No abstract

The pathogenesis of emphysema is considered to be an imbalance of protease and antiprotease activity in the lower respiratory tract leading to uninhibited degradation of lung interstitium by elastolytic enzymes. An increased amount of the serine protease neutrophil elastase (NE) is though to play a major role in this degradation. Because the expression of NE is limited to neutrophil precursors in the bone marrow, we hypothesized that nicotine, which is readily absorbed from lung and distributed to tissue, including bone marrow, would increase expression of the NE gene and protein. HL-60 cells, a myeloblast/promyelocyte cell line, were cultured in the presence or absence of 0.06 and 0.8 microM nicotine for 5 d. Both concentrations of nicotine caused a 2.4- to 3.3-fold increase, respectively, in NE gene expression over unstimulated cells, and NE protein increased 4.8- to 3.4-fold over unstimulated cells, respectively, similar to our positive control DMSO. Nicotine did not induce upregulation of the NE gene by initiating cell differentiation. Both low and high nicotine concentrations upregulate the NE gene in HL-60 cells leading to increased NE protein concentration per cell suggesting a pathophysiologic mechanism for emphysema.

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Recently it has been reported from the senior author's laboratory that artificial alkaptonuria may be readily produced in the guinea pig by the supplementation of a vitamin C deficient diet with extra tyr0sine.l With the subsequent administration of the vitamin the homogentisic acid in the urine was promptly reduced in amount and within 48 to 72 hr was completely absent. These findings suggested that the relation of ascorbic acid to the excretion of homogentisic acid by the alkaptonuric patient should be investigated. However, in the course of the experiments with the guinea pigs, the results of two such investigations appeared. These reports by Monsonyi2 and by Diaz, Mendoza and Rodriquez3 indicate that ascorbic acid is without effect, but since, in our own mure recent studies* it has been apparent that in the guinea pig the effectiveness of the dose of ascorbic acid is dependent upon the state of vitamin saturation in the tissues, it was considered imperative to investigate the effect of doses of the vitamin greatly in excess of the normal human requirement, and also of the relatively small amounts used by the above investigators.Experimental. The individual who served as a subject for this study is an essentially normal 65-year-old white male who exhibited at the time of these experiments alkaptonuria and ochronosis-a deposition of pigment mainly in cartilage which is characteristic of these individuals in later years. Since the patient had previously been on an experiment in which he consumed a relatively high intake of protein, he was continued on this level, the diet being a mixed diet with considerable variety from day to day but so planned that it