Biomedical Engineering Reference
In-Depth Information
Table 3
Novel Targets for Inhibition of the Mucus Hypersecretory Phenotype in
COPD
Target
Requirement
Example drug(s)
Reference
Bax
Inducer
-
(131)
Bcl-2
Inhibitor
Antisense
oligonucleotides (e.g.,
ODN64 and ODN83)
(130)
EGFR tyrosine
kinase
Inhibitor
AG1478,
BIBX1522, and
ZD1839 (Iressa)
(115)
Epoxyeicosanoids
Adjunct therapy
-
-
Epoxygenase
Inducer
Benzafibrate
(111)
hCLCAl
Inhibitor
MSI1956 (talniflumate)
(149)
MAP kinase
Inhibitor
SB203580, SB202190
(120)
MARCKS
Inhibitor
Synthetic peptide to
N-terminal region,
antisense oligonucleotide
(116)
MEK
Inhibitor
PD98059 and U0126
(121)
MUC gene
expression
Inhibitor
Antisense oligonucleotide
(129)
Muncl8B
Inhibitor
Antisense oligonucleotide
(117)
Nitric oxide (NO)
iNOS inhibitor
GW273629, L-NIL
(114)
Oxidants
Inhibitors
N-acetylcysteine, superoxide
dismutase mimetics, and
spin trap compounds
(150)
P2Y
2
purinoceptors
Agonist
INS365
(132)
P2Y
2
purinoceptors
Antagonist
? reactive blue 2 derivatives
(134)
PtdIns 3-kinase
Inhibitor
LY294002
(121)
RAR-
a
Antagonist
RO-41-5253
(127)
hCLCAl, human calcium-activated chloride channel 1; EGFR, epidermal growth factor tyro-
sine kinase receptor; iNOS, inducible nitric oxide synthase; MAP, mitogen-activated protein
(kinase); MARCKS, myristoylated alanine-rich C kinase substrate; MEK, mitogen-activated
protein
=
extracellular signal-regulated kinase (ERK) 1
=
2 kinase; PtdIns, phosphatidylinositol;
RAR-
a
, retinoic acid receptor-
a
Inhibitors of Mucin Exocytosis
Inhibition of mucin exocytosis is a therapeutic option for mucus hypersecre-
tion in COPD. However, it should be noted that inhibition of secretion
could lead to excessive accumulation of intracellular mucins, with unknown,
and potentially detrimental, effects on secretory cell function. Myristoylated
alanine-rich C kinase substrate (MARCKS) protein is a key intracellular
molecule involved in intracellular movement and exocytosis of mucin
granules (116). Blockade of MARCKS by a synthetic peptide to its N-term-
inal region inhibited mucin secretion by normal human bronchial epithelial
