Biomedical Engineering Reference
In-Depth Information
agents (201), and it appears that some of the same mechanisms of activa-
tion of migration may also act on epithelial cells. The TNF-
a
is able to
stimulate bronchial epithelial cell motility and the effects are mediated
by PKC (202,203). Other inflammatory mediators that have been shown
to enhance bronchial epithelial cell migration are tachykinins and bombe-
sin analogues (204,205). Inflammatory mediators such as combinations of
IFN-gamma and IL-2 can drive repair activity of type II alveolar cells by
stimulating migration and preventing programmed cell death (206). In
contrast to mesenchymal cells, bronchial epithelial cell migration is
enhanced by agents that activate protein kinase A (PKA) (207). TGF-
b
has been described as a chemoattractant for fibroblasts and bronchial
epithelial cells (208,209). The effect of TGF-
b
in in vivo models is thought
to be one of cellular accumulations, particularly the accumulation of fibro-
blasts (210). The effects of TGF-
b
maybe multiphasic, with initial effects
on increasing cell accumulation in wounds, followed by later effects that
alter morphology of the cells and increase cell attachment and wound
strength. Bronchial epithelial cells also respond to growth factors including
insulin, IGF-1, and EGF (211,212).
B. Airway Remodeling
Airway remodeling may be defined as the development of disrupted, abnor-
mal airway morphology. Abnormal morphology influences function of the
airway in COPD, contributing to airflow obstruction and bronchial
hyper-responsiveness (177,213). Inflammation and injury of the epithelium
likely contribute to airway wall remodeling in several ways. Epithelial cell
metaplasia and increased mucin gene expression contribute to airflow
obstruction. Epithelial cells produce matrix proteins that can be deposited
in the airway wall and interact with fibroblasts to modulate fibroblast
migration, proliferation, and contraction. The interactions of epithelial cells
with fibroblasts and other mesenchymal cells are being increasingly recog-
nized as part of a coordinated system that forms and maintains airway
structure (214).
Mucus hypersecretion from hyperplastic airway goblet cells is a hall-
mark of COPD (215). A number of mediators are now known to modulate
mucin gene expression and the formation of goblet cells. Activation of
epidermal growth factor receptors is responsible for mucin production after
inhalation of cigarette smoke in airways in vitro and in vivo (215,216). The
TNF-
a
and neutrophil elastase augment mucin gene expression (110,217).
The PKC and one of its substrates, MARCKS, have been reported to be
involved in mucus hypersecretion (218-220).
Epithelial cells modulate the extracellular matrix in several ways. First,
epithelial cells directly produce matrix proteins. Production of fibronectin
