined. A right lung was used for estimation of lung edema formation (expressed as a wet/dry weight ratio) and for analysis of concentrations of pro-inflammatory cytokines (IL-1β, IL-8, TNF). The cytokines were measured also in the blood plasma taken at the end of experiment.Meconium instillation seriously worsened the gas exchange and induced inflammation and lung edema formation. In the Aura group, slightly lower concentrations of cytokines were found and better gas exchange early after creating the MAS model was observed. However, there were no significant differences in the respiratory parameters between the ventilated groups at the end of experiment (P>0.05).Concluding, the newly developed neonatal version of the ventilator Aura V was found to be fully comparable to widely used neonatal ventilator SLE5000. Results provided by Aura V in CMV ventilation of rabbits with meconium-induced acute lung injury suggest its great potential also for future clinical use, i.e. for ventilation of the neonates with MAS.

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