Aneurysm Papers of the Month - November 1995

HIGHLIGHTS RE ANEURYSMS FROM THE SURGICAL FORUM, AMERICAN
COLLEGE OF SURGEONS, OCTOBER 1995, NEW ORLEANS...

1. Shireman PK, McCarthy WJ, Pearce WH, Kwaan HC. 
Plasminogen activators are elevated in diseased aorta. 
Surg Forum, 1995, pp 362-364.

Abstract (adapted from authors):

Introduction - Elevations of plasmin have been implicated
in the pathogenesis of the AAA due to plasmin's ability
to digest ECM and to activate MMP's.  t-PA is thought to
be more important in modulation of fibrinolysis, and uPA
is predominant in matrix remodeling.  This study
determines the levels of both activators in normal,
occlusive, and AAA aortic wall.

Methods - Tissue explant supernatants & ELISA assays. 
uPA mRNA also measured by northern blots with GAPDH
normalization for loads.

Results - tPA elevated in both AAA and OCC tissue. 
However, uPA elevated ~ 4x in OCC and ~8x in AAA (versus
normal).  p<.005 for AAA vs OCC.  mRNA followed same
pattern.

Discussion - uPA differentially expressed in aortic
pathology.


Comment by mdt - This interesting study cited previous
work by Jean-Claude et al (Surg 116:472-8, 1994), which
suggested that plasmin might play a key role in AAA
pathogenesis.  If plasmin leaches into the aortic wall
from the intraluminal clot, there might be an answer to
the question posed by the work of Bernstein et al (see
citations in Jean-Claude), e.g. why should the arc
subtended by the intraluminal clot have an apparent
relationship to the rate of AAA expansion.  See also the
recent work of Reilly and colleagues on plasminogen
activators: Reilly JM, Sicard GA, Lucore CL.  Abnormal
expression of plasminogen activators in aortic aneurymal
and occlusive disease.  J Vasc Surg  1994; 19: 865-72.

2. Halloran BG, So BJ, Grange JJ, Baxter BT.  Human
macrophage products inhibit human arterial SMC
proliferation and down-regulate 1-alpha(I) procollagen
expression.  Surgical Forum, pp 367-370, 1995.  

Purpose: To study the effects of soluble factors from
stimulated macrophages on the proliferation of SMC's from
aortic media and their expression of the gene for the
alpha chain of Type I collagen.  

Methods: SMC's cultured from infrarenal aorta of organ
donors, and macrophages from human peripheral blood
stimulated with LPS.  Coulter counting for cell
proliferation, and reverse-PCR & Southerns for expression
of mRNA of 1aI and GAPDH.  

Results: There was about a 13% decrease in SMC
proliferation at 48 hrs when SMC's were exposed to
supernatants from stimulated versus unstimulated
macrophages.  Data for SMC proliferation with a control
blank stimulus were not given.  Statistically significant
suppression of 1aI collagen mRNA was detectable at 12
hours.

Conclusion:  "These in vitro changes in SMC growth and
matrix expression are consistent with the loss of SMC and
attenuation of the media present in aortic occlusive and
aneurym disease."

Comment by mdt - I'm not sure the paper laid an adequate
groundwork for the conclusion as stated.  It has been my
impression that SMC's are less abundant in AAA media than
in OCC media, but my lab has never done the quantitative
morphometrics to prove it.  Also, I am not impressed that
the media is severely attenuated in OCC.  The senior
author of this paper has actually proposed that aortic
mass is *increased* in AAA disease, and past studies on
collagen content have had mixed findings.  It is not easy
to make a clear interpretation of all of this
information.

Last year we took an approach to the potential role of
the macrophage that is perhaps easier to speculate about
(Hingorani A, Newman K, Gregory A, Tilson MD.  A soluble
extract from abdominal aortic aneurysm wall stimulates
protein secretion and gelatinase expression in cultured
macrophage-like cells (U937).  Surgical Forum, 1994, 45:
375-7).  It appeared that there were soluble factors in
the wall of the AAA that stimulated activation of a
macrophage-like cell line.  This information fits with
other recent studies of the presence of cytokines that
activate proteolysis in the wall of AAA (Circulation
90:II 224-227, 1994).

3. Kosierkiewicz TA, Capella JR, Yin NX, Tilson MD. 
Expression of the major histocompatibility complex (MHC)
Class II (DR) antigen by SMC of the media of AAA. 
Surgical Forum, pp 365-367, 1995.

This paper was the contribution from my lab that the
Forum accepted this year.  We have had a dramatic
crescendo of curiosity in the last several years about
numerous features of the AAA that suggest an autoimmune
response.  Double-staining with HAM56/LN-3 and SMalpha-A
revealed that 4.8 % of SMC's expressed HLA-DR, versus
0.3% of SMC's in the controls (3 OCC & 3 organ donors
combined) [p=.002, Mann-Whitney]. In an unguarded moment
of friendship with my anonymous net friends, I predict
that MHC Class II genotyping may be very informative in
revealing the basis for genetic susceptibility to AAA (as
it has been in rheumatoid arthritis).