Effect of cyclooxygenase inhibition on ethchlorvynol-induced acute lung injury in dogs

1986 ◽  
Vol 61 (3) ◽  
pp. 1058-1064 ◽  
Author(s):  
R. S. Sprague ◽  
A. H. Stephenson ◽  
T. E. Dahms ◽  
A. J. Lonigro
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Vascular Reactivity ◽  
Arachidonic Acid Metabolism ◽  
Cyclooxygenase Inhibitors ◽  
Lung Water ◽  
Edema Formation ◽  
Cyclooxygenase Inhibition ◽  
Cyclooxygenase Activity ◽  
The Right

In anesthetized dogs ethchlorvynol (ECV, 9 mg/kg) was selectively administered into the right pulmonary circulation to produce unilateral acute lung injury (ALI) characterized by nonhydrostatic pulmonary edema and systemic hypoxemia. To investigate the hypothesis that products of cyclooxygenase activity are mediators of the arterial hypoxemia, but not the edema formation in this injury, animals were pretreated with one of two chemically dissimilar cyclooxygenase inhibitors, indomethacin (5 mg/kg), or ibuprofen (12.5 mg/kg), or vehicle (0.1 M sodium carbonate) prior to the administration of ECV. Pretreatment with either inhibitor prevented the ECV-induced systemic hypoxemia observed in animals pretreated with vehicle (P less than 0.01). Despite this protection of systemic oxygenation, there was no redistribution of blood flow to the uninjured lung following unilateral ECV administration. Cyclooxygenase inhibition prior to ALI did not attenuate the accumulation of lung water. In the ibuprofen group, left atrial pressure increased significantly following ECV administration. We conclude that a product(s) of cyclooxygenase-mediated arachidonic acid metabolism is responsible for the altered vascular reactivity and consequent systemic hypoxemia in this model, but that the edema formation following ECV is not related to cyclooxygenase activity. In addition, ibuprofen, administered prior to the induction of ALI, exhibits properties not shared by indomethacin but is not different in its capacity to attenuate hypoxemia or in its failure to limit edema formation.

Effect of eicosanoid inhibition on the development of pulmonary edema after acute lung injury

1996 ◽  
Vol 80 (3) ◽  
pp. 915-923 ◽  
Author(s):  
D. P. Schuster ◽  
A. H. Stephenson ◽  
S. Holmberg ◽  
P. Sandiford
Keyword(s):  
Acute Lung Injury ◽  
Oleic Acid ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Experimental Models ◽  
Nuclear Medicine Imaging ◽  
Lung Water ◽  
Edema Formation ◽  
Cyclooxygenase Inhibition ◽  
Positron Emission

In experimental models of acute lung injury, cyclooxygenase inhibition improves oxygenation, presumably by causing a redistribution of blood flow away from edematous lung regions. This effect on perfusion pattern could also reduce alveolar edema formation. On the other hand, pulmonary pressures usually increase after cyclooxygenase inhibition, an effect that could exacerbate edema accumulation. Therefore we tested the following hypothesis: the total accumulation of pulmonary edema in dogs during a 24- to 28-h period of observation after acute lung injury caused by oleic acid will be less in a group of animals treated with meclofenamate (n = 6) or with the thromboxane-receptor blocker ONO-3708 (n = 5) than in a group of animals treated with oleic acid alone (placebo, n = 6). Lung water concentrations (LWC), the regional pattern of pulmonary perfusion, and protein permeability were measured with the nuclear medicine imaging technique of positron emission tomography. After 24-28 h, LWC was significantly less (P < 0.05) in the ONO-3708 group than in the meclofenamate group (a similar trend was seen compared with the placebo group, P = 0.12). After 24-28 h, pulmonary arterial pressures were highest in the meclofenamate group. Regardless of group, the only significant correlation with the change in LWC was with the integral of pulmonary pressures over the 24- to 28-h period. The data suggest that thromboxane inhibition will reduce edema accumulation in acute lung injury but that this effect depends on reducing as much as possible the simultaneous development of pulmonary hypertension from other causes.

scholarly journals Effects of Antibiotic Therapy on Pseudomonas aeruginosa-Induced Lung Injury in a Rat Model

1999 ◽  
Vol 43 (10) ◽  
pp. 2389-2394 ◽  
Author(s):  
Erika J. Ernst ◽  
Satoru Hashimoto ◽  
Joseph Guglielmo ◽  
Teiji Sawa ◽  
Jean-Francois Pittet ◽  
...  
Keyword(s):  
Pseudomonas Aeruginosa ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Rat Model ◽  
In Vivo Model ◽  
Antibiotic Administration ◽  
Lung Water ◽  
Alveolar Epithelial ◽  
The Right

ABSTRACT The effect of antibiotics on the acute lung injury induced by virulent Pseudomonas aeruginosa PA103 was quantitatively analyzed in a rat model. Lung injury was induced by the instillation of PA103 directly into the right lower lobes of the lungs of anesthetized rats. The alveolar epithelial injury, extravascular lung water, and total plasma equivalents were measured as separate, independent parameters of acute lung injury. Four hours after the instillation of PA103, all the parameters were increased linearly depending on the dose of P. aeruginosa. Next, we examined the effects of intravenously administered antibiotics on the parameters of acute lung injury in d-galactosamine-sensitized rats. One hour after the rats received 107 CFU of PA103, an intravenous bolus injection of aztreonam (60 mg/kg) or imipenem-cilastatin (30 mg/kg) was administered. Despite an MIC indicating resistance, imipenem-cilastatin improved all the measurements of lung injury; in contrast, aztreonam, which had an MIC indicating sensitivity, did not improve any of the lung injury parameters. The antibiotics did not generate different quantities of plasma endotoxin; therefore, endotoxin did not appear to explain the differences in lung injury. This in vivo model is useful to quantitatively compare the efficacies of parenteral antibiotic administration on Pseudomonas airspace infections.

OKY-046 prevents increases in LTB4 and pulmonary edema in phorbol ester-induced lung injury in dogs

1992 ◽  
Vol 73 (6) ◽  
pp. 2493-2498 ◽  
Author(s):  
R. S. Sprague ◽  
A. H. Stephenson ◽  
A. J. Lonigro
Keyword(s):  
Arachidonic Acid ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Pulmonary Edema ◽  
Phorbol Ester ◽  
Leukotriene B4 ◽  
Myristate Acetate ◽  
Lung Water ◽  
Edema Formation ◽  
Synthase Inhibitor

Thromboxanes (Txs) were implicated as possible participants in the altered microvascular permeability of acute lung injury when the Tx synthase inhibitor, OKY-046, was reported to prevent pulmonary edema induced by phorbol myristate acetate (PMA). Recently, however, we found that OKY-046, at a dose just sufficient to block Tx synthesis in intact dogs, did not prevent PMA-induced pulmonary edema but rather merely reduced it modestly. The present study was designed to explore other mechanisms whereby OKY-046 might prevent PMA-induced pulmonary edema. The finding that 5-lipoxygenase (5-LO) metabolites of arachidonic acid were increased within the lung after PMA administration, coupled with the report that OKY-046 inhibited slow-reacting substance of anaphylaxis formation, permitted formulation of the hypothesis that OKY-046, at a dose in excess of that required to inhibit Tx synthesis, inhibits the formation of a product(s) of 5-LO and, thereby, prevents edema formation. In vehicle-pretreated pentobarbital-anesthetized male mongrel dogs (n = 4), PMA (20 micrograms/kg i.v.) increased pulmonary vascular resistance (PVR) from 4.4 +/- 0.3 to 26.3 +/- 8.8 mmHg.l-1 x min (P < 0.01) and extravascular lung water from 6.7 +/- 0.5 to 19.1 +/- 6.2 ml/kg body wt (P < 0.05). Concomitantly, both TxB2 and leukotriene B4 (LTB4) were significantly increased in the lung. Pretreatment with OKY-046 (100 mg/kg i.v., n = 8) prevented PMA-induced increases in TxB2, LTB4, and pulmonary edema formation but did not prevent the increase in PVR.(ABSTRACT TRUNCATED AT 250 WORDS)

Modulation of endoperoxide product levels and cyclophosphamide-induced injury by glutathione repletion

1989 ◽  
Vol 67 (6) ◽  
pp. 2316-2322 ◽  
Author(s):  
J. A. Cooper ◽  
W. W. Merrill
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Bronchoalveolar Lavage ◽  
Arachidonic Acid Metabolism ◽  
Glutathione Depletion ◽  
Enzymatic Reactions ◽  
Variable Degree ◽  
Cyclophosphamide Treatment ◽  
Dose Dependent

Glutathione is a tripeptide important in a number of diverse cellular functions including enzymatic reactions involved in prostaglandin endoperoxide metabolism. We have previously reported that cyclophosphamide administration to rats results in acute lung injury manifested by increased bronchoalveolar lavage albumin concentrations. In the current study we examine whether cyclophosphamide treatment affects pulmonary glutathione stores or bronchoalveolar endoperoxide metabolic product levels and whether these effects may be related to acute lung injury caused by the drug. We show that cyclophosphamide treatment causes a dose-dependent reduction in pulmonary glutathione stores 4 h after drug administration. In addition, acute lung injury as the result of cyclophosphamide can be abrogated by coadministration of oxothiazolidine carboxylate, an intracellular cysteine delivery system that also reverses pulmonary glutathione depletion induced by cyclophosphamide in our study. Finally, cyclophosphamide treatment reduces prostaglandin E2 concentrations in bronchoalveolar lavage and alveolar macrophage culture supernatant in a dose-dependent fashion and increases bronchoalveolar thromboxane concentrations in low dose-treated animals. These effects are reversed to a variable degree by coadministration of oxothiazolidine carboxylate. Our study suggests in vivo pulmonary arachidonic acid metabolism and cyclophosphamide-induced acute lung injury are modulated by cellular glutathione stores. These findings may have important implications for the treatment of acute lung injury.

A positron emission tomographic comparison of diffuse and lobar oleic acid lung injury

1988 ◽  
Vol 64 (6) ◽  
pp. 2357-2365 ◽  
Author(s):  
D. P. Schuster ◽  
J. W. Haller ◽  
M. Velazquez
Keyword(s):  
Oleic Acid ◽  
Lung Injury ◽  
Dorsal Region ◽  
Lung Water ◽  
Positron Emission ◽  
Transcapillary Escape Rate ◽  
Severity Of Injury ◽  
Water Accumulation ◽  
The Right ◽  
Lung Lobes

We tested whether severity of injury measured from the pulmonary transcapillary escape rate for transferrin (PTCER), lung water accumulation, and changes in regional pulmonary blood flow (PBF) would be similar after oleic acid (OA) injection into either all lung lobes or directly into the pulmonary artery feeding the left caudal lobe (LCL) only. Measurements were made with positron emission tomography. After 0.015 ml/kg OA was injected into the LCL (Lobar, n = 5), lung water increased in the left dorsal region from 37 +/- 5 to 50 +/- 8 ml/100 ml lung (P less than 0.05), PTCER was 533 +/- 59 10(-4)/min, and regional PBF decreased 62%. No significant change occurred in the uninjured right dorsal lung where PTCER was 85 +/- 32. In the left ventral region PTCER was 357 +/- 60, PBF decreased only 31%, and the increase in lung water was less (25 +/- 3 to 30 +/- 6). In contrast after 0.08 ml/kg OA was injected via the right atrium (Diffuse, n = 6), PTCER (283 +/- 94) was lower in the left dorsal region of this group than in the corresponding region of the Lobar group (P less than 0.05). The increase in lung water, however, was the same, but no change occurred in PBF distribution. These results indicate important differences between the two methods of causing lung injury with OA. After injury lung water accumulates primarily in dependent portions of lung and is not always accompanied by a decrease in regional PBF. These decreases, when they occur, may instead indicate severe vascular injury.

Repeated lung injury due to alpha-naphthylthiourea causes right ventricular hypertrophy in rats

1984 ◽  
Vol 56 (2) ◽  
pp. 388-396 ◽  
Author(s):  
N. S. Hill ◽  
R. F. O'Brien ◽  
S. Rounds
Keyword(s):  
Pulmonary Hypertension ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Right Ventricular ◽  
Ventricular Hypertrophy ◽  
Vascular Reactivity ◽  
Tween 80 ◽  
Left Ventricular ◽  
Right Ventricular Hypertrophy ◽  
Arterial Blood

Acute lung injury due to alpha-naphthylthiourea (ANTU) is associated with increased permeability edema, transient pulmonary hypertension, and increased vascular reactivity. We sought to determine whether repeated administration of ANTU caused right ventricular hypertrophy. Rats were injected weekly for 4 wk with ANTU or an equivalent volume of the vehicle Tween 80. Rats injected repeatedly with ANTU in doses of 5–10 mg/kg body wt had increased ratios of right ventricular to left ventricular plus septal weights. The right ventricular hypertrophy in ANTU-treated rats was associated with right ventricular systolic hypertension. Repeated injections of ANTU also caused transient pulmonary edema after each dose, as evidenced by increased wet-to-dry lung weight ratios after 4 h, which returned to normal by 24 h. Lungs isolated from ANTU-injected rats had greater pressor responses to hypoxia and to angiotensin II than lungs from Tween 80-injected rats. Pressure-flow curves of isolated lungs, arterial blood gases, and hematocrits were similar in rats treated repetitively with ANTU or Tween alone. Lung histology was also similar in ANTU and control lungs, as were measurements of arterial medial thickness and ratios of numbers of arteries/100 alveoli, indicating that substantial vascular remodeling had not occurred. Thus, four weekly ANTU injections in rats caused right ventricular hypertrophy, probably due to pulmonary hypertension. We speculate that the pulmonary hypertension was due, at least in part, to sustained vasoconstriction, which somehow resulted from repeated acute lung injury.

Eicosanoid balance and perfusion redistribution of oleic acid-induced acute lung injury

1992 ◽  
Vol 73 (5) ◽  
pp. 2126-2134 ◽  
Author(s):  
A. H. Stephenson ◽  
A. J. Lonigro ◽  
S. W. Holmberg ◽  
D. P. Schuster
Keyword(s):  
Acute Lung Injury ◽  
Oleic Acid ◽  
Lung Injury ◽  
Water Concentration ◽  
Dependent Lung ◽  
Lung Water ◽  
Tissue Concentrations ◽  
Tissue Samples ◽  
Positron Emission ◽  
Regional Lung

We have proposed that endogenous prostacyclin opposes the vasoconstriction responsible for redistribution of regional pulmonary blood flow (rPBF) away from areas of increased regional lung water concentration (rLWC) in canine oleic acid- (OA) induced acute lung injury (D. P. Schuster and J. Haller. J. Appl. Physiol. 69: 353–361, 1990). To test this hypothesis, we related regional lung tissue concentrations of 6-ketoprostaglandin (PG) F1 alpha and thromboxane (Tx) B2 in tissue samples obtained 2.5 h after administration of OA (0.08 ml/kg iv) to rPBF and rLWC measured by positron emission tomography. After OA only (n = 16), rLWC increased in dependent lung regions. Some animals responded to increased rLWC by redistribution of rPBF away from the most edematous regions (OA-R, n = 6), whereas others did not (OA-NR, n = 10). In another six animals, meclofenamate was administered after OA (OA-meclo). After OA, tissue concentrations of 6-keto-PGF1 alpha were greater than TxB2 in all groups, but concentrations of 6-keto-PGF1 alpha were not different between OA-R and OA-NR animals. TxB2 was increased in the dependent regions of animals in both OA-R and OA-NR groups compared with controls (no OA, n = 4, P < 0.05). The tissue TxB2/6-keto-PGF1 alpha ratio was smaller in controls and OA-NR in which no perfusion redistribution occurred than in OA-R and OA-meclo in which it did occur. This TxB2/6-keto-PGF1 alpha ratio correlated significantly with the magnitude of perfusion redistribution.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Acute lung injury inhibition by juglone in LPS induced sepsis mouse model involves Sirt1 activation

2020 ◽  
Vol 19 (5) ◽  
pp. 1001-1007
Author(s):  
Qiong Hu ◽  
Chunai Yang ◽  
Fenshuang Zheng ◽  
Hongdan Duan ◽  
Yangshan Fu ◽  
...  
Keyword(s):  
Acute Lung Injury ◽  
Lung Injury ◽  
Mouse Model ◽  
Inflammatory Cytokines ◽  
Alveolar Epithelial Cells ◽  
Control Group ◽  
Western Blot Assay ◽  
Edema Formation ◽  
Sirt1 Expression ◽  
Treatment Groups

Purpose: To investigate the effect of juglone on LPS induced lung injury in a mouse model and in TC 1cell line.Methods: Edema formation in lungs were measured by determination of lung wet/dry weight. Expressions of various proteins were assessed by western blot assay, while Sirt1 level was assessed using immunohistochemistry. Mice were randomly assigned to nine groups of 10 mice each: normal control, untreated and seven juglone treatment groups. Acute lung injury was induced in mice by injecting LPS (10 mg/kg) via intraperitoneal route (ip). The treatment groups were given 10, 20, 30, 40, 50, 60 and 100 μM of juglone, ip, respectively.Results: The levels of MMP-9, IL-6, IL-1β and iNOS were significantly higher in acute lung injury induced mice compared than the control group (p < 0.05). Treatment of the mice with juglone significantly decreased LPS-induced up-regulation of inflammatory cytokines in a dose-dependentmanner. The production of inflammatory cytokines was almost completely inhibited in the mice treated with 100 mg/kg dose of juglone, while treatment of the LPS-stimulated TC 1 cells with juglone upregulated the expression of Sirt1 mRNA. Down-regulation of Sirt1 expression by siRNA inhibited the effect of juglone on LPS-induced increase in inflammatory cytokine production.Conclusion: Juglone prevents lung injury in mice via up-regulation of Sirt1 expression. Therefore, juglone might be useful for the development of a treatment strategy for lung injury. Keywords: Inflammatory, Sirtuin, Edema, Cytokines, Lung injury, TC 1 lung alveolar epithelial cells, Sirt1

scholarly journals Propofol Activation of the Nrf2 Pathway Is Associated with Amelioration of Acute Lung Injury in a Rat Liver Transplantation Model

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Weifeng Yao ◽  
Gangjian Luo ◽  
Guosong Zhu ◽  
Xinjin Chi ◽  
Ailan Zhang ◽  
...  
Keyword(s):  
Liver Transplantation ◽  
Acute Lung Injury ◽  
Lung Injury ◽  
Water Content ◽  
High Dose ◽  
Lung Pathology ◽  
Lung Water ◽  
Sod Activity ◽  
Nrf2 Pathway ◽  
Lung Water Content

Objective. This study aimed to investigate whether propofol pretreatment can protect against liver transplantation-induced acute lung injury (ALI) and to explore whether Nrf2 pathway is involved in the protections provided by propofol pretreatment.Method. Adult male Sprague-Dawley rats were divided into five groups based on the random number table. Lung pathology was observed by optical microscopy. Lung water content was assessed by wet/dry ratio, and PaO2was detected by blood gas analysis. The contents of H2O2, MDA, and SOD activity were determined by ELISA method, and the expression of HO-1, NQO1, Keap1, and nuclear Nrf2 was assayed by western blotting.Results. Compared with saline-treated model group, both propofol and N-acetylcysteine pretreatment can reduce the acute lung injury caused by orthotopic autologous liver transplantation (OALT), decrease the lung injury scores, lung water content, and H2O2and MDA levels, and improve the arterial PaO2and SOD activity. Furthermore, propofol (but not N-acetylcysteine) pretreatment especially in high dose inhibited the expression of Keap1 and induced translocation of Nrf2 into the nucleus to further upregulate the expression of HO-1 and NQO1 downstream.Conclusion. Pretreatment with propofol is associated with attenuation of OALT-induced ALI, and the Nrf2 pathway is involved in the antioxidative processes.

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