Biomedical Engineering Reference
In-Depth Information
IV.
ELAFIN
The mature form of elafin is a 6-kDa protein possessing a WAP domain,
homologous to the WAP domains present in the SLPI protein and is found
in bronchial secretions and skin (61,62). Elafin is expressed not only by
many cell types present in the lung, but also by endothelium and AMs
(63-65). The elafin gene is 2.3 kb in length, composed of three exons and
two introns, and possesses transcription factor binding sites for AP-1 and
NF-
k
B (65-67). Elafin is expressed as a 117-amino acid protein, which
includes a 22-residue signal peptide (65). TNF-
a
and IL-1 have both been
demonstrated to induce elafin expression in pulmonary epithelial cells,
although LPS does not (67). The primary function of elafin is the inhibition
of the neutrophil serine proteases NE and proteinase 3 but not cathepsin G
(68,69). In contrast, SLPI inhibits cathepsin G but not proteinase 3 (44). As
with SLPI, elafin is a potent inhibitor of NE with an association rate con-
stant of 3.6
10
6
M
1
sec
1
. Other activities of elafin have been described.
For example, overexpression of elafin improves acute lung injury induced by
Pseudomonas aeruginosa in mice, although it is not clear if this effect is
dependent on the antiprotease activity of elafin or an antibacterial
=
anti-
inflammatory effect (70). Recently, it has been demonstrated that pre-elafin
can protect against LPS-induced lung inflammation in mice by decreasing
neutrophil influx into the lung, decreasing gelatinase activity, and reducing
levels and expression of a number of proinflammatory mediators (71). How-
ever, the full extent of elafin's antibacterial
=
anti-inflammatory properties
has not been fully elucidated.
V. TISSUE INHIBITORS OF METALLOPROTEASES
Four human TIMPs (TIMP-1, -2, -3, and -4) have been identified to date
and their expression is regulated during development and tissue remodeling
(72). Mature TIMP proteins have similar molecular weights of between 21
and 28 kDa (73). Each TIMP is composed of an N-terminal and C-terminal
domain, and each domain contains three disulfide bridges that make the
protein quite stable (74). Most of the biological functions of TIMPs reside
within the N-terminal domain, although the C-terminal domain mediates
interactions with some MMP zymogens. The primary function of TIMPs
is to act as endogenous inhibitors of MMP activity and, as with other
antiproteases, TIMPs play an important role in controlling extracellular
protease activity in order to prevent undesired tissue damage by MMPs
(Fig. 3). However, as with the other antiproteases described so far, TIMPs
have a multiplicity of roles, which are not related to inhibition of MMP
activity and include growth-promoting activity, apoptosis, and immunomo-
dulation of growth factor-induced cell growth.
