Biomedical Engineering Reference
In-Depth Information
In the future, it might also be possible to identify new classes of drug that
may activate HDACs.
VII. CONCLUSIONS
Several mechanisms have been proposed to account for a failure to respond
to corticosteroids including a reduced number of GR, altered affinity of the
ligand for GR, reduced ability of the GR to bind to DNA, reduction of
HDAC or increased activation of transcription factors, such as AP-1, which
compete for DNA binding. However, information about the molecular
mechanism of steroid resistance in COPD is still limited. One potential rea-
son for the failure of corticosteroids to function effectively in reducing
inflammation in COPD is that oxidative stress may reduce HDAC activity
and expression (Fig. 4). Patients with severe asthma also have increased oxi-
dative stress and this could account for the need for high doses of inhaled or
oral corticosteroids in these patients. Asthmatic patients who smoke also
have a marked reduction in the anti-inflammatory response to corticoster-
oids (111,112), and this may be explained by the effect of cigarette smoking
on HDAC activity in asthmatic airways as well as COPD. Patients with
other severe inflammatory diseases, such as rheumatoid arthritis and inflam-
matory bowel diseases, are also likely to have local oxidative stress, which
may reduce their responsiveness to corticosteroids. ''Resensitization'' of
steroid responsiveness using the therapeutic strategies described above
may considerably reduce the requirement for corticosteroids and therefore
the risk of systemic side effects that currently limit the use of oral
corticosteroids in these common diseases. Thus, add-on treatment of the
compounds
enhancing HDAC2 activity specifically may give
some
resolutions of corticosteroid resistance.
REFERENCES
1. Adcock IM, Lane SJ. Corticosteroid-insensitive asthma: molecular mechan-
isms. J Endocrinol 2003; 178:347-355.
2. Leung DY, Bloom JW. Update on glucocorticoid action and resistance.
J Allergy Clin Immunol 2003; 111:3-22.
3. Chikanza IC. Mechanisms of corticosteroid resistance in rheumatoid arthritis:
a putative role for the corticosteroid receptor beta isoform. Ann NY Acad Sci
2002; 966:39-48.
4. Barnes PJ. Inhaled cortico steroids are not beneficial in chronic obstructive
pulmonary disease. Am J Respir Crit Care Med 2000; 161:342-344.
5. Hill A, Gompertz S, Stockley R. Factors influencing airway inflammation in
chronic obstructive pulmonary disease. Thorax 2000; 55:970-977.
6. Barnes PJ. Mechanisms in COPD: differences from asthma. Chest 2000; 117
(2 suppl):10S-14S.
