DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

INFLAMMATORY CELLS
Cell number
( apoptosis)
Cytokines,
traffic
Eosinophil
T-lymphocyte
STRUCTURAL CELLS
Airway smooth
muscle
Bronchodilatation
Endothelial cell
1041
CHAPTER 36
Mediators
Cytokines
Mast cell
Macrophage
THEOPHYLLINE
Respiratory skeletal
muscles
Leak
Strength?
PULMONARY PHARMACOLOGY
Figure 36–6. Theophylline affects multiple cell types in the airway.
minimal at concentrations of theophylline that are within the
so-called therapeutic range. PDE inhibition and the concomitant
elevation of cellular cAMP and cyclic guanosine monophosphate
(cGMP) almost certainly account for the bronchodilator
action of theophylline, but PDE inhibition is unlikely to
account for the nonbronchodilator effects of theophylline that
are seen at lower concentrations. Inhibition of PDE should lead
to synergistic interaction with agonists through an increase in
cAMP (Figure 36–5), but this has not been convincingly
demonstrated in clinical studies. Several isoenzyme families of
PDE have now been recognized and those important in smooth
muscle relaxation include PDE3, PDE4, and PDE5.
Theophylline is a weak inhibitor of all PDE isoenzymes.
• Adenosine receptor antagonism. Theophylline antagonizes
adenosine receptors at therapeutic concentrations. Adenosine
causes bronchoconstriction in airways from asthmatic patients
by releasing histamine and leukotrienes. Adenosine antagonism
is unlikely to account for the anti-inflammatory effects of theophylline
but may be responsible for serious side effects, including
cardiac arrhythmias and seizures through the antagonism of
A 1
receptors. Of interest may be the adenosine A 2B
receptor
on mast cells, which is activated by adenosine in asthmatic
patients (Wilson, 2008).
• Interleukin-10 release. IL-10 has a broad spectrum of antiinflammatory
effects, and there is evidence that its secretion is
reduced in asthma. IL-10 release is increased by theophylline,
and this effect may be mediated via inhibition of PDE activities,
although this has not been seen at the low doses that are
effective in asthma (Oliver et al., 2001).
• Effects on gene transcription. Theophylline prevents the translocation
of the pro-inflammatory transcription factor NF-B into the
nucleus, potentially reducing the expression of inflammatory
genes in asthma and COPD. Inhibition of NF-B appears to be
due to a protective effect against the degradation of the inhibitory
protein I-B (Ichiyama et al., 2001). However, these effects are
seen at high concentrations and may be mediated by inhibition
of PDE.
• Effects on apoptosis. Prolonged survival of granulocytes due
to a reduction in apoptosis may be important in perpetuating
chronic inflammation in asthma (eosinophils) and COPD
(neutrophils). Theophylline promotes apoptosis in eosinophils
and neutrophils in vitro. This is associated with a reduction in
the anti-apoptotic protein Bcl-2 (Chung et al., 2000). This
effect is not mediated via PDE inhibition, but in neutrophils
may be mediated by antagonism of adenosine A 2A
receptors
(Yasui et al., 2000). Theophylline also induces apoptosis in T
lymphocytes, reducing their survival; this effect appears to be
mediated via PDE inhibition (Ohta and Yamashita, 1999).
• Histone deacetylase activation. Recruitment of histone deacetylase-2
(HDAC2) by glucocorticoid receptors switches off inflammatory
genes. Therapeutic concentrations of theophylline activate
HDAC, thereby enhancing the anti-inflammatory effects of corticosteroids
(Cosio et al., 2004; Ito et al., 2002). This mechanism is
independent of PDE inhibition or adenosine receptor antagonism
and appears to be mediated by inhibition of PI3-kinase-, which
is activated by oxidative stress (Marwick et al., 2009). The antiinflammatory
effects of theophylline are inhibited by a HDAC
inhibitor, trichostatin A. Low doses of theophylline increase
HDAC activity in bronchial biopsies of asthmatic patients and correlate
with the reduction in eosinophil numbers in the biopsy.
• Other effects. Several other effects of theophylline have been
described, including an increase in circulating catecholamines,
inhibition of calcium influx into inflammatory cells, inhibition
of prostaglandin effects, and antagonism of tumor necrosis