This file is a new feature for the Aneurysm Information Project. 
Every month the editor will pick one or more papers from the 
current biomedical literature, usually relating to the biology of
the abdominal aortic aneurysm (AAA).  Publications on causation
and/or prevention will be preferred.  A brief abstract will be
offered based on the summary and data published by the authors,
with some (usually minor) editing.  Following the abstract, there
may be some brief commentary by the editor.

Investigators in the field are invited to bring newly published
work to the attention of the editor.  Please E-mail abstracts to
mdt1@columbia.edu.  

DECEMBER 1994 (papers from the November journal issues)

#1.  Keen RR, Nolan KD, Cipollone M, Scott E, Shively VP, Yao JST,
Pearce WH.  Interleukin-1-beta induces differential gene expression
in aortic smooth muscle cells.  J Vasc Surg 1994; 20: 774-86.

ABSTRACT (adapted from authors):

Purpose.  AAA's are characterized by accelerated turnover of ECM
proteins and an inflammatory infiltrate that releases the cytokines
interleukin-1-beta (IL-1b) and tumor necrosis factor-alpha (TNF-a). 
The authors examined expression of the genes for COL I, COL III,
elastin, MMP-1, MMP-2, TIMP-1, and TIMP-2 in smooth muscle cells
(SMC's) cultured from biopsies of AAA (n=6) and normal  donor aorta
(n=3).

Methods.  SMC's were cultured, passaged (P2-P4), incubated with IL-
1b, TNF-a, or PDGF for 24 hrs.  Total RNA was harvested, and gene
expression was determined by Northern blots.

Results.  IL-1b resulted in significant, dose-dependent increases
in MMP-1 mRNA at all concentrations tested in AAA and control SMC
cultures, in the range of 3.5-4.5 fold.  IL-1b caused a 40-50%
decrease in COL I expression in AAA and control SMC's.  The only
qualitative difference observed between the AAA and control SMC
responses to IL-1b was with respect to TIMP-1.  The TIMP-1 message
increased about 80% in AAA, but it remained constant in the
control.  TNF-a and PDGF did not result in significant changes in
any of the expressed genes in AAA SMC's.

Conclusions:  The findings suggest that IL-1b, through its effect
on smooth  muscle cell collagenase and collagen gene expression,
may mediate the increased matrix turnover observed in AAA's.  

COMMENTARY (by MDT)

The Northwestern University research group has previously shown
that AAA aortic explants release the macrophage-derived cytokines
IL-1b and TNF-a.  My research group has just published similar
findings, based on tissue extraction instead of cultured explants
(See Paper #2 this month).  Our group has also localized MMP-1 to
mesenchymal cells immunohistochemically in AAA tissue (See Paper #3
this month).  The present work from the Northwestern group fills in
another important piece of the puzzle.

IMHO the most interesting finding is the persistance of a
difference in SMC response between AAA and controls after 2-4
passages.  AAA SMC's respond to IL-1b with an increase in TIMP-1
gene expression, whereas control SMC's do not.  We once considered
the TIMP-1 gene a candidate for the AAA gene and sequenced it in 6
patients.  Two had an identical point polymorphism, but it was in
the third position of the codon and turned out to be trivial. 
Perhaps some  post-transcriptional alteration occurs in normal TIMP
physiology and/or regulation in the AAA phenotype.



#2.  Newman KM, Johnson CL, Jean-Claude J, Li H, Ramey WG, Tilson
MD.  Cytokines which activate proteolysis are increased in
abdominal aortic aneurysms.  Circulation. 1994; 90 [part 2]: II-
224-7.  

ABSTRACT

Background:  AAA disease is characterized by an increase in
proteolysis and loss of matrix components.  TNF-a and IL-1b,
products of activated macrophages and T-cells, are known to
increase production of matrix-degrading enzymes in some
pathological states.

Methods and results:  Seven AAA and five control aortic tissue
extracts were assayed for TNF-a and IL-1b with ELISA.  IL-1b was
elevated in AAA about 4-fold; and TNF-a was elevated almost 90-
fold.  Western blots revealed known isoforms of both cytokines in
AAA tissue.

Conclusion:  The presence of TNF-a and IL-1b in AAA tissue
underscores the importance of the infiltrating inflammatory cells
present in the media and adventia of the aneurysmal aortic wall.



#3.  Newman KM, Jean-Claude J, Li H, Scholes JV, Ogata Y, Nagase H,
Tilson MD.  Cellular localization of matrix metalloproteinases in
the abdominal aortic aneurysm wall.  J Vascular Surgery.  1994; 20:
814-20.  


ABSTRACT

Purpose.  This study explored the sources of the matrix-degrading
proteinases MMP-1 (collagenase), MMP-3 (stromelysin 1), and MMP-9
(gelatinase-B), previously implicated in AAA development.  The
possible involvement of the plasmin cascade in the activation of
these proteinases was also explored by examining the presence of
the urokinase-type plasminogen activator (uPA) in AAA wall.

Methods.  Immunohistochemical techniques were used to detect the
presence of MMP-1, MMP-3, and MMP-9 proteins and uPA in fixed,
paraffin-embedded tissue sections from AAA (n=10) and control (n=2)
aortas.

Results:  MMP-9  localized to mononuclear cells in AAA wall. 
Dual-labeling techniques confirmed the identity of these cells as
macrophages.  MMP-3 and uPA were also detected primarily in the
macrophages.  Immunoreactive material to MMP-1 was found in
mesenchymal (and occasionally adventitial endothelial) cells,
suggesting alternative expression and delivery of this enzyme in
AAA.  

Conclusions:  This work establishes a role for the macrophage in
the delivery and possible activation of MMP-9 and MMP-3 and for the
mesenchymal cell in the delivery of MMP-1 in AAA disease.