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Article, 信州医学雑誌 41(2): 89-101(1993)

We investigated the molecular pathogenesis of bronchial asthma focusing on the contribution of neutrophil elastase （NE） and arachidonic acid metabolites to asthma exacerbations and their recovery phase. Serum eosinophil cationic protein （ECP）, plasma NE levels, and urinary leukotriene E4 （LTE4） concentrations significantly increased during exacerbations （n=118） as compared with the stable state （n=48）. Serum soluble interleukin-2-receptor, and thromboxane A2 and prostaglandin I2 urinary metabolites were unchanged. Within the exacerbation group, plasma NE levels in a severe group （n=12） were significantly higher （p＜0.05） than those in a moderate group （n=42）, which in turn, were significantly higher （p＜0.01） than those in a mild group （n=64）. Urinary LTE4 levels in the severe group were significantly elevated （p＜0.05） compared to the mild group, but no difference existed between the moderate and mild groups. Seven days of steroid therapy inhibited the rises in serum ECP and urinary LTE4 but not that of NE. Plasma NE might be one of the good markers of asthma exacerbation severity which is not inhibited by current steroid therapy. NE inhibitor might be an effective therapy for moderate to severe acute asthma exacerbations when they are associated with high levels of plasma NE.

In recent years, it has been reported that leukotrienes （LTs） play an important role in endotoxin shock. In the present investigation the author measured leukotrienes in ascites and venous blood of peritonitis rats using high performance liquid chromatography. The following results were obtained. （1） In ascites of peritonitis rats, LTC4, LTD4, LTE4 and LTB4 were detected. LTC4 level in ascites was unchanged at the time course of peritonitis. However, LTD4 and LTB4 levels in ascites showed a decrease while LTE4 level showed an increase. （2） In venous blood of peritonitis rats, LTC4, LTD4 and LTE4 were detected. LTC4 level in blood was for the most part unchanged at the time course of peritonitis. It was found that LTD4 level in blood showed a decrease while LTE4 level showed an increase. （3） The amounts of leukotrienes in ascites and venous blood were gradually decreased by pretreatment with the specific 5-lipoxygenase inhibitor AA-861 after peritonitis. The decrease continued for 5 hours after the start of peritonitis. （4） Intravenous administration of 1 mg/kg dexamethasone showed no change in amounts of leukotrienes in ascites and venous blood. Administration of 10 mg/kg dexamethasone, however, brought about a decrease of leukotrienes after peritonitis. These findings indicated that leukotrienes when elevated play an important role in endotoxin shock.

Rat α2AP was isolated from the sera of turpentine induced inflammatory rats by an immunoaffinity chromatography and the inhibitory activity of α2AP on rat adjuvant arthritis was investigated. The results obtained were as follows: 1） Rat α2AP administration inhibited both the primary inflammation and the secondary inflammation （adjuvant arthritis） induced by Freund's complete adjuvant. The inhibitory effects of α2AP on adjuvant arthritis were found to be enhanced by inhibiting the primary inflammatory processes. 2） In the α2AP injected groups, serum α2AP levels on the 23rd experimental day were significantly correlated with the score of the arthritis and were good indices for grading the inflammatory changes. 3） In comparing the histological changes in the subsynovial tissues of the α2AP injected groups with the α2AP non-injected groups, the inflammatory processes, such as proliferation of mononuclear cells and collagen fibers, were less active in the former groups. 4） Rat α2AP suppressed the chemotaxis of mouse abdominal neutrophils and the release of β-glucuronidase, one of the lysosomal enzymes, and leukotrienes B4/C4/D4/E4 from rat abdominal leucocytes. It was suggested that these biological activities may participate, at least in part, in the inhibitory effects of α2AP on adjuvant arthritis.