Lung Superoxide Dismutase Activity Research Articles

Azilsartan attenuates lipopolysaccharide-induced acute lung injury via the Nrf2/HO-1 signaling pathway.

Acute lung injury (ALI) is a severe complication of sepsis and hemorrhagic shock with high morbidity. In the present study, the protective effect of Azilsartan on lipopolysaccharide (LPS)-induced ALI in mice was investigated to explore the potential therapeutic property of Azilsartan for the treatment of ALI. LPS was used to induce an ALI model in mice. Hematoxylin-eosin (HE) staining sections were then evaluated for the pathological state of lung tissues. Bronchoalveolar lavage fluid (BALF) protein concentration, wet/dry weight ratios of lung tissues, and pulmonary myeloperoxidase (MPO) activity were detected to determine the degree of pulmonary injury. The number of total cells, macrophages, and neutrophils in BALF were counted using a hemocytometer to illustrate the inflammatory cell infiltration. The lung function was monitored using a spirometer. The concentrations of interleukin-1β (IL-1β), monocyte chemoattractant protein-1 (MCP-1), and interleukin-8 (IL-8) were determined using enzyme-linked immunosorbent assay (ELISA). Oxidative stress was evaluated by the superoxide dismutase (SOD) activity, glutathione (GSH), and malondialdehyde (MDA) concentrations in the lung tissue. The expressions of nuclear erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) were determined using Western blot analysis. Azilsartan therapy alleviated LPS-induced lung tissue damage, increased BALF protein concentration, lung wet to dry weight ratio, MPO activity, and macrophage and neutrophils infiltration. Also, Azilsartan ameliorated the production of inflammatory factors (IL-1β, MCP-1, and IL-8). Azilsartan ameliorated LPS-impaired lung SOD activity, the GSH concentration, and the MDA concentration. Mechanistically, Azilsartan activated the LPS-impaired Nrf2/HO-1 signaling pathway. Azilsartan therapy attenuates LPS-induced ALI via the Nrf2/HO-1 signaling pathway.

Biological Effects of Scattered Versus Scanned Proton Beams on Normal Tissues in Total Body Irradiated Mice: Survival, Genotoxicity, Oxidative Stress and Inflammation.

Side effects of proton therapy are poorly studied. Moreover, the differences in the method of dose delivery on normal tissues are not taken into account when proton beams are scanned instead of being scattered. We proposed here to study the effects of both modalities of proton beam delivery on blood; skin; lung and heart in a murine model. In that purpose; C57BL/6 mice were total body irradiated by 190.6 MeV proton beams either by Double Scattering (DS) or by Pencil Beam Scanning (PBS) in the plateau phase before the Bragg Peak. Mouse survival was evaluated. Blood and organs were removed three months after irradiation. Biomarkers of genotoxicity; oxidative stress and inflammation were measured. Proton irradiation was shown to increase lymphocyte micronucleus frequency; lung superoxide dismutase activity; erythrocyte and skin glutathione peroxidase activity; erythrocyte catalase activity; lung; heart and skin oxidized glutathione level; erythrocyte and lung lipid peroxidation and erythrocyte protein carbonylation even 3 months post-irradiation. When comparing both methods of proton beam delivery; mouse survival was not different. However, PBS significantly increased lymphocyte micronucleus frequency; erythrocyte glutathione peroxidase activity and heart oxidized glutathione level compared to DS. These results point out the necessity to take into account the way of delivering dose in PT as it could influence late side effects.

Effects of dietary supplementation of DL-2-hydroxy-4(methylthio) butanoic acid on antioxidant capacity and its related gene expression in lung and liver of broilers exposed to low temperature

DL-2-hydroxy-4(methylthio) butanoic acid (DL-HMTBA) exhibits a higher antioxidant capability in vitro as compared to DL-Met, but the mechanism is still not known. A total of 400 8-day-old broiler chicks were allotted to a 2 [low (12 to 14°C) vs. control temperature (thermoneutral, 24 to 26°C)] × 2 (0.17% or 0.51% of DL-HMTBA) factorial arrangement to investigate effects of DL-HMTBA on antioxidant capacity and its related gene expression in lung and liver of broilers exposed to low temperature. The hepatic glutathione (GSH), superoxide dismutase (SOD), and glutathione peroxidase (GSH-Px) activities were decreased, whereas protein carbonyl and malodndialdehyde contents in lung were increased in low temperature (P < 0.05). Dietary supplementation of 0.51% DL-HMTBA increased (P < 0.05) GSH and GSH-Px activity in liver and SOD activity in lung in spite of the temperature. The greater gene expression of GSH reductase and lower expression of GSH synthetase (P < 0.01) were observed in lung of broilers that were maintained at low temperature. Higher DL-HMTBA supplementation induced greater (P < 0.05) mRNA expression of glutathione-S transferase in lung, GSH synthetase in liver and lung, as well as lower expression of GSH reductase in lung, and this effect were more obvious for the chicks exposed to low temperature (interaction, P < 0.05). Chicks that were maintained under low temperature had the lower expression of cystathionine β-synthase (CβS), whereas those fed 0.51% DL-HMTBA increased the CβS expression in liver under low temperature (interaction, P ≤ 0.05). The γ-glutamylcysteine synthetase and Met adenosyltransferase 1 (MAT1) gene expression were downregulated (P < 0.05) by low temperature and the higher (P = 0.02) expression of MAT1 was observed in lung of chicks fed 0.51% DL-HMTBA. It indicated that under low temperature, DL-HMTBA supplementation at 0.51% upregulated gene expression of GSH synthesis and Met transsulfuration pathway in liver and lung to increase the antioxidant capacity, and then mitigate the negative effects of cold stress for broilers.

Effect of ischemic preconditioning combined with ?7 nAchR agonists on limb ischemia-reperfusion lung injury in rat

Objective: To investigate the effect of ischemic preconditioning combined with α7 nAchR agonists on limb ischemia-reperfusion lung injury in rats. Methods: Fifty healthy male Sprague-Dawley rats weighing 230-280 g were randomly divided into 5 groups: sham operation group (S, also means the control group), model group(M), model and ischemic preconditioning (IP) group, model and α7 nAchR agonists group (PNU) and model and united treatment (U) group. The model of lung injury was induced by 3 h of ischemia and 3 h of reperfusion. The arterial blood was collected at 3 h- reperfusion for blood gas analysis; The lung tissues were collected for determination of Pulmonary coefficient, malondialdehyde (MDA) content, superoxide dismutase (SOD) activity and lung tissue inflammatory cytokines (IL-6 and TNF-a). The pathological changes of lung tissues were observed under light microscope, and the pathological score of lung tissue was conducted. Results: Compared with S group, the PaO2, pH and the activity of SOD in lung tissue of M group at 3 h reperfusion were significantly decreased, Pulmonary coefficient, MDA,IL-6, TNF-a and pulmonary pathological score of lung tissue were significantly increased (P<0.05), the difference of PaCO2 was not statistically significant (P>0.05). Compared with M group, arterial PaO2and lung SOD activity of IP group, PNU Group, U group at 3 h-reperfusion decreased, while Pulmonary coefficient, lung group, MDA,IL-6, TNF-a and pulmonary pathological score of lung tissue were significantly increased (P<0.05), there was no statistically significant difference in pH and PaCO2 between the two groups (P>0.05). Compared with IP group and PNU group, PaO2 and SOD activity of lung tissue decreased in U group at 3 h reperfusion, Pulmonary coefficient, MDA, IL-6, TNF-a, pulmonary pathology scores of lung tissue increased (P<0.05). There was no significant difference in PH and PaCO2 between the two groups (P>0.05). Conclusion: Ischemic preconditioning and α7 nAchR agonists can attenuate limb ischemia-reperfusion lung injury in rat to a certain extent, and the combined effect of the two is better than the separate application.

The Anti-Inflammatory and Antioxidant Effects of Salvia officinalis on Lipopolysaccharide-Induced Inflammation in Rats.

Salvia officinalis, which has a high phenolic acid and flavonoid content, is a powerful antioxidant and anti-inflammatory herb. Inflammation plays an important role in the pathophysiology of many diseases and could cause damage by means of oxidative stress. The aim of this study was to investigate the anti-inflammatory and antioxidant activity of S. officinalis formed lipopolysaccharide (LPS)-induced experimental inflammation model. Four- to five-month-old 42 female Wistar albino rats were divided into six groups. Three groups were administered intraperitoneally 1 mg/kg LPS. Twenty-four hours after injection of LPS, 10 and 30 mg/kg S. officinalis extract were given orally to treatment groups. Pulmonary and hepatic 18F-fluoro-deoxy-D-glucose (18F-FDG) uptake was calculated to determine the status of inflammation by 18F-fluoro-deoxy-D-glucose-positron emission tomography (18FDG-PET) scan. Antioxidant enzyme activities and nitric oxide (NO) and malondialdehyde (MDA) levels were determined. Nuclear factor-kappa B (NF-κB) and tumor necrosis factor-alpha (TNF-α) levels were also detected in serum. As a result, lung and liver 18F-FDG uptake was found to be higher in the inflammation group than control group. MDA levels in erythrocyte and all tissue samples (liver, lung, and kidney) were found to be significantly higher compared to treatment groups. Superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase activities of the inflammation group in the liver, lung, kidney tissues, and erythrocyte SOD and CAT activities were determined to significantly lower than groups treated with S. officinalis. Increased NO, NF-κB, and TNF-α levels were found in the inflammation group. S. officinalis has been observed to have useful effects on LPS-induced inflammation and oxidative stress in rats.

Role of autophagy in ameliorating sepsis-induced acute lung injury by allicinin in mice

To investigate roles of autophagy in ameliorating sepsis-induced acute lung injury by allicinin in mice. Methods: A total of 152 male Balb/c mice (8-week old) were randomly divided into a sham group, a septic model group, an allicin treatment group, and an autophagy inhibition group. Septic mouse model was established by cecal ligation and puncture (CLP). Mice in the allicin treatment group were given allicin (30 mg/kg, intra-peritoneal injection) at 6 and 12 h, while those in the autophagy inhibition group were given autophagy inhibitor 3-MA (15 mg/kg, intra-peritoneal injection) at half an hour after allicin administration. Mice in the model and sham group were administered with the same amount of saline. Twenty mice in each group were randomly chosen to observe the 7 d survival rate. The other 12 mice were killed at 24 h, and the bronchoalveolar lavage fluid (BALF) (n=6) and lung tissues (n=6) were collected. ELISA was used to detect the tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in the BALF. Hematoxylin-eosin staining was preformed to show the morphological changes in the lung tissues. Malondialdehyde (MDA) content and the activity of superoxide dismutase (SOD) in the lung tissues were examined. The expression of LC3B and Beclin-1 was determined by immunohistochemical analysis. Results: Compared with the sham group, the 7 d survival rate and lung SOD activity were decreased in the CLP group (P<0.05); the lung morphological damage score, the levels of TNF-α and IL-6 in the BALF, MDA content in the lung, and expression of LC3B and Beclin-1 were increased greatly in the CLP group (P<0.05). Compared with the CLP group, the 7 d survival rate, lung SOD activity and the expressions of LC3B and Beclin-1 were increased significantly in the allicin treatment group (P<0.05); the lung morphological damage scores, the levels of TNF-α and IL-6 in the BALF and MDA content in the lung were decreased obviously in the allicin treatment group (P<0.05). Compared with the allicin treatment group, the 7 d survival rate, lung SOD activity, and the expressions of LC3B and Beclin-1 were decreased in the 3-MA group (P<0.05); the lung morphological damage scores, the levels of TNF-α and IL-6 in the BALF, and MDA content in the lung were increased significantly in the 3-MA group (P<0.05). Conclusion: Allicin may ameliorate sepsis-induced acute lung injury in mice by enhancing the level of autophagy.

Effect of Dermal Application of Bifenthrin on Acetylcholinesterase and Oxidative Stress Indices in Rat Blood, Lung and Kidney

The oxidative stress inducing potential of bifenthrin was evaluated in the blood, lung and kidney homogenates of rats following its repeated dermal application for a period of 30 days. Bifenthrin treated animals showed significant increase in lipid peroxidation after 20 and 30 days of treatment in erythrocytes, lung and kidney. Blood glutathione decreased significantly both after 20 and 30 days of exposure. Superoxide dismutase increased significantly after 20th day of application of bifenthrin followed by significant decrease after 30th day. In lung superoxide dismutase activity decreased non-significantly after 20th day which decreased significantly after 30th day of application. Superoxide dismutase in kidney decreased significantly both after 20th and 30th day of treatment. The activity of glutathione peroxidase significantly decreased in erythrocytes, lung and kidney both after 20 and 30 days of exposure. No significant change in the activity of glutathione–S-transferase was observed after 20th day in blood and a significant decrease was observed after 30th day. Significant increase of glutathione–S-transferase was observed in lung both after 20 and 30 days of treatment where as in kidney significant increase was observed only after 30 days. There was a significant decrease of catalase in erythrocytes, lung and kidney both after 20th and 30th day of application. Non-significant changes were observed in acetylcholinesterase activities in treatment group both after 20th and 30th day. In conclusion bifenthrin treated animals showed alteration in antioxidant enzyme system suggesting its oxidative stress potential.

Effect of ozone oxidative preconditioning in preventing early radiation-induced lung injury in rats

Ionizing radiation causes its biological effects mainly through oxidative damage induced by reactive oxygen species. Previous studies showed that ozone oxidative preconditioning attenuated pathophysiological events mediated by reactive oxygen species. As inhalation of ozone induces lung injury, the aim of this study was to examine whether ozone oxidative preconditioning potentiates or attenuates the effects of irradiation on the lung. Rats were subjected to total body irradiation, with or without treatment with ozone oxidative preconditioning (0.72 mg/kg). Serum proinflammatory cytokine levels, oxidative damage markers, and histopathological analysis were compared at 6 and 72 h after total body irradiation. Irradiation significantly increased lung malondialdehyde levels as an end-product of lipoperoxidation. Irradiation also significantly decreased lung superoxide dismutase activity, which is an indicator of the generation of oxidative stress and an early protective response to oxidative damage. Ozone oxidative preconditioning plus irradiation significantly decreased malondialdehyde levels and increased the activity of superoxide dismutase, which might indicate protection of the lung from radiation-induced lung injury. Serum tumor necrosis factor alpha and interleukin-1 beta levels, which increased significantly following total body irradiation, were decreased with ozone oxidative preconditioning. Moreover, ozone oxidative preconditioning was able to ameliorate radiation-induced lung injury assessed by histopathological evaluation. In conclusion, ozone oxidative preconditioning, repeated low-dose intraperitoneal administration of ozone, did not exacerbate radiation-induced lung injury, and, on the contrary, it provided protection against radiation-induced lung damage.

Piper sarmentosum Roxb protects lungs against oxidative stress induced by carbon tetrachloride in rats

This study was designed to investigate the effects of Piper sarmentosum supplementation on carbon tetrachloride (CCl4) induced oxidative stress in lung. Thirty-two male Wistar rats were divided into two groups; a control and a treatment group which was given 125 mg/kg body weight P. sarmentosum orally for 28 days, after which each group was further subdivided into two groups. A group was exposed to CCl4 (1 ml/kg body weight, orally), while another group was given corn oil. After 24 h, blood and lung were taken. CCl4 increased lung lipid peroxidation (TBARS) and glutathione peroxidase significantly. P. sarmentosumsupplementation was able to reduce these increases. However, both CCl4 and P. sarmentosum extract did not affect lung superoxide dismutase activity. In conclusion, P. sarmentosum is capable in reducing the oxidative stress in lungs by decreasing lipid peroxidation and maintaining the glutathione peroxidase activity towards the normal level. Key words: Piper sarmentosum, oxidative stress, antioxidant, carbon tetrachloride.

Superoxide dismutase protects against apoptosis and alveolar enlargement induced by ceramide

The molecular events leading to emphysema development include generation of oxidative stress and alveolar cell apoptosis. Oxidative stress upregulates ceramides, proapoptotic signaling sphingolipids that trigger further oxidative stress and alveolar space enlargement, as shown in an experimental model of emphysema due to VEGF blockade. As alveolar cell apoptosis and oxidative stress mutually interact to mediate alveolar destruction, we hypothesized that the oxidative stress generated by ceramide is required for its pathogenic effect on lung alveoli. To model the direct lung effects of ceramide, mice received ceramide intratracheally (Cer(12:0) or Cer(8:0); 1 mg/kg) or vehicle. Apoptosis was inhibited with a general caspase inhibitor. Ceramide augmentation shown to mimic levels found in human emphysema lungs increased oxidative stress, and decreased, independently of caspase activation, the lung superoxide dismutase activity at 48 h. In contrast to their wild-type littermates, transgenic mice overexpressing human Cu/Zn SOD were significantly protected from ceramide-induced superoxide production, apoptosis, and air space enlargement. Activation of lung acid sphingomyelinase in response to ceramide treatment was abolished in the Cu/Zn SOD transgenic mice. Since cigarette smoke-induced emphysema in mice is similarly ameliorated by the Cu/Zn SOD overexpression, we hypothesized that cigarette smoke may induce ceramides in the mouse lung. Utilizing tandem mass spectrometry, we documented increased lung ceramides in adult mice exposed to cigarette smoke for 4 wk. In conclusion, ceramide-induced superoxide accumulation in the lung may be a critical step in ceramide's proapoptotic effect in the lung. This work implicates excessive lung ceramides as amplifiers of lung injury through redox-dependent mechanisms.

Protective Effects of Erdosteine and Vitamins C and E Combination on Ischemia–Reperfusion-Induced Lung Oxidative Stress and Plasma Copper and Zinc Levels in a Rat Hind Limb Model

The aim of this study was to investigate the protective effects of erdosteine and vitamins C and E (VCE) on the lungs after performing hind limb ischemia-reperfusion (I/R) by assessing oxidative stress, plasma copper (Cu), and zinc (Zn) analysis. The animals were divided randomly into four groups as nine rats each as follows: control, I/R, I/R plus erdosteine, and I/R plus VCE combination. I/R period for 60 min was performed on the both hind limbs of all the rats in the groups of I/R, erdosteine with I/R, VCE with I/R allowing 120 min of reperfusion. The animals received orally erdosteine one time in a day and 3 days before I/R in the erdosteine group. In the VCE group, the animals VCE combination received one time in a day and 3 days before I/R, although placebo was given to control and I/R group animals. Lung lipid peroxidation (malondialdehyde [MDA]) level, superoxide dismutase (SOD), and catalase activities were increased, although lung glutathione (GSH) and plasma Zn levels decreased in I/R group in lung tissue compared with the control group. Serum MDA level, creatine kinase, and lactate dehydrogenase activities were increased in I/R group compared with the control. Lung MDA and plasma Zn levels and lung SOD activity were decreased by erdosteine administration, whereas lung GSH levels after I/R increased. The plasma Zn levels and lung SOD activity were decreased by VCE administration, although the plasma Cu and lung GSH levels increased after I/R. In conclusion, erdosteine has an antioxidant role on the values in the rat model, and it has more protective affect than in VCE in attenuating I/R-induced lung injury in rats.

Antioxidant effects of melatonin in rats during chronic exposure to hyperbaric oxygen

In addition to its beneficial effects, hyperbaric oxygen (HBO) exposure causes some detrimental effects via oxidative stress. Previous experimental studies showed that melatonin is a useful agent to block single session HBO-induced oxidative stress. In the present study, we investigated the antioxidant effect of exogenously administered as well as endogenously produced melatonin in lung and brain tissues of rats exposed to long term HBO. The HBO procedure was set as daily exposures to 2.5 ATA of oxygen for 1 hr and a total of 10 sessions. Twenty-eight male Sprague-Dawley rats were divided into four groups as follows: control, daytime HBO, daytime HBO plus melatonin (5 mg/kg), nighttime HBO. Tissue oxidative/antioxidant status was examined by determining the protein carbonyl content as a criteria for oxidative stress and the activities of the antioxidant enzymes, superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). HBO exposure for 10 days caused significant increases in protein carbonyl content and SOD levels of lung and brain, but GSH-Px activities remained unaffected. The increases in protein carbonyls were blocked by exogenously administered melatonin and in part by nighttime exposure to darkness whereas the increase of SOD activity was only impeded by endogenously produced melatonin in brain tissue. Lung SOD activity was augmented by endogenous melatonin. In conclusion, melatonin blocks long-term HBO-induced cumulative oxidative stress as indicated changes in protein carbonyls. Both exogenously injected and physiologically secreted melatonin has this potential. The effects of HBO-exposure and melatonin on the activities of the antioxidative enzymes are less clear.

Role of oxidative stress in thuringiensin-induced pulmonary toxicity

To understand the effect of thuringiensin on the lungs tissues, male Sprague-Dawley rats were administrated with thuringiensin by intratracheal instillation at doses 0.8, 1.6 and 3.2 mg/kg of body weight, respectively. The rats were sacrificed 4 h after treatment, and lungs were isolated and examined. Subsequently, an effective dose of 1.6 mg/kg was selected for the time course study (4, 8, 12, and 24 h). Intratracheal instillation of thuringiensin resulted in lung damage, as evidenced by increase in lung weight and decrease in alkaline phosphatase (10-54%), an enzyme localized primarily in pulmonary alveolar type II epithelial cells. Furthermore, the administration of thuringiensin caused increases in lipid peroxidation (21-105%), the indices of lung injury. In addition, the superoxide dismutase (SOD) and glutathione (GSH) activities of lung tissue extracts were measured to evaluate the effect of thuringiensin on antioxidant defense system. The SOD activity and GSH content in lung showed significant decreases in a dose-related manner with 11-21% and 15-37%, respectively. Those were further supported by the release of proinflammatory cytokines, as indicated by increases in IL-1beta (229-1017%) and TNF-alpha (234%) levels. Therefore, the results demonstrated that changes in the pulmonary oxidative-antioxidative status might play an important role in the thuringiensin-induced lung injury.

Effect of Wen-Pi-Tang extract on lung damage by influenza virus infection

The effect of Wen-Pi-Tang extract on influenza virus infection in mice was investigated. The administration of Wen-Pi-Tang extract at a dose of 100mg/kg body wt. for 8 consecutive days to influenza virus-infected mice reversed the lack of body wt. gain and prevented the increase in lung weight caused by the infection in comparison with uninfected mice, while allopurinol, a xanthine oxidase (XOD) inhibitor, did not show these effects. The serum levels of uric acid and allantoin in influenza virus-infected mice were reduced by Wen-Pi-Tang extract administration. Moreover, Wen-Pi-Tang extract reduced the uric acid level more as the dose increased, although it exerted lower activity than allopurinol. The XOD activity of the lungs was elevated by influenza virus infection, but Wen-Pi-Tang extract administration inhibited this activity, indicating prevention of lung damage by oxygen free radicals generated by XOD. After the administration of Wen-Pi-Tang extract to influenza virus-infected mice, the lung superoxide dismutase activity was not significantly different from that of uninfected mice, whereas lung catalase activity was lower in the former than the latter, but slightly higher than that of influenza virus-infected mice, suggesting that Wen-Pi-Tang extract may prevent the generation of highly toxic hydroxyl radicals in the lung. In addition, the administration of both Wen-Pi-Tang extract and allopurinol reduced the degree of lung consolidation caused by influenza virus infection. In particular, Wen-Pi-Tang extract reduced the consolidation score in a dose-dependent manner and more markedly than allopurinol did. This study suggests that Wen-Pi-Tang extract could improve pathological conditions of the lungs induced by influenza virus infection.

Effect of oxygen on lung superoxide dismutase activities in premature baboons with bronchopulmonary dysplasia.

We investigated the effects of gestational age and oxygen exposure on superoxide dismutase (SOD) activities in distal fetal lung tissue in primate models of bronchopulmonary dysplasia. During the final third of fetal life, lung coppper-zinc SOD (Cu,ZnSOD) specific activity decreased, whereas lung manganese SOD (MnSOD) specific activity tended to increase. In the premature newborn (140 days, 78% of term gestation), lung total SOD and Cu,ZnSOD specific activities decreased after 6-10 days of ventilation with as needed [pro re nada (PRN)] or 100% oxygen compared with fetal control animals. Neither Cu,ZnSOD mRNA nor protein expression changed after either oxygen exposure at this gestation (140 days) relative to fetal control animals. At this age (6-10 days), lung MnSOD specific activity did not change in oxygen-exposed relative to fetal control animals, even though lung expression of MnSOD mRNA and protein increased after PRN or 100% oxygen exposure. In the very premature 125-day newborn (69% of term), lung Cu,ZnSOD specific activity and protein decreased, whereas Cu,ZnSOD mRNA increased, after 6-10 days of ventilation with PRN oxygen compared with fetal control animals. In fetal lung explants, hyperoxia also decreased expression of SOD activity acutely (16-h exposure, 125 and 140 days gestation). To conclude, expression of SOD activity in the premature primate lung did not increase in response to elevated oxygen tension, apparently due to effects occurring subsequent to the expression of these mRNAs.

Antifibrotic effect of decorin in a bleomycin hamster model of lung fibrosis

We reported previously that treatment with antibody to transforming growth factor-β (TGF-β) caused a marked attenuation of bleomycin (BL)-induced lung fibrosis (LF) in mice. Decorin (DC), a proteoglycan, binds TGF-β and thereby down-regulates all of its biological activities. In the present study, we evaluated the antifibrotic potential of DC in a three-dose BL-hamster model of lung fibrosis. Hamsters were placed in the following groups: (1) saline (SA) + phosphate-buffered saline (PBS) (SA + PBS); (2) SA + DC; (3) BL + PBS; and (4) BL + DC. Under pentobarbital anesthesia, SA (4 mL/kg) or BL was instilled intratracheally in three consecutive doses (2.5, 2.0, 1.5 units/kg/4 mL) at weekly intervals. DC (1 mg/mL) or PBS was instilled intratracheally in 0.4 mL/hamster on days 3 and 5 following instillation of each dose of SA or BL. In week 4, hamsters received three doses of either DC or PBS every other day. The hamsters were killed at 30 days following the first instillation, and their lungs were appropriately processed. Lung hydroxyproline levels in SA + PBS, SA + DC, BL + PBS, and BL + DC groups were 965, 829, 1854, and 1387 μg/lung, respectively. Prolyl hydroxylase activities were 103, 289, and 193% of SA + PBS control in SA + DC, BL + PBS, and BL + DC groups, respectively. The myeloperoxidase activities in the corresponding groups were 222, 890, and 274% of control (0.525 units/lung). Intratracheal instillation of BL caused significant increases in these biochemical markers, and instillation of DC diminished these increases in the BL + C group. DC treatment also caused a significant reduction in the infiltration of neutrophils in the bronchoalveolar lavage fluid (BALF) of hamsters in the BL + DC group. However, DC treatment had little effect on BL-induced increases in lung Superoxide dismutase activity and lipid peroxidation and leakage of plasma proteins in the BALF of the BL + DC group. Hamsters in the BL + PBS group showed severe multifocal fibrosis and accumulation of mononuclear inflammatory cells and granulocytes. In contrast, hamsters in the BL + DC group showed mild multifocal septal thickening with aggregations of mononuclear inflammatory cells. Hamsters in both control groups (SA + PBS and SA + DC) showed normal lung structure. Frozen lung sections following immunohistochemical staining revealed an intense staining for EDA-fibronectin and collagen type I in the BL + PBS group as compared with all other groups. It was concluded that DC potentially offers a novel pharmacological intervention that may be useful in treating pulmonary fibrosis.

Hepatic involvement in pancreatitis-induced lung damage.

The role of liver in the respiratory dysfunction associated with acute pancreatitis has been evaluated. For this purpose, an experimental necrohemorrhagic pancreatitis was induced in rats by intraductal administration of 3.5% sodium taurocholate. Additionally, a portocaval shunt was performed before induction of acute pancreatitis to prevent the initial passage through the liver of substances released by the pancreas. Twelve hours after the induction of pancreatitis, increases in lung prostacyclin and thromboxane B2 synthesis, decreased lung superoxide dismutase activity, and increases in plasma phospholipase A2 activity were found. In addition, inflammatory injury was evidenced in lung by histopathological analysis. The portocaval shunt was able to prevent the metabolic changes and ameliorate the inflammatory process in the lung, suggesting that the liver plays an active role in the systemic inflammatory response to acute pancreatitis.

Pertussis toxin treatment alters manganese superoxide dismutase activity in lung. Evidence for lung oxygen toxicity in air-breathing rats.

Exposure of rats to hyperoxia or to treatment with endotoxin, increases lung manganese superoxide dismutase (MnSOD) gene expression. However, the paths by which these environmental signals are transduced into enhanced MnSOD gene expression are unknown. We now provide evidence that heterotrimeric G proteins are involved in the hyperoxia-induced increase in lung MnSOD gene expression but that pertussis toxin-sensitive G proteins are not involved in the endotoxin-induced elevation of lung MnSOD gene expression. We also show that treating rats with pertussis toxin decreased lung MnSOD activity approximately 50%. This decline in MnSOD activity occurred without a change in the lung activity of copper-zinc SOD, catalase, or glutathione peroxidase. In air-breathing rats, the pertussis toxin-induced decrease in MnSOD activity was associated with the development of lung edema, pleural effusion with a high concentration of protein, and biochemical evidence of lung oxygen toxicity. Compared to air-breathing rats, maintenance of pertussis toxin-treated rats under hypoxic or hyperoxic conditions respectively decreased or increased intrathoracic fluid. Endotoxin treatment elevated lung MnSOD activity and protected pertussis toxin-treated rats from an increase in intrathoracic fluid.

Toxic effects of fatty acid anilides on the oxygen defense systems of guinea pig lungs and erythrocytes

Toxic oil syndrome (TOS) is caused by ingestion of denatured edible oils. Even though the etiology and pathogenesis of this disease are not fully known, it is quite clear that generation of free radicals caused by ingestion of fatty acid anilides is responsible for the pathogenetic mechanism in many TOS patients. Fatty acid anilides may also alter the free radical status of lungs and erythrocytes; this possibility may shed some light on understanding toxic oil syndrome. The present study describes the effects of oral administration of fatty acid anilides on the activities of major enzymes involved in the oxygen defense systems of lungs and erythrocytes. Feeding fatty acid anilides caused an increase in the superoxide dismutase (SOD) activity in erythrocytes, whereas it caused a decrease in the SOD activity in lungs. GSH-Px activity was not significantly changed in erythrocytes but was decreased in lungs. Although the activity of catalase was increased only by a higher dose in the erythrocytes, it was not affected in the lung at any dosage. Even though the ingestion of fatty acid anilides caused an increase in the SOD activity in the erythrocytes and a decrease in the SOD activity in the lungs, there was an increase in the lipid peroxidation in both cases. The increase in lipid peroxidation in erythrocytes is probably caused by the accumulation of H2O2, and that in the lungs is due to the accumulation of superoxide anion.

Effects of niacin on bleomycin-induced increases in myeloperoxidase, prolyl hydroxylase, and superoxide dismutase activities and collagen accumulation in the lungs of hamsters.

It has been shown that lung nicotinamide adenine dinucleotide (NAD) depletion accompanies bleomycin (BL)-induced lung fibrosis in the hamster and that treatment with niacin (NA), a precursor of NAD, was found to attenuate lung fibrosis caused by this agent. Niacin was used in the present study to investigate changes in some biochemical parameters and enzymes involved in the development of BL-induced lung fibrosis in the hamster. Niacin (500 mg/kg, IP), or an equivalent volume of saline (SA, IP), was given daily 2 days prior to intratracheal instillation of BL (7.5 U/5 mL/kg) or SA and everyday thereafter throughout the study. Hamsters were killed at 1, 4, 7, 10, and 14 days after the BL or SA instillation and their lungs processed for various biochemical assays. Hydroxyproline content and superoxide dismutase (SOD) activity in SABL treated animals were significantly (P < or = 0.05) elevated at 7 and 10 days, peaking at 14 days to 161 +/- 11% and 159 +/- 11% of the SASA treated animals, respectively. Although the hydroxyproline level of NABL treated animals was significantly elevated at 7 and 10 days and peaked at 14 days to 123 +/- 8% of the NASA control, these values were significantly lower than the SABL treated animals at the corresponding times. The lung SOD activity of NABL groups was significantly higher at 4 days but significantly lower at 10 and 14 days than the SABL groups at the corresponding times. Prolyl hydroxylase (PH) activity and total lung calcium in SABL treated groups were significantly elevated compared to SASA treated groups starting at 4 days, with PH peaking at 10 days to 163 +/- 13% and calcium peaking at 7 days to 148 +/- 8% of SASA treated groups. The NABL treated animals displayed a significant elevation in PH activity at 4 days only (132 +/- 15%), while the calcium content in this group was significantly increased at 4 and 14 days compared to NASA treated animals. However, the activity of PH in the NABL treated animals was significantly lower than the SABL treated animals at 7, 10, and 14 days. The calcium content of the NABL group was significantly lower than the SABL group at 7 and 10 days. The thiobarbituric acid reactive substance equivalents (TBARS) content and myeloperoxidase (MPO) activity were significantly elevated at all time points in SABL groups as compared to SASA groups, with peak elevation of TBARS to 160 +/- 9% at 4 days and MPO to 268 +/- 40% at 1 day.(ABSTRACT TRUNCATED AT 400 WORDS)