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Title: INDUCTION OF ADRENOMEDULLIN MRNA AND PROTEIN BY LIPOPOLYSACCHARIDE AND PACLITAXEL (TAXOL) IN MURINE MACROPHAGES

Author
item ZAKS-ZILBERMAN, MEIRAV - UNIVERSITY OF HEALTH SCI.
item SALKOWSKI, CINDY - UNIVERSITY OF HEALTH SCI.
item Elsasser, Theodore
item CUTTITTA, FRANK - NATIONAL CANCER INSTITUTE
item VOGEL, STEFANIE - UNIVERSITY OF HEALTH SCI

Submitted to: Infection and Immunity
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/21/1998
Publication Date: N/A
Citation: N/A

Interpretive Summary: Serious problems are seen during infection when the severity of the infection is great enough to cause invading microorganisms to access vital organs in the body through the blood stream. The reason that this is so serious relates to the complication of the development of shock, In this situation, blood pressure fall dangerously low and in the process some organs and tissues in the body suffer irreversible damage because oxygen can not reach the tissues and metabolic waste products can not be quickly removed. The newly discovered hormone adrenomedullin is known to cause changes in blood pressure that resemble those seen in serious infection and sepsis. This research was the first to demonstrate that the administration of very small doses of bacterial toxins that substitute for active infection are capable of causing cells of the immune system to release increased amounts of adrenomedullin. In addition, the data also show that tissues that are characteristically affected by the rapid onset of severe disease (lung, liver and the spleen) also increase the amount of adrenomedullin directly with in those tissues in response to this simulated disease. The data suggest that adrenomedullin may participate in the development of shock and the fall in blood pressure during illness. Furthermore, the data suggest that strategies that could limit the production of adrenomedullin could affect the outcome of disease processes.

Technical Abstract: Lipopolysaccharide (LPS), a potent inflammatory stimulus derived from the outer membrane of Gram negative bacteria, ha been implicated in septic shock. Plasma levels of adrenomedullin (AM), a potent vasorelaxant, are increased in septic shock and possibly contribute to the characteristic hypotension. As macrophages play a central role in the host response to LPS, we studied AM production by LPS-stimulated macrophages. When peritoneal exudate macrophages from C3H/OuJ mice were treated with protein- LPS (100 ng/ml) or the LPS-mimetic, Taxol (35 micromolar), a ~ 10-fold increase in AM steady-state mRNA levels was observed, which peaked between 2 and 4 h. A 3-4 fold maximum increase in levels of immunoreactive AM protein was detected after 6-8 h of stimulation. While LPS-hypotensive C3H/HeJ macrophages failed to respond to protein-free LPS, increased levels were observed after stimulation of these cells with protein-rich (butanol-e eted) LPS preparation. In addition, increased AM mRNA was observed following treatment of macrophages with T. gonsii parasite antigen. Interferon also stimulated macrophages to express increased AM mRNA levels, yet was inhibitory in the presence of LPS or Taxol. In vivo, mice challenged with LPS exhibited increased AM mRNA levels in lung, liver and spleen, with the greatest increase (>50 fold) observed in liver and lung. Thus AM is produced by macrophages and is induced by LPS in a number of tissues. These data support a possible role for AM in the pathophysiology pf sepsis and shock.