Yasuhide Uejima

Endothelin-1 stimulates arachidonate 15-lipoxygenase activity and oxygen radical formation in the rat distal lung

We investigated the effects of intravenous bolus of endothelin-1 on the metabolism of eicosanoids and oxygen radicals in the distal lung unit of the rat. Intravenous bolus of endothelin-1 caused a significant increase in 15-hydroxyeicosatetraenoic acid of bronchoalveolar lavage fluid and oxygen radicals produced by the bronchoalveolar cells. Endothelin-1 exhibited a stimulatory effect on the 15-lipoxygenase activity in the lung homogenate. Thus, endothelin-1 may contribute to the inflammatory and hyperreactive process of lungs, by enhancing the release of 15-hydroxyeicosatetraenoic acid and oxygen radicals in the distal lung unit.

Biochemical characteristics of lungs in senescence-accelerated mouse (SAM).

This study examined age-related biochemical changes of the lung in an animal model of senile lung, senescence-accelerated mouse (SAM). Bronchoalveolar lavage (BAL) was performed on two strains of SAM, the senescence-prone strain (SAM P2) and the senescence-resistant strain (SAM R1), as well as on normal ageing C57 black mice (C57BL), aged 1-24 months. Elastase-like and elastase inhibitory activity of BAL fluid (BALF), glutathione (GSH) and oxidized GSH (GSSG) content both of BALF and lung tissue, and oxygen radical generation of free lung cells obtained by BAL were examined in the three strains of mice. Cell populations did not change throughout the life in SAM strains and C57BL. The elastolytic activity in SAM was greater than in C57BL, but there was no change with age. Both a decreased content of GSH and an increased oxidation of the GSH in BALF were markedly observed with ageing in SAM P2. In the lung tissue, the GSSG/GSH ratio in SAM strains was consistently greater than that in C57BL, suggesting that the GSH redox cycle of the lung may be impaired in SAM strains. The oxygen radical generation by free lung cells increased with age in all three strains, but the increase was earlier and more pronounced in SAM P2 than in the other two strains. In conclusion, an impaired GSH redox cycle and an increased formation of oxygen radicals are observed in the lungs of SAM with increasing age.

A new murine model of aging lung : the senescence accelerated mouse (SAM)-P

The senescence accelerated mouse (SAM) has recently been characterized as a unique model to investigate age-related disorders, including amyloidosis, cataract, osteoporosis and dementia. However, little is known as to the properties of the lung in these animals. Tobacco smoke is also associated with enhanced loss of elastic recoil and the development of emphysema. We have attempted to examine morphological as well as biochemical changes of the distal lung in SAM-P/2, as the senescence-prone series and SAM-R/1, as the senescence-resistant series. The animals were intermittently exposed to tobacco smoke or air by Hamburg II machines for 5 weeks. Then both groups of animals were killed for histologic and biochemical study. Compared with SAM-R/1, SAM-P/2, even with air exposure, showed a higher value of the mean linear intercept without alveolar wall destruction. It became even greater due to tobacco exposure with emphysematous change. Tobacco exposure accumulated inflammatory cells into alveoli in SAM-P/2, but not in SAM-R/1. Oxygen radical generation by those cells was also higher in SAM-P/2. Analysis of bronchoalveolar lavage fluid in SAM-P/2 after tobacco exposure disclosed increases in albumin content, total protein content and elastase-like activity. There were decreases in the ratio of elastase inhibitory capacity (EIC) to trypsin inhibitory capacity (TIC), contents of glutathione and total free thiol groups. Moreover, SAM-P/2 showed significantly lower EIC/TIC ratio in serum, even with air exposure, than that of SAM-R/1. These results indicate that SAM-P/2 can be a good model for the study of natural evolution of the aging lung as well as its susceptibility to tobacco smoke in the development of emphysema.

Age changes in visceral content of glutathione in the senescence accelerated mouse (SAM)

Free radical formation is known to play a role in the aging processes. However, it is still disputable whether the scavengers of free radicals including glutathione (GSH) decrease during aging. The senescence accelerated mice (SAM) are known to show age-related disorders. Some of these syndromes were thought to be closely associated with oxidative damages. Using the two strains of SAM, SAM-R/1 and SAM-P/2, we examined age-related changes in GSH content in the tissues and its oxidation. In the eye, GSH levels were significantly decreased at the age of 16 months in SAM-P/2 and female SAM-R/1. The ratio of oxidized glutathione to total GSH increased, indicating GSH may play an important role in the eyes. But there were no remarkable age-related changes in GSH contents of other tissues such as liver, kidney and lung in both SAM-R/1 and SAM-P/2. These data suggest that the GSH level of the tissues in general can not be a proper indicator for senescence.

Influences of Tobacco Smoke and Vitamin E Depletion on the Distal Lung of Weanling Rats

Tobacco smoke is associated with pulmonary emphysema via elastase-antielastase and oxidant-antioxidant imbalance. This study addressed the tobacco smoke-induced changes in the lungs of weanling rats with vitamin E depletion. Three-week-old Wistar rats fed on vitamin E-depleted or normal diet were intermittently exposed to tobacco smoke by Hamburg II machines for 4 weeks. Tobacco smoke significantly suppressed body weight increases, particularly in the vitamin E-depleted group. In the normal diet group, tobacco smoke induced emphysematous changes with significant increases in the mean linear intercept (Lm) and the destructive index (DI), which was supported by an increase in elastase-like activity and a decrease in elastase inhibitory capacity (EIC) in bronchoalveolar lavage (BAL) fluid. Vitamin E depletion alone altered neither Lm nor DI. In tobacco-exposed animals in addition to vitamin E depletion, elastase-like activity, EIC in BAL fluid and DI were comparable to that in tobacco-exposed animals on a normal diet. However, Lm was markedly decreased with thickened epithelium and shrunk alveolar space. These results suggest that vitamin E depletion, when linked to tobacco exposure, might induce impaired lung development in the weanling rats, which is different from the emphysematous changes.

Intravenous bolus of prednisolone decreases 15-hydroxyeicosatetraenoic acid formation in the rat model of acid aspiration

Background and MethodsTo test the hypothesis that the effect of steroids on hydrochloric acid aspiration may be involved in the metabolism of eicosanoids, we investigated the effects of an iv bolus of prednisolone on the metabolism of 15-hydroxyeicosatetraenoic acid and 11-dehydrothromboxane B2 (11-dehydro-TxB2) in the rat model of acid aspiration. Wistar rats were randomly selected for three groups and treated with either a) an iv bolus of saline after intratracheal injection of saline (control group), b) an iv bolus of saline after intratracheal injection of acid (acid-saline group), or c) an iv bolus of prednisolone after intratracheal injection of acid (acid-prednisolone group). The concentrations of 15-hydroxyeicosatetraenoic acid and 11-dehydro-TxB2 in bronchoalveolar lavage fluid were measured by radioimmunoassay. ResultsThe concentration of 15-hydroxyeicosatetraenoic acid in bronchoalveolar lavage fluid of either acid-saline group (804 ± 129 pg/ mL) or acid-prednisolone group (748 ± 112 pg/ mL) was significantly greater than that of the control group (143 ± 27 pg/mL, p < .01) 1 hr after the administration. The iv bolus of prednisolone caused a significant decrease in 15-hydroxyeicosatetraenoic acid (acid-saline group 1027 ± 43 pg/mL; acid-prednisolone group 514 ± 62 pg/mL; p < .01) and cell counts of bronchoalveolar lavage fluid 48 hrs after intratracheal injection of acid, while there was no significant change in 11-dehydro-TxB2. ConclusionThese findings suggest that corticosteroid administration may contribute to the inhibition of the inflammatory process of lungs after acid aspiration by decreasing the release of 15-hydroxyeicosatetraenoic acid in the distal lung unit. (Crit Care Med 1991; 19:950)