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Papers of the Month - June 1998
Highlights of the Soc Vasc Surg/ International Soc CV
Surg presentations on AAA disease at the annual meeting
in San Diego, June 7-10, 1998.
1. McMillan WD, Pearce WH. Increased plasma levels of
MMP-9 are associated with abdominal aortic aneurysms.
(in man!)
Shortened abstract: Sandwich ELISA was used to measure
plasma MMP-9 in 22 patients with AAA, 9 with AOD, and 8
normals; and also in 48 hour supernatants from organ
cultures. Plasma MMP-9 was more than 3x greater in AAA
than in AOD; and the organ culture studies suggest that
diseased aortic tissue is the source of MMP-9. Also,
patients with multiple aneurysms had higher plasma levels
than those with an isolated AAA.
Comment by mdt: I think it is accurate to say that our
lab was the first to report that an activated form of
MMP-9 is present in the walls of AAA specimens
(Arterioscler Thromb 1994; 14: 1315-20); and that
antibody against MMP-9 inhibits the most conspicuous
gelatinase evident on substrate gel enzymography
(purified with r-TIMP @ MW 80 kDa). The present work is
an important contribution, suggesting that MMP-9 escapes
from the aneurysmal wall to circulate in plasma, where it
may be a useful marker of proteolytic activity in the
aneurysm.
2. Grange JJ, Baca-Regen LM, Lie J, Barent BL, Davis VA,
Baxter BT. MMP-2 expression can be regulated in human
aortic smooth muscle cells (SMC's) by
macrophage/lymphocyte interactions.
Short statement of principal findings: SMC exposed to
media from macrophages co-cultured with activated T-cells
produced more MMP-2 than controls stimulated with media
from either macrophages or T-cells alone. Upregulation
of MMP-2 by inflammatory cell coculture media was
attenuated when the macrophages were pretreated with
indomethacin.
Comment by mdt: These findings are interesting and
provide additional impetus to the notion that anti-
inflammatory therapies, directed against MMP activities
in particular, may be useful as a therapeutic approach to
stabilizing the growth of small aneurysms (or perhaps
even preventing them in people found to be genetically
susceptible). Work from our lab (Surgical Forum 1994;
45: 375) suggested that extracts from aneurysmal aortas
(which are somewhat equivalent in a clinical sense to a
macrophage/lymphocyte co-culture) stimulated production
of MMP-9 in a cultured macrophage-like cell line. Baxter
et al might find it informative to determine whether
lymphocytes harvested from AAA specimens had greater
stimulatory properties than lymphocytes from other
tissues in non-AAA patients.
3. Miralles M, Wester W, Thompson RW, Sicard GA, Reilly
JM. Prostaglandin E2 (PGE2) synthesis correlates with
aneurysmal expansion of the aorta and is regulated by
cyclooxygenase-2 (cox2).
Brief statement of principal findings: The authors use
the Anidjar/Dobrin rat model to show that AAA formation
is associated with the production of PGE2, and that the
synthesis of PGE2 is probably regulated by the cox2
isoform of cycloogenase. By in-situ hybridization, the
source of cox2 appears to be the Aneurysm-Infiltrating-
Macrophage (which we named the "AIM" cell in a
communication several years ago). This paper, as does #2
above, points in the direction of pharmacological
approaches to down-modulating AAA growth. (BTW, I can't
resist expressing satisfaction at seeing one of my former
students, Jeff Reilly, now leading his own research
program at Washington Univ, St. Louis; and, incidentally,
the previous paper on the program was given by another
former student, Colleen Brophy, who is leading a major
research project on the biology of the vascular smooth
muscle cell at the Medical College of Georgia.)