Consequences of Elastolysis - Extracellular Matrix Degradation - page 227

9.4 Biological Consequences of Elastolysis
Elastic fibers and other matrix proteins have traditionally been considered solely as
structural support for surrounding tissues. In addition to the structural abnormalities
generated by matrix degradation (above), we now know that products of matrix
degradation possess bioactive properties (Maquart et al. 2004 ). Such matrix-derived
peptides have subsequently been termed “matrikines.” Elastin fragments (EFs) or
elastin degradation products (EDPs) are the best characterized of the matrikines to
date and exert diverse biological functions including chemotaxis, gene transcrip-
tion, and cell cycle regulation (Duca et al. 2004 ). While it would be advantageous
for an injury significant enough to damage resilient elastic fibers to elicit a repara-
tive response, unfortunately, EFs evoke detrimental responses in the setting of
chronic, low-grade elastin degradation.
9.4.1 Chemotactic Properties of EFs
Senior and Mecham first described the monocyte chemotactic properties of EFs
in vitro in 1980 (Senior et al. 1980 ), which were independently corroborated by
Hunninghake et al. shortly thereafter (Hunninghake et al. 1981 ). Since that time,
EFs have been confirmed to possess in vitro chemotactic activity for fibroblasts
(Jacob et al. 1987 ), smooth muscle cells (Ooyama et al. 1987 ), endothelial cells
(Long et al. 1989 ), lymphocytes (Hauck et al. 1995 ), and a number of malignant cell
lines including Lewis lung carcinoma (Grosso and Scott 1993a , b ).
EFs are now recognized as the major source of monocyte chemotactic activity in
cigarette smoke-induced emphysema (Houghton et al. 2006a , b ). As discussed
above, emphysema is characterized by the degradation of elastic fibers and loss
of elastic recoil that is caused by a chronic inflammatory cell infiltrate composed
of macrophages, lymphocytes, and neutrophils. While investigating the role of
MMP12 in cigarette smoke-induced emphysema, MMP12 / mice were noted to
be protected not only from emphysema but also from the accumulation of macro-
phages in the lung (Hautamaki et al. 1997 ). After the identification of EFs in the
BALF of WT mice exposed to cigarette smoke, antibodies to EFs were adminis-
tered to mice demonstrating that both the accumulation of lung macrophages and
the subsequent development of emphysema were dependent upon EFs. Based on
this work, and other recent studies, the means by which macrophages are recruited
to the lung is coming into focus. Upon cigarette smoke-exposure, CD8 + lympho-
cytes release IP-10, a member of the CXC chemokine family (Grumelli et al. 2004 ).
IP-10 interacts with CXCR3 on macrophages, which induces the expression and
release of MMP12 (Maeno et al. 2007 ). These activated macrophages also release
neutrophil chemokines that will bring neutrophils, and hence NE, into the lungs.
In turn, EFs recruit na ¨ ve monocytes to the lung where they differentiate into
mature tissue macrophages, ultimately propagating the destruction of lung tissue.