Biomedical Engineering Reference
In-Depth Information
eosinophils, mast cells, macrophages, epithelial cells, fibroblasts, and even
bronchial smooth-muscle cells are involved in asthma and become activated
(19,87). At the cellular epicenter of this process are CD4
รพ
T-helper memory
cells. These produce an array of cytokines that directly or indirectly ''pro-
gram'' the leukocytes that are responsible ultimately for acute and chronic
inflammation in the airways (87). The principal type 2 helper (Th2) cyto-
kines implicated in this process include interleukin (IL) -4, which is required
to drive production of allergen-specific immunoglobulin E (IgE) (88), IL-3,
which controls mast cells and basophil development (89), and IL-5 in con-
junction with IL-3 and granulocyte-macrophage colony-stimulating factor
(GM-CSF), which regulate eosinophil recruitment and activation. In addi-
tion, there is growing interest in the role in Th2-derived IL-9 in regulation
of IgE production and mast cell growth, and in I1-13 in relation to airways
hyperreactivity. Furthermore, it has been recently observed that T cells infil-
trating the airway mucosa of atopic asthmatic express the Th2 chemokine
receptors CCR4 and, to a lesser extent, CCR8, and that their number
increases after allergen challenge, but not the Th1 chemokine receptor
CXCR3 (49). CCR4 is the high-affinity receptor for the CC chemokines thy-
mus- and activation-regulated chemokine (TARC) and monocyte-derived
chemokine (MDC). CCR4 is very highly expressed by Th2 cells. It is also
found on dendritic cells, monocytes, basophils, and platelets (51). After
allergen challenge, it has been demonstrated that virtually all T cells
obtained from asthmatic patients express CCR4. Also CCR8 is coexpressed
on T cells, but to a lower extent. The expression of CCR4 was paralleled by
strong expression of its ligands MDC and TARC in the airway epithelial
cells after allergen challenge, suggesting that the CCR4
=
ligands axis may
be involved in the Th2 cell recruitment (Fig. 2).
Eosinophils store and release, on appropriate activation, a wide spec-
trum of proinflammatory mediators including cationic granule proteins,
major basic protein (MBP), eosinophil cationic protein (ECP) and eosino-
phil-derived neurotoxin (90). They have also been shown to synthesise up
to 28 cytokines, chemokines and growth factors, many of which are stored
in their crystalloid granules (91). Major basic protein directly increases
smooth-muscle reactivity by causing the dysfunction of vagal muscarinic
M2 receptors. It also triggers the degranulation of mast cells and basophils.
In addition, eosinophils amplify the inflammatory cascade by producing their
own chemoattractants [e.g., RANTES (regulated upon activation normal T-
cell expressed and secreted), eotaxin, and platelet-activating factor), which
accelerate the recruitment of eosinophils into the inflammatory focus (92).
Further damage is caused by hydrogen peroxide and halide acids,
which are generated by eosinophil peroxidase, and by superoxide, which
is generated by the respiratory-burst-oxidase pathway in eosinophils. Eosi-
nophils also generate large amounts of the cysteinyl leukotriene, LTC
4
,
which is metabolized to LTD
4
and LTE
4
. These three lipid mediators are
