Monocyte maturation to macrophages and transformation into epithelioid granuloma cells in some granulomatous diseases are accompanied by the induction of membrane-bound angiotensin-converting enzyme (ACE). The physiologic and pathophysiologic roles of ACE generated in these processes are not known. The pattern and the mechanism of ACE induction in human monocytes are also not well understood. Dexamethasone is one of the agents reported to induce elevated ACE activity in human monocytes, and therefore a suitable tool for studying the phenomenon. This study shows that dexamethasone augments monocyte ACE in a biphasic dose-dependent manner with maximum effect at 10(-8) M concentration. Although it enhances the level of ACE activity, dexamethasone does not alter the time course for ACE induction from that found in unstimulated monocytes. The ACE activity of monocytes cultivated in 10 nM dexamethasone and then exposed to 10(-3) M diazosulfanilic acid (DASA) is reduced approximately by 80% in comparison with cells not treated with DASA, demonstrating that dexamethasone-induced ACE is an ectoenzyme. Dexamethasone does not increase the activity of other monocyte ectoenzymes: gamma-glutamyltransferase, alkaline phosphodiesterase-I, and leucine aminopeptidase, showing that dexamethasone induction of ACE is a specific, rather than generalized, effect on plasma membrane enzymes. It is suggested that the increase in ACE activity is due to the increased rate of enzyme synthesis.
The condensed tannin present in cotton mill dust profoundly alters the functional capabilities of resident alveolar macrophages. Previous studies from this laboratory have shown that in vitro exposure of rabbit resident alveolar macrophages to condensed tannin significantly inhibits the ability of these cells to produce reactive oxygen intermediates or to ingest particles. In the present study, we demonstrate that condensed tannin also alters arachidonic acid (C20:4) metabolism in these cells. Exposure of rabbit resident alveolar macrophages to condensed tannin results in the time- and dose-dependent release of C20:4 from the membrane phospholipids. The release of C20:4 occurred only at tannin concentrations greater than 25 micrograms/ml and was maximal 90 min after the onset of exposure. The EC50 for release was 75 micrograms/ml. Exposure to 100 micrograms/ml tannin resulted in the release of 20 +/- 3% of the [14C]C20:4 incorporated in the cell membrane. In comparison, exposure to 160 micrograms/ml zymosan resulted in the release of 14 +/- 4% of the [14C]C20:4. For both tannin and zymosan, phosphatidylcholine and phosphatidylinositol were the principal sources of the released C20:4. Approximately 63% of the C20:4 released after zymosan stimulation was further metabolized, mainly via the cyclooxygenase pathway. The major metabolites were 6-keto-prostaglandin F1 alpha, prostaglandin F2 alpha, and prostaglandin E2. In contrast, only 24% of the C20:4 released by tannin was subsequently further metabolized. The metabolites formed were essentially evenly distributed between products of the cyclooxygenase pathway and the lipoxygenase pathway. Exposure of alveolar macrophages to 50 micrograms/ml tannin for 30 min reduced the ability of the cells to subsequently incorporate C20:4 by 50 to 70%. In contrast, exposure of the cells to 160 mg/ml zymosan for 30 min had only a minimal effect on the subsequent ability of these cells to incorporate C20:4. These results indicate that tannin promotes C20:4 release, at least in part, by inhibiting its reacylation back into phospholipids, a mechanism that differs from that of zymosan.
Inhalation of cotton mill dust or condensed tannin, a major botanical component of cotton mill dust, induces an acute pulmonary inflammatory response characterized by a rapid influx of neutrophils into the airways. The development of neutrophil alveolitis caused by tannin inhalation is accompanied by the accumulation of low molecular weight neutrophil chemotactic factor (NCF) in the airways. To determine if the alveolar macrophage is the source of this NCF, the ability of tannin to induce the secretion of NCF from rabbit alveolar macrophages was examined in vitro. Tannin did promote the secretion of NCF from alveolar macrophages in a time- and dose-dependent manner. Secretion began immediately after challenge and was maximal after 4 to 5 h. Maximal secretion occurred at a tannin concentration of 50 micrograms/ml. Comparison with the dose response for NCF secretion by cotton dust extract indicated that tannin was the major component in the dust responsible for NCF secretion from alveolar macrophages in the time period examined. The NCF had an apparent molecular weight of greater than 800 as determined by gel chromatography. The NCF could be extracted into organic solvents, suggesting it was a lipid. Its secretion, however, could not be prevented by treatment of the macrophages with the 5-lipoxygenase inhibitor, nordihydroguaretic acid, demonstrating that the NCF was not leukotriene B4. These data indicate that the action of tannin on resident alveolar macrophages results in the secretion of a NCF that may be responsible for the acute neutrophil alveolitis associated with inhalation of cotton dust.
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