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 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.

Hypoxia enhances unilateral lung injury by increasing blood flow to the injured lung

1987 ◽  
Vol 63 (6) ◽  
pp. 2516-2523 ◽  
Author(s):  
K. Takeda ◽  
M. J. Knapp ◽  
W. G. Wolfe ◽  
J. D. Crapo
Keyword(s):  
Blood Flow ◽  
Lung Injury ◽  
Left Lung ◽  
Weight Ratio ◽  
Normal Lung ◽  
Lung Edema ◽  
Lung Weight ◽  
Edema Formation ◽  
Concomitant Decrease ◽  
Injured Lung

We hypothesized that in unilateral lung injury, bilateral hypoxic ventilation would induce vasoconstriction in the normal lung, redirect blood flow to the injured lung, and cause enhanced edema formation. Unilateral left lung injury was induced by intrabronchial instillation of 1.5 ml/kg of 0.1 N HCl. After HCl injury, blood flow to the injured left lung decreased progressively from 0.70 +/- 0.04 to 0.37 +/- 0.05 l/min and percent of flow to the injured left lung (QL/QT) decreased from 37.7 +/- 2.2 to 23.6 +/- 2.2% at 240 min. Exposure to hypoxia (12% O2) for three 10-min episodes did not affect QL/QT in normal animals, but after unilateral HCl injury, it caused blood flow to the injured left lung to increase significantly. A concomitant decrease in blood flow occurred to the noninjured right lung, resulting in a significant increase in QL/QT. The enhanced blood flow to the injured lung was associated with a significant increase in the wet-to-dry lung weight ratio in the dependent regions of the injured lung. These findings demonstrate that in unilateral HCl-induced lung injury, transient hypoxia can enhance blood flow to the areas of injury and increase lung edema formation.

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.

Leukotriene B4 induces lung injury in the rabbit: role of neutrophils and effect of indomethacin

1993 ◽  
Vol 74 (5) ◽  
pp. 2174-2179 ◽  
Author(s):  
K. Yoshimura ◽  
S. Nakagawa ◽  
S. Koyama ◽  
T. Kobayashi ◽  
T. Homma
Keyword(s):  
Arachidonic Acid ◽  
Lung Injury ◽  
Weight Ratio ◽  
Leukotriene B4 ◽  
Arachidonic Acid Metabolism ◽  
Microvascular Permeability ◽  
Lung Edema ◽  
Lung Weight ◽  
Fluid Filtration ◽  
Pmn Leukocytes

The effects of exogenous leukotriene B4 (LTB4) on the pulmonary microvascular permeability and the roles of polymorphonuclear (PMN) leukocytes and the cyclooxygenase products of arachidonic acid in the microvascular response to LTB4 in the isolated non-blood-perfused rabbit lungs were studied. Microvascular permeability and lung edema were evaluated by use of the fluid filtration coefficient (Kf) and the wet-to-dry lung weight ratio (W/D ratio), respectively. Pulmonary capillary pressure was estimated by the double occlusion technique. We studied five groups of lungs: lungs were given 1) both PMN leukocytes and a bolus injection of LTB4 (5 micrograms, n = 6), 2) LTB4 alone (n = 5), 3) PMN leukocytes alone (n = 5), 4) control vehicles (n = 5), or 5) indomethacin (40 micrograms/ml) before PMN leukocytes and LTB4 (n = 6). We observed that LTB4 increased Kf and W/D ratio in the presence of PMN leukocytes in the perfusate without affecting the pulmonary arterial and capillary pressures. Neither LTB4 alone nor PMN leukocytes alone produced changes in Kf and W/D ratio. Indomethacin failed to inhibit the LTB4-induced increases in Kf and W/D ratio. These results suggest that LTB4 produces lung injury that is dependent on PMN leukocytes but not on the cyclooxygenase pathway of arachidonic acid metabolism.

Shen-Fu Attenuates Endotoxin-Induced Acute Lung Injury in Rats

2006 ◽  
Vol 34 (04) ◽  
pp. 613-621 ◽  
Author(s):  
Yanning Qian ◽  
Jie Sun ◽  
Zhongyun Wang ◽  
Jianjun Yang
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Pulmonary Inflammation ◽  
Weight Ratio ◽  
Dry Weight ◽  
Nf Kappa B ◽  
Lung Weight ◽  
Tnf Α ◽  
Male Wistar Rats

Sepsis is associated with the highest risk of progression to acute lung injury or acute respiratory distress syndrome. Shen-Fu has been advocated to treat many severely ill patients. Our study was designed to investigate the effect of Shen-Fu on endotoxin-induced acute lung injury in vivo. Adult male Wistar rats were randomly divided into 6 groups: controls; those challenged with endotoxin (5 mg/kg) and treated with saline; those challenged with endotoxin (5 mg/kg) and treated with Shen-Fu (1 mg/kg); those challenged with endotoxin (5 mg/kg) and treated with Shen-Fu (10 mg/kg); increase challenged with endotoxin (5 mg/kg) and treated with Shen-Fu (100 mg/kg); saline injected and treated with Shen-Fu (100 mg/kg). TNF-α, IL-6, and NF-kappa B were investigated in the lung two hours later. Myeloperoxidase (MPO) activity and wet/dry weight ratio were investigated six hours later. Intravenous administration of endotoxin provoked significant lung injury, which was characterized by increment increase of MPO activity and wet/dry lung weight ratio, and TNF-α and IL-6 expression and NF-kappa B activation. Shen-Fu (10,100 mg/kg) decreased MPO activity and wet/dry weight ratio and inhibited TNF-α and IL-6 production, endotoxin-induced NF-kappa B activation. Our results indicated that Shen-Fu at a dose of higher than 10 mg/kg inhibited endotoxin-induced pulmonary inflammation in vivo.

Therapeutic Effects of Baicalin on Lipopolysaccharide-Induced Acute Lung Injury in Rats

2008 ◽  
Vol 36 (02) ◽  
pp. 301-311 ◽  
Author(s):  
Kun-Lun Huang ◽  
Chien-Sheng Chen ◽  
Ching-Wang Hsu ◽  
Min-Hui Li ◽  
Hung Chang ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Weight Ratio ◽  
Histological Finding ◽  
Neutrophil Infiltration ◽  
Lavage Fluid ◽  
Blue Dye ◽  
Therapeutic Effects ◽  
Lung Weight ◽  
Lactate Dehydrogenase Activity

Baicalin is a flavonoid present in many traditional Chinese medicines. A number of studies show that baicalin has anti-inflammatory actions and protects against a variety of tissue and organ injuries. The effect of baicalin in lipopolysaccharide (LPS)-induced acute lung injury is not well studied. In this study, typically acute lung injury was induced in rat by intratracheal injection of LPS, which increased lactate dehydrogenase activity and protein content in bronchoalveolar lavage fluid, wet/dry lung weight ratio, Evan's blue dye leakage, and neutrophil infiltration. Baicalin (20 mg/kg) was administrated 1 hour before or 30 min after LPS injection. Both pre and post-treatment with baicalin attenuated the increase of these parameters and improved histological finding. Our results suggest that baicalin has a therapeutic effect on LPS-induced acute lung injury.

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 Effects of Nitric Oxide Donor on the Lung Functions in a Saline Lavage-Induced Model of ARDS

2019 ◽  
pp. S265-S273 ◽  
Author(s):  
P. KOSUTOVA ◽  
P. MIKOLKA ◽  
S. BALENTOVA ◽  
M. ADAMKOV ◽  
D. MOKRA
Keyword(s):  
Nitric Oxide ◽  
Lung Injury ◽  
Cell Count ◽  
Nitric Oxide Donor ◽  
Control Group ◽  
Lung Edema ◽  
Edema Formation ◽  
Respiratory Parameters ◽  
Lung Functions ◽  
Saline Lavage

Acute respiratory distress syndrome (ARDS) is characterized by acute hypoxemia, neutrophil-mediated inflammation, and lung edema formation. Whereas lung damage might be alleviated by nitric oxide (NO), goal of this study was to evaluate if intratracheal NO donor S-nitroso-N-acetylpenicillamine (SNAP) can positively influence the lung functions in experimental model of ARDS. New Zealand rabbits with respiratory failure induced by saline lavage (30 ml/kg, 9±3 times) were divided into: ARDS group without therapy, ARDS group treated with SNAP (7 mg/kg i.t.), and healthy Control group. During 5 h of ventilation, respiratory parameters (blood gases, ventilatory pressures) were estimated. After anesthetics overdosing, left lung was saline-lavaged and cell count, cell viability and protein content in bronchoalveolar lavage fluid (BALF) were measured. Right lung tissue was used for estimation of wet/dry weight ratio, concentration of NO metabolites, and histomorphological investigation. Repetitive lung lavage induced lung injury, worsened gas exchange, and damaged alveolar-capillary membrane. Administration of SNAP reduced cell count in BALF, lung edema formation, NO metabolites, and histopathological signs of injury, and improved respiratory parameters. Treatment with intratracheal SNAP alleviated lung injury and edema and improved lung functions in a saline-lavaged model of ARDS suggesting a potential of NO donors also for patients with ARDS.

Early changes in lungs of rats exposed to 70 per cent O2

1975 ◽  
Vol 38 (1) ◽  
pp. 136-142 ◽  
Author(s):  
R. A. Redding ◽  
T. Arai ◽  
W. H. Douglas ◽  
H. Tsurutani ◽  
J. Overs
Keyword(s):  
Lung Surfactant ◽  
Weight Ratio ◽  
Lung Compliance ◽  
Lung Edema ◽  
Lung Weight ◽  
Morphological Alterations ◽  
Loop Area ◽  
Protein Contamination ◽  
Hysteresis Loop Area ◽  
Alveolar Capillary

Sixty-six respiratory disease-free rats, divided into four groups, were exposed to 70% O2 for 1.5, 4, 7, and 10 days and compared with 31 littermates exposed to room air for equal times. Lung surfactant was separated from macrophages and potential serum protein contamination by differential centrifugation of endobronchial washings. In the O2-exposed rats, developing lung edema was demonstrated by decreased dried/fresh lung weight ratio and increased alveolar protein content at 7 and 10 days. At 7 days, lung compliance slope and hysteresis loop area decreased, while critical opening pressure increased. Ultrastructurally, the only abnormality seen was an irregular widening of the alveolar capillary basement membrane on day 10. Alveolar lecithin content decreased slightly during the 10 days exposure, but remained highly saturated, whereas whole lung lecithin content increased. These results suggest that the initial mechanical and morphological alterations in rats exposed to 70% O2 are related to lung edema and are not dependent upon lung surfactant alterations.

Prevention of interleukin 2-induced acute lung injury in guinea pigs by pentoxifylline

1989 ◽  
Vol 67 (6) ◽  
pp. 2432-2437 ◽  
Author(s):  
A. Ishizaka ◽  
J. R. Hatherill ◽  
H. Harada ◽  
M. Yonemaru ◽  
H. Hoffmann ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Guinea Pigs ◽  
Interleukin 2 ◽  
Weight Ratio ◽  
Saline Control ◽  
Control Group ◽  
Lung Water ◽  
Lung Weight ◽  
Cell Counts

We administered recombinant human interleukin 2 (IL-2) to guinea pigs to investigate whether IL-2 would cause acute lung injury. In addition, we examined the effects of pentoxifylline (PTXF) on IL-2-induced acute lung injury. Three groups of animals were studied over a period of 8 h. The saline control group was injected intravenously with 2 ml of pyrogen-free saline; the IL-2 group was injected intravenously with 4 X 10(6) U/kg recombinant IL-2; and the IL-2-PTXF group was injected with a 20-mg/kg bolus of PTXF followed by a continuous infusion (6 mg.kg-1.h-1) started 60 min before injection of 4 X 10(6) U/kg IL-2. Lung water (wet-to-dry lung weight ratio), the concentration ratios of 125I-albumin in bronchoalveolar lavage (BAL) fluid and lung tissue compared with plasma (125I-albumin BAL-to-plasma, 125I-albumin lung-to-plasma), and cell counts in BAL fluid were examined. An intravenous injection of IL-2 caused an increased lung water (P less than 0.01), an increased 125I-albumin lung-to-plasma ratio (P less than 0.05), and a significant increase in the absolute number of neutrophils, lymphocytes, and macrophages in BAL fluid compared with the saline control. In contrast, the PTXF-pretreated group did not demonstrate IL-2-induced acute lung injury (lung water, 125I-albumin lung-to-plasma) or increased accumulation of neutrophils, lymphocytes, and macrophages in the BAL. These data suggest a possible role for PTXF in attenuating the side effects of IL-2.

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