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.

Roles of neutrophil elastase and superoxide anion in leukotriene B4-induced lung injury in rabbit

1994 ◽  
Vol 76 (1) ◽  
pp. 91-96 ◽  
Author(s):  
K. Yoshimura ◽  
S. Nakagawa ◽  
S. Koyama ◽  
T. Kobayashi ◽  
T. Homma
Keyword(s):  
Superoxide Dismutase ◽  
Lung Injury ◽  
Capillary Pressure ◽  
Neutrophil Elastase ◽  
Superoxide Anion ◽  
Weight Ratio ◽  
Leukotriene B4 ◽  
Microvascular Permeability ◽  
Lung Edema ◽  
Fluid Filtration

The effects of a competitive neutrophil elastase (NE) inhibitor, ONO-5046, and a recombinant human superoxide dismutase on leukotriene B4 (LTB4)-induced polymorphonuclear leukocyte (PMN)-mediated increase in microvascular permeability in isolated non-blood-perfused rabbit lungs were studied. Pulmonary 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), respectively. Pulmonary capillary pressure was estimated by the double occlusion technique. NE activity in the perfusate was determined using a spectrophotometric method. The PMNs (2–3 x 10(8) cells) were added into the perfusate in all groups of lungs. Injection of LTB4 (5 micrograms) increased Kf and W/D without affecting pulmonary arterial or capillary pressure. The LTB4-induced lung injury was closely associated with the increase in NE activity in the perfusate. Infusion of ONO-5046 (1 or 10 mg.kg-1 x h-1) inhibited the LTB4-induced increases in Kf, W/D, and perfusate NE activity in a dose-dependent fashion. Infusion of recombinant human superoxide dismutase (80,000 U.kg-1 x h-1) attenuated the LTB4-induced increases in Kf and W/D, although it did not influence the elevation of perfusate NE activity induced by LTB4. These results suggest that both NE and superoxide anion play important roles in the LTB4-induced PMN-mediated increase in pulmonary microvascular permeability.

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.

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.

Recombinant human VEGF treatment transiently increases lung edema but enhances lung structure after neonatal hyperoxia

2006 ◽  
Vol 291 (5) ◽  
pp. L1068-L1078 ◽  
Author(s):  
Anette M. Kunig ◽  
Vivek Balasubramaniam ◽  
Neil E. Markham ◽  
Gregory Seedorf ◽  
Jason Gien ◽  
...  
Keyword(s):  
Lung Injury ◽  
Pulmonary Edema ◽  
Recovery Period ◽  
Weight Ratio ◽  
Lung Edema ◽  
Sprague Dawley ◽  
Lung Weight ◽  
Lung Structure ◽  
Neonatal Hyperoxia ◽  
Enos Protein

Recent studies suggest that VEGF may worsen pulmonary edema during acute lung injury (ALI), but, paradoxically, impaired VEGF signaling contributes to decreased lung growth during recovery from ALI due to neonatal hyperoxia. To examine the diverse roles of VEGF in the pathogenesis of and recovery from hyperoxia-induced ALI, we hypothesized that exogenous recombinant human VEGF (rhVEGF) treatment during early neonatal hyperoxic lung injury may increase pulmonary edema but would improve late lung structure during recovery. Sprague-Dawley rat pups were placed in a hyperoxia chamber (inspired O2 fraction 0.9) for postnatal days 2–14. Pups were randomized to daily intramuscular injections of rhVEGF165 (20 μg/kg) or saline (controls). On postnatal day 14, rats were placed in room air for a 7-day recovery period. At postnatal days 3, 14, and 21, rats were killed for studies, which included body weight and wet-to-dry lung weight ratio, morphometric analysis [including radial alveolar counts (RAC), mean linear intercepts (MLI), and vessel density], and lung endothelial NO synthase (eNOS) protein content by Western blot analysis. Compared with room air controls, hyperoxia increased pulmonary edema by histology and wet-to-dry lung weight ratios at postnatal day 3, which resolved by day 14. Although treatment with rhVEGF did not increase edema in control rats, rhVEGF increased wet-to-dry weight ratios in hyperoxia-exposed rats at postnatal days 3 and 14 ( P < 0.01). Compared with room air controls, hyperoxia decreased RAC and increased MLI at postnatal days 14 and 21. Treatment with VEGF resulted in increased RAC by 181% and decreased MLI by 55% on postnatal day 14 in the hyperoxia group ( P < 0.01). On postnatal day 21, RAC was increased by 176% and MLI was decreased by 58% in the hyperoxia group treated with VEGF. rhVEGF treatment during hyperoxia increased eNOS protein on postnatal day 3 by threefold ( P < 0.05). We conclude that rhVEGF treatment during hyperoxia-induced ALI transiently increases pulmonary edema but improves lung structure during late recovery. We speculate that VEGF has diverse roles in hyperoxia-induced neonatal lung injury, contributing to lung edema during the acute stage of ALI but promoting repair of the lung during recovery.

Endothelin-1 potentiates leukotoxin-induced edematous lung injury

1995 ◽  
Vol 79 (4) ◽  
pp. 1106-1111 ◽  
Author(s):  
T. Ishizaki ◽  
K. Shigemori ◽  
T. Nakai ◽  
S. Miyabo ◽  
M. Hayakawa ◽  
...  
Keyword(s):  
Lactate Dehydrogenase ◽  
Lung Injury ◽  
Venous Pressure ◽  
Weight Ratio ◽  
Lung Edema ◽  
Lung Weight ◽  
Lactate Dehydrogenase Activity ◽  
Endothelin 1 ◽  
Endothelin A Receptor ◽  
Endothelin A

We tested the hypothesis that leukotoxin (Lx), a cytochrome P-450-dependent linoleate product of leukocytes, can stimulate the release of endothelin-1 (ET-1) from the lung and further that exogenous ET-1 synergizes with Lx to produce edematous lung injury. In isolated rat lungs perfused with Earle's balanced salt solution, Lx (10 mumol) alone caused lung edema and increased the perfusate and lung tissue ET-1 levels. The combination of ET-1 (5 nM) and Lx (5 mumol), at concentrations that by themselves did not increase wet lung weight, significantly increased wet lung weight, wet-to-dry lung weight ratio, as well as the lung effluent lactate dehydrogenase activity. Pretreatment with BQ-123 (5 x 10(-6) M), an endothelin A receptor antagonist that significantly attenuated the ET-1 (5 nM)-induced increase in pulmonary arterial pressure (Ppa) and pulmonary capillary pressure (Ppc), suppressed the edematous lung injury generated by the combination of ET-1 and Lx, suggesting that the edema-enhancing effect of ET-1 in Lx-treated lungs occurred through endothelin A receptor-dependent elevation of Ppa and Ppc. Elevation of the pulmonary venous pressure in Lx-treated lungs (13.5 cmH2O) mimicked the effect of ET-1 on Ppa and Ppc and produced a degree of lung edema that was comparable to that after combined ET-1 + Lx treatment but without increase in the perfusate lactate dehydrogenase. These data support the idea that ET-1 and Lx promote lung edema in a synergistic fashion.

Fructose 1,6-diphosphate augments paraquat injury in isolated dog lungs

1991 ◽  
Vol 71 (5) ◽  
pp. 1830-1835 ◽  
Author(s):  
T. Shibamoto ◽  
J. C. Parker
Keyword(s):  
Free Radicals ◽  
Vascular Permeability ◽  
Cyclic Oxidation ◽  
Oxygen Free Radicals ◽  
Weight Ratio ◽  
Reduction Reaction ◽  
Microvascular Permeability ◽  
Lung Weight ◽  
Activated Neutrophils ◽  
Pretreated Group

Paraquat (PQ; 1,1'-dimethyl-4,4′-bipyridylium dichloride), a widely used herbicide, causes pulmonary edema by a cyclic oxidation and reduction reaction with oxygen molecules with the production of oxygen free radicals. Because fructose 1,6-diphosphate (FDP) has recently been shown to inhibit the generation of oxygen free radicals by activated neutrophils, we determined the effects of FDP on PQ-induced increase in microvascular permeability in isolated blood-perfused dog lungs. Vascular permeability was assessed using the capillary filtration coefficient (Kf,c) and isogravimetric capillary pressure (Pc,i). There was no change in these variables over 5 h in the control lungs treated with saline (n = 5). A significant increase in Kf,c and a decrease in Pc,i, both of which indicated increased vascular permeability, were observed at 5 h of perfusion with 4 x 10(-3) M PQ (n = 5). Unexpectedly, an increase in microvascular permeability occurred within 4 h after administration of PQ in the lungs that were pretreated with FDP (2.7–14.2 mM, n = 6). Moreover the increases of Kf,c in the FDP-pretreated lungs were significantly greater than those in the lungs treated with PQ alone. Also, the final-to-initial lung weight ratio of the FDP-pretreated group was greater than those of the other groups. Thus the FDP dose used in the present study accentuated rather than prevented the PQ lung injury.

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.

Paraquat-induced lung injury: prevention by N-tert-butyl-alpha-phenylnitrone, a free-radical spin-trapping agent

1992 ◽  
Vol 262 (2) ◽  
pp. L147-L152
Author(s):  
T. Sata ◽  
E. Kubota ◽  
H. P. Misra ◽  
M. Mojarad ◽  
H. Pakbaz ◽  
...  
Keyword(s):  
Free Radical ◽  
Lung Injury ◽  
Guinea Pig ◽  
Weight Ratio ◽  
Spin Trapping ◽  
Lung Weight ◽  
Paramagnetic Resonance ◽  
Arterial Perfusion ◽  
Tert Butyl ◽  
Trapping Agent

The herbicide paraquat causes lung injury that is believed to be oxygen-radical mediated. To further characterize this injury and explore new methods of preventing it, we used the spin-trapping agent N-tert-butyl-alpha-phenylnitrone (PBN) to identify the paraquat radical in lung tissue and to reduce the injury resulting from the subsequent generation of reactive oxygen species. The formation of a paraquat free radical by guinea pig lung was detected under anaerobic conditions by electron paramagnetic resonance spectrometry. Infused (25, 50, or 100 mg/kg) into guinea pig lungs (perfused at constant flow with Krebs solution containing 4% bovine serum albumin and ventilated with 95% O2-5% CO2), paraquat produced dose-dependent increases in peak airway pressure (Paw), mean pulmonary arterial perfusion pressure (Ppa), and wet-to-dry (W/D) lung weight ratio. At 100 mg/kg, paraquat increased Paw by 589.6 +/- 59.8% (mean +/- SE, n = 8) and W/D ratio from 5.33 +/- 0.07 to 6.29 +/- 0.11 (P less than 0.001). Pulmonary vascular leak index increased from 0.40 +/- 0.09 to 1.96 +/- 0.45 (P less than 0.02), without changes in pulmonary microvascular pressure. Perfusate concentrations of thromboxane B2 and 6-ketoprostaglandin F1 alpha increased, but indomethacin did not reduce the injury. PBN (2.3 mM) markedly attenuated all evidence of lung injury, which was also reduced by catalase, mannitol, ethanol, and vitamin E.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Role of neutrophils in xanthine/xanthine oxidase-induced oxidant injury in isolated rabbit lungs

1999 ◽  
Vol 87 (6) ◽  
pp. 2319-2325 ◽  
Author(s):  
Masashi Kishi ◽  
Lois F. Richard ◽  
Robert O. Webster ◽  
Thomas E. Dahms
Keyword(s):  
Lung Injury ◽  
Xanthine Oxidase ◽  
Neutrophil Elastase ◽  
Weight Ratio ◽  
Dry Weight ◽  
Neutrophil Elastase Inhibitor ◽  
Fluid Filtration ◽  
Elastase Inhibitor ◽  
Pulmonary Arterial

Reactive oxygen species have been shown to play an important role in the pathogenesis of lung injury. This study was designed to clarify the role of intrapulmonary neutrophils in the development of xanthine/xanthine oxidase (X/XO)-induced lung injury in isolated buffer-perfused rabbit lungs. We measured microvascular fluid filtration coefficient ( K f) and wet-to-dry weight ratio to assess lung injury. X/XO induced a significant increase in K f and wet-to-dry weight ratio in neutrophil-replete lungs, whereas the lung injury was attenuated in neutrophil-depleted lungs. A neutrophil elastase inhibitor, ONO-5046, also attenuated the lung injury. In addition, X/XO induced a transient pulmonary arterial pressure (Ppa) increase. The thromboxane inhibitor OKY-046 attenuated the Ppa increase but did not alter the increase in permeability. Neutrophil depletion reduced the K f increase but had no effect on the Ppa increase. These results suggest that intrapulmonary neutrophils activated by X/XO play a major role in development of the lung injury, that neutrophil elastase is involved in the injury, and that the X/XO-induced vasoconstriction is independent of intrapulmonary neutrophils.

scholarly journals Alda-1 Prevents Pulmonary Epithelial Barrier Dysfunction following Severe Hemorrhagic Shock through Clearance of Reactive Aldehydes

2019 ◽  
Vol 2019 ◽  
pp. 1-9 ◽  
Author(s):  
Tianfeng Hua ◽  
Min Yang ◽  
Yangyang Zhou ◽  
Limin Chen ◽  
Huimei Wu ◽  
...  
Keyword(s):  
Lung Injury ◽  
Hemorrhagic Shock ◽  
Rat Model ◽  
Weight Ratio ◽  
Dry Weight ◽  
Epithelial Barrier ◽  
Lung Edema ◽  
Epithelial Tissue ◽  
Diffuse Infiltration ◽  
Reactive Aldehydes

Severe hemorrhagic shock and resuscitation (HS/R) can lead to lung injury, resulting in respiratory insufficiency. We investigated whether treatment with Alda-1, an ALDH2 activator, decreased lung injury induced by severe HS/R in a rat model. Male Sprague-Dawley rats were randomized into three groups, hemorrhagic shock + placebo, hemorrhagic shock + Alda-1, and sham. All animals were heparinized, and then 50% of the total calculated blood volume was collected over 60 minutes. After 40 minutes of hemorrhagic shock, animals were reinfused with the shed blood over 40 minutes and then observed for an additional 2 hours. Concentrations of 4-HNE, TNF-α, IL-6, and ALDH2 activity were detected; lung injury and lung wet-to-dry weight ratios were assessed. Expression of occludin and ZO-1 proteins in lung tissues was also determined. At 2 hours after resuscitation, lung injury was significantly reduced and the wet-to-dry weight ratio was notably decreased in the Alda-1 group compared with placebo (P<0.05). Alda-1 treatment also significantly increased the activity of ALDH2 and decreased the levels of toxic 4-HNE (P<0.05). In the Alda-1 group, IL-6 and TNF-α were dramatically decreased compared with placebo-treated animals (P<0.05). Expression of occludin and ZO-1 proteins was significantly decreased in the placebo group compared with the Alda-1 group (P<0.05). Thus, in a rat model of severe HS/R, treatment with Alda-1 increased the activity of ALDH2, significantly accelerated the clearance of reactive aldehydes, and concomitantly alleviated lung injury through improvement of pulmonary epithelial barrier integrity resulting in decreased alveolar epithelial tissue permeability, lung edema, and diffuse infiltration of inflammatory cells.

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