Lipid Peroxidation In Lung Tissue Research Articles

Posttreatment with Eicosatetraynoic Acid Decreases Lung Edema in Guinea Pigs Exposed to Phosgene: The Role of Leukotrienes

Acetylenic acids such as 5,8,11,14-eicosatetraynoic acid (ETYA), have been shown to be effective in preventing pulmonary edema formation (PEF). In phosgene-exposed guinea pigs, we examined the effects of ETTA on PEF, measured as real time lung weight gain (Iwg). Pulmonary artery pressure (Ppa), airway pressure (Paw), perfusate leukotrienes (LT) C4/D4/E4/B4, and lung tissue lipid peroxidation (TBARS) were measured using the isolated, buffer-perfused lung model. Guinea pigs were challenged to 175 mg/m3 (44 ppm) phosgene for 10 minutes giving a concentration × time product of 1750 mg. min/m3 (437 ppm.min). Five minutes after removal from the exposure chamber, guinea pigs were treated, ip, with 200 µL of 100 µM ETYA. 200 µL of 50 µM ETYA was added to the perfusate every 40 minutes, beginning at 60 minutes after start of exposure (t = 0). There were four groups in this study: air-treated, phosgene-exposed, ETYA-posttreated + phosgene, and ETYA-posttreated + air ETYA-posttreated + phosgene guinea pigs had significantly lower Ppa (P = .006), Paw (P = .009), and Iwg (P = .016) compared with phosgene-exposed animals. Phosgene exposure reduced LTB4 compared with air-treated controls (P=.09). ETYA-posttreatment + phosgenemx had significantly increased perfusate LTB4 (P = .0006) compared with phosgene exposure only group. Total perfusate, LTC4 + LTD4 + LTE4,was not different between phosgene-exposed, air-treated or ETYA-posttreatment + phosgene over time. Posttreatment with ETYA significantly lowered TBARS formation, 206 ± 13 versus 285±23 nmol/mg protein (P = .016), compared with phosgene-exposed lungs. Paradoxically,ETYA posttreatment decreased PEF and lipid peroxidation, but increased sulfidopeptide LT release from the lung during perfusion. We conclude that LTC4/D4/E4, and B4, May-June play different roles than previously thought for PEF in the isolated perfused lung model.

Augmentation of pulmonary reactions to quartz inhalation by trace amounts of iron-containing particles.

Fracturing quartz produces silica-based radicals on the fracture planes and generates hydroxyl radicals (.OH) in aqueous media. .OH production has been shown to be directly associated with quartz-induced cell damage and phagocyte activation in vitro. This .OH production in vitro is inhibited by desferrioxamine mesylate, an Fe chelator, indicating involvement of a Fenton-like reaction. Our objective was to determine if Fe contamination increased the ability of inhaled quartz to cause inflammation and lung injury. Male Fischer 344 rats were exposed 5 hr/day for 10 days to filtered air, 20 mg/m3 freshly milled quartz (57 ppm Fe), or 20 mg/m3 freshly milled quartz contaminated with Fe (430 ppm Fe). High Fe contamination of quartz produced approximately 57% more reactive species in water than quartz with low Fe contamination. Compared to inhalation of quartz with low Fe contamination, high Fe contamination of quartz resulted in increases in the following responses: leukocyte recruitment (537%), lavageable red blood cells (157%), macrophage production of oxygen radicals measured by electron spin resonance or chemiluminescence (32 or 90%, respectively), nitric oxide production by macrophages (71%), and lipid peroxidation of lung tissue (38%). These results suggest that inhalation of freshly fractured quartz contaminated with trace levels of Fe may be more pathogenic than inhalation of quartz alone.

The development of free radical processes in experimental bronchospasm. Effect of the bronchodilator preparation troventol

The development of bronchospasm is shown to be accompanied by lipid peroxidation (LPO) activation; 3-fold and 8-fold rises of malondialdehyde concentration are found in homogenate of lung from sensitized animals and from animals provoked with egg albumin antigen, respectively. The use of luminol-dependent chemiluminescence (CL) reveals that in sensitized rats the production of oxygen free radicals is increased by alveolar macrophages activated with phorbol myristate acetate. Troventol at 10−3 mg/ml inhibits the CL response of phagocytes both in intact and in sensitized rats and lowers the level of Fe2+-induced LPO in lung tissue but not in the liver of intact animals.

Relation between lipid peroxidation and inflammation in the pulmonary toxicity of cadmium.

Lipid peroxidation (LPO), measured as thiobarbituric acid reactive substances (TBARS), was evaluated in lungs of rats 24 h after intraperitoneal injection of 50, 250, and 1000 micrograms Cd/kg body weight as CdCl2. In order to gain some insight into possible causative factors responsible for these oxidative phenomena, the redox-active elements iron (Fe) and copper (Cu), and total lung protein content (an indication of pulmonary inflammatory processes) were also measured. Results obtained demonstrate a similar dose-related, non-linear evolution of total lung TBARS and total lung protein as a function of increasing lung Cd concentrations. Standardization of total lung TBARS to lung protein content further resulted in a linear relationship with lung Cd concentrations, thus suggesting a possible cause-effect relationship between these parameters. No statistically significant association was observed between the dose-related evolution of lung TBARS, and iron (Fe) and copper (Cu) after Cd exposure. The results obtained provide support for the possible involvement of inflammatory phenomena as the most likely events responsible for the generation of LPO in lung tissue following acute exposure to Cd salts.

CHANGES IN LUNG AND SYSTEMIC OXIDANT AND ANTIOXIDANT ACTIVITY AFTER SMOKE INHALATION

We determined the oxidant activity in lung airways, parenchyma, and systemic tissues in response to smoke inhalation, comparing lipid peroxidation with physiologic and histologic change. Adult sheep were given a controlled amount of cooled smoke from burned cotton toweling, containing a uniform particle diameter of 3-4 microns. The mean peak carboxyhemoglobin was 45 +/- 4%. Animals were monitored unanesthetized for 24 h and killed. Severe respiratory failure was noted, as a result of airways mucosal ulceration, submucosal edema, and atelectasis, along with increased airways fluid, but minimal alveolar edema. Airway fluid malondialdehyde (MDA) content was threefold greater than plasma. However, airways mucosa and lung parenchymal tissue, lipid peroxidation, and oxidized glutathione were not increased, suggesting the only direct oxidant activity was present only at the airways surface. Other factors besides oxidants are likely to be involved in the lung injury. However, a marked systemic oxidant stress was noted as evidenced by a significant increase in liver tissue MDA and decrease in reduced glutathione and catalase activity. The tissue oxidant stress also corresponded with a 75% increase in systemic oxygen consumption and an increase in soft tissue vascular permeability. We conclude that: 1) the only direct lung oxidant stress after smoke was noted in airways fluid, while lung tissue lipid peroxidation was not seen despite severe airways injury and atelectasis, and 2) major systemic physiologic changes, as evidenced by increased systemic oxygen demands and systemic microvascular permeability are seen with smoke exposure in addition to evidence of systemic tissue oxidant stress. The likely source of the oxidant activity was a smoke-induced systemic inflammation.

Oxygen free radical scavengers and reperfusion injury in dog lung preserved in cold ischemia.

Oxygen-derived free radicals are now considered important contributors to tissue injury associated with ischemia and reperfusion. The purpose of this study was to determine the influence of oxygen free radical scavengers on reperfusion injury. The left lower lobes of 15 canine lungs were isolated, preserved, and then reperfused for 120 minutes. Three groups of lobes were studied: Group 1 (n = 5), without ischemia, group 2 (n = 5) four hours of cold ischemia in Euro-Collins solution, group 3 (n = 5) four hours cold ischemia+oxygen free radical scavenger glutathione (0.1 nmol/L) given at the moment of perfusion. Extravascular lung water (grams per gram of blood-free dry lobe weight) after reperfusion was 2.82 +/- 0.32, 5.06 +/- 0.45, 4.21 +/- 0.33 for groups 1 through 3 respectively (p less than 0.001 group 1 versus group 2, p less than 0.001 group 2 versus group 3). Lung tissue lipid peroxidation, measured as thiobarbituric acid reactive material was 125 +/- 11, 270 +/- 30, and 185 +/- 17 nmol/g dry lobe weight for groups 1, 2 and 3 respectively (p less than 0.05 group 2 versus 1 and group 3 versus group 2). The data suggest that oxygen free radical scavengers attenuate reperfusion injury.

Application of the EPR spin-trapping technique to the detection of radicals produced in vivo during inhalation exposure of rats to ozone

Ozone is known to induce lipid peroxidation of lung tissue, although no direct evidence of free radical formation has been reported. We have used the electron paramagnetic resonance (EPR) spin-trapping technique to search for free radicals produced in vivo by ozone exposure. The spin trap α-(4-pyridyl-1-oxide)- N-tert-butylnitrone (4-POBN) was administered ip to male Sprague-Dawley rats. The rats were then exposed for 2 hr to either 0, 0.5, 1.0, 1.5, or 2.0 ppm ozone with 8% CO 2 to increase their respiratory rate. A six-line 4-POBN/radical spin adduct signal ( a N = 15.02 G and a β H = 3.27 G) was detected by EPR spectroscopy in lipid extracts from lungs of rats treated with 4-POBN and then exposed to ozone. Only a weak signal was observed in the corresponding solution from rats exposed to 0 ppm ozone (air with CO 2 only). The concentration of the radical adduct increased as a function of ozone concentration. After administration of 4-POBN, rats were exposed for either 0.5, 1.0, 2.0, or 4.0 hr to either 0 or 2.0 ppm ozone (with CO 2). The radical adduct concentration of the ozone-exposed groups at exposure times of 2.0 and 4.0 hr was significantly different from that of the corresponding air control groups. A correlation was observed between the radical adduct concentration and the lung weight/body weight ratio. These results demonstrate that ozone induces the production of free radicals in rat lungs during inhalation exposure and that radical production may be involved in the induction of pulmonary toxicity by ozone. This is the first direct evidence for ozone-induced free radical production in vivo.

Application of the EPR spin-trapping technique to the detection of radicals produced in vivo during inhalation exposure of rats to ozone

Abstract Ozone is known to induce lipid peroxidation of lung tissue, although no direct evidence of free radical formation has been reported. We have used the electron paramagnetic resonance (EPR) spin-trapping technique to search for free radicals produced in vivo by ozone exposure. The spin trap α-(4-pyridyl-1-oxide)- N-tert -butylnitrone (4-POBN) was administered ip to male Sprague-Dawley rats. The rats were then exposed for 2 hr to either 0, 0.5, 1.0, 1.5, or 2.0 ppm ozone with 8% CO 2 to increase their respiratory rate. A six-line 4-POBN/radical spin adduct signal ( a N = 15.02 G and a β H = 3.27 G) was detected by EPR spectroscopy in lipid extracts from lungs of rats treated with 4-POBN and then exposed to ozone. Only a weak signal was observed in the corresponding solution from rats exposed to 0 ppm ozone (air with CO 2 only). The concentration of the radical adduct increased as a function of ozone concentration. After administration of 4-POBN, rats were exposed for either 0.5, 1.0, 2.0, or 4.0 hr to either 0 or 2.0 ppm ozone (with CO 2 ). The radical adduct concentration of the ozone-exposed groups at exposure times of 2.0 and 4.0 hr was significantly different from that of the corresponding air control groups. A correlation was observed between the radical adduct concentration and the lung weight/body weight ratio. These results demonstrate that ozone induces the production of free radicals in rat lungs during inhalation exposure and that radical production may be involved in the induction of pulmonary toxicity by ozone. This is the first direct evidence for ozone-induced free radical production in vivo .

Reperfusion injury in the lung preserved for 24 hours

The left lower lobes of 28 canine lungs were isolated, preserved, and then reperfused for 150 minutes. Five groups of lobes were studied: group 1, control (n = 5); group 2, one hour of warm ischemia (n = 5); group 3, one hour of warm ischemia + oxygen free radical scavengers (n = 5); group 4, 24 hours of cold ischemia (n = 8); and group 5, 24 hours of cold ischemia + oxygen free radical scavengers (n = 5). Oxygen free radical scavengers consisted of superoxide dismutase and catalase (100 μg/mL) given at the moment of reflow. Extravascular lung water (grams per gram of blood-free dry lobe weight) after reperfusion was 2.75 ± 0.19, 5.46 ± 0.60, 4.08 ± 0.37, 9.43 ± 0.98, and 6.91 ± 0.95 for groups 1 through 5, respectively ( p < 0.05, groups 2 through 5 versus group 1; p < 0.05, group 2 versus group 3 and group 4 versus group 5), Lung tissue lipid peroxidation, measured as thiobarbituric add reactive material, was 117 ± 14, 314 ± 19, and 163 ± 25 nmol/g dry lobe weight for groups 1, 4, and 5, respectively ( p < 0.05, group 4 versus group 1 and group 4 versus group 5). The data suggest that oxygen free radical scavengers attenuate reperfusion injury after long-term hypothermic lung preservation.

Lung dysfunction after thermal injury in relation to prostanoid and oxygen radical release.

We studied whether changes in lung function after burns (1- to 12-h period) were due to changes in lung water or airways resistance and the relationship of the changes to prostanoid and O2 radical activity (measured as lipid peroxidation). Twenty-five anesthetized mechanically ventilated adult sheep were given a 40% of body surface scald burn and resuscitated to restore and maintain base-line filling pressures. Dynamic lung compliance (Cdyn) decreased by 40% from 38 +/- 5 to 24 +/- 4 ml/cmH2O at 12 h. Venous thromboxane B2 transiently increased from 210 +/- 40 to 1,100 +/- 210 pg/ml, and the value in lung lymph increased from 180 +/- 80 to 520 +/- 80 pg/ml. Prostacyclin levels in lung lymph and plasma remained at base line. Protein-poor lung lymph flow increased two- to threefold, but postmortem lung analysis revealed no increase in lung water from the control of 3.5 +/- 0.3 g H2O/g dry wt. No increase in protein permeability was seen. However, the lipid peroxidation of lung tissue measured as malondialdehyde was significantly increased from the control value of 56 +/- 4 nmol/g lung to a value of 69 +/- 6. Ibuprofen pretreatment (12.5 mg/kg) markedly attenuated the decrease in Cdyn, with the value at 12 h being 90% of base line. Ibuprofen also decreased the amount of lung lipid peroxidation but did not decrease the lung lymph response. We conclude that the decrease in Cdyn seen early postburn is not due to increased lung water, but, rather, is due to a mediator-induced bronchoconstriction, attenuated by ibuprofen; the mediator being either thromboxane or a byproduct of O2 radicals as evidenced by increased lipid peroxide production in lung tissue.

Endotoxemia causes increased lung tissue lipid peroxidation in unanesthetized sheep.

Our purpose was to determine whether lipid peroxidation of lung tissue, a reflection of O2 radical injury, occurs with endotoxin, and whether the degree of tissue change corresponds with the degree of increased protein permeability. Unanesthetized adult sheep with lung lymph fistulas were given Escherichia coli endotoxin at a dose of 2 micrograms/kg (n = 34). Tissue lipid peroxidation was measured using the thiobarbituric acid assay for malondialdehyde (MDA). The MDA content of lung tissue in nanomoles per gram increased from a control value of 48 +/- 8 to 98 +/- 18 at 5 h postendotoxin (2 micrograms/kg), whereas lung lymph protein transport (Cp), was increased 3- to 4-fold. The MDA content returned to base line with Cp by 24 h postendotoxin. Six sheep given endotoxin were pretreated with 12.5 mg/kg of ibuprofen, and six were infused with dimethylthiourea (DMTU) 0.75 g/kg. With ibuprofen, Cp was only increased 2.5- to 3-fold and MDA was increased to 69 +/- 15 nmol/g. With DMTU, the increase in Cp was comparable to that with endotoxin alone, as was the MDA of lung tissue with a value of 92 +/- 12 nmol/g. The correlation of tissue MDA with Cp in all animals was 0.83. We conclude that lipid peroxidation occurs in lung tissue after a moderately severe endotoxin injury with the degree of change corresponding to the degree of increased Cp.

Lipid peroxidation in lung of rats exposed to hyperoxic, hypoxic and ischemic effects

Rat experiments were undertaken to describe the range of the endogenous lipid peroxidation (measured by formation of malondialdehyde [MDA] in lung tissue) and to analyze the effects of hyperoxic, hypoxic and ischemic influences. The acute hyperoxia caused a moderate increase in lipid peroxidation. The MDA formation in lungs of rats was perceptibly higher in low oxygen environment, while the highest values were found in ischemic lungs. The cytotoxic metabolites cause unfavourable influences on the lung structure (perivascular, interstitial and alveolar edema, destroyed epithelial lining with disintegration of lamellar membranes of the type II-pneumocytes). The findings suggest that potential danger of the oxygen free radicals is an increased lipid peroxidation of lung tissue causing alveolocapillary destruction and extensive exudation with pathologic dwindling of lung function.

Effects of vitamin E deficiency and nitrogen dioxide exposure on lung lipid peroxidation: use of lipid epoxides and malonaldehyde as measures of peroxidation.

The effect of vitamin E deficiency in male Sprague-Dawley rats upon lipid peroxidation in lung tissue was examined by measuring malonaldehyde and lipid epoxide production. In addition to controls, some animals were also exposed to 3 +/- 0.1 ppm NO2 continuously for 7 d in order to study the effects of oxidant stress on lung lipid peroxidation and vitamin E content. The observed changes in malonaldehyde and epoxide content could serve as good indices of lipid peroxidation, particularly under conditions of vitamin E deprivation. The responses measured indicated an inverse relation in the lung between tissue vitamin E content and quantity of lipid peroxidation products. Measurement of lipid epoxides served as a reliable indicator of lung tissue lipid peroxidation. Finally, NO2 inhalation appeared to elicit a response characterized by increased assimilation of vitamin E into lung tissue.