Library Open Repository

Epithelial Activation in Chronic Obstructive Pulmonary Disease (COPD)

Downloads

Downloads per month over past year

Sohal, SS (2010) Epithelial Activation in Chronic Obstructive Pulmonary Disease (COPD). PhD thesis, University of Tasmania.

[img]
Preview
PDF (Front matter)
SSSohal_01_fron...pdf | Download (135kB)
Available under University of Tasmania Standard License.

[img] PDF (Chapter 1)
SSSohal_02_Chap...pdf | Request a copy
Full text restricted until 2110.
Available under University of Tasmania Standard License.

[img]
Preview
PDF (Chapter 2)
SSSohal_03_Chap...pdf | Download (7MB)
Available under University of Tasmania Standard License.

[img]
Preview
PDF (Chapter 3)
SSSohal_04_Chap...pdf | Download (833kB)
Available under University of Tasmania Standard License.

[img] PDF (Chapter 4)
SSSohal_05_Chap...pdf | Request a copy
Full text restricted until 2110.
Available under University of Tasmania Standard License.

[img] PDF (Chapter 5)
SSSohal_06_Chap...pdf | Request a copy
Full text restricted
Available under University of Tasmania Standard License.

[img] PDF (Chapter 6)
SSSohal_07_Chap...pdf | Request a copy
Full text restricted
Available under University of Tasmania Standard License.

[img]
Preview
PDF (Chapter 7)
SSSohal_08_Chap...pdf | Download (3MB)
Available under University of Tasmania Standard License.

[img]
Preview
PDF (Chapter 8)
SSSohal_09_Chap...pdf | Download (53kB)
Available under University of Tasmania Standard License.

[img]
Preview
PDF (Bibliography)
SSSohal_Bibliog...pdf | Download (159kB)
Available under University of Tasmania Standard License.

[img]
Preview
PDF (Response to examiners)
SSSohal_Respons...pdf | Download (79kB)
Available under University of Tasmania Standard License.

Abstract

Background: Early on I identified that reticular basement membrane (Rbm) in
current smokers with COPD was highly fragmented, with cracks termed “clefts”
containing cells. This looked like the described hallmark of EMT (epithelial
mesenchymal transition). I followed this preliminary observation with a
comprehensive cross-sectional study in which I hypothesized that the airway
epithelium is activated in smokers, and that this may promote EMT, but that this will
be especially active in COPD. As a part of my thesis, I also investigated the
expression and activity of the anti-inflammatory enzyme HDAC2 (histone
deacetylase 2) which is reported to be reduced in COPD lungs and may account for
associated pulmonary inflammation. I hypothesised that the current literature is
correct in stating that HDAC2 is down-regulated in COPD airways and also that
these reduced HDAC2 levels are normalised by aggressive inhaled corticosteroid
(ICS) therapy and smoking cessation in patients with COPD.
Methods and results: Endobronchial biopsies (ebb) from current smokers with
COPD (COPD-CS) and ex-smokers with COPD (COPD-ES), smokers with normal
lung function (NS) and never-smoking controls (NC) stained for markers of EMT,
matrix metalloproteinase-9 (MMP-9), fibroblast protein (S100A4), epidermal growth
factor receptor (EGFR), vimentin and cytokeratins. To confirm the extent of
suppressed HDAC2 ebb were immuno-stained for HDAC2. In a double-blind,
randomized, placebo-controlled study, I assessed the effects of ICS on Rbm
fragmentation and HDAC2. Compared to NC, there was significant fragmentation of
the Rbm in COPD-CS, COPD-ES and NS groups. COPD-CS, NS and COPD-ES
demonstrated increases in staining for: basal epithelial S100A4, epithelial EGFR and
MMP-9 and S100A4 for cells in Rbm ``clefts`` compared to NC. Dual staining
revealed that vimentin (a mesenchymal marker) co-stained with cytokeratin (an
epithelial marker). ICS normalised Rbm fragmentation. Compared to NC there was
significant increase in HDAC2 positive cells in NS in the lamina propria (LP) but a
decrease in COPD-CS. However, this latter abnormality was due to a reduction in
total LP cells and not % cell HDAC2 staining. There were significantly more HDAC2 positive cells in COPD-ES compared to COPD-CS, but again due to an
increase in total cell numbers. ICS made no difference to HDAC2 staining.
Conclusions: This is the first description of likely EMT in smoking and COPD. ICS
reversed Rbm fragmentation. HDAC2 expression was reduced in smokers but
confounded by changes in cellularity. Quitting does seem to have a real effect on upregulating
HDAC2, but it is not affected by ICS.

Item Type: Thesis (PhD)
Keywords: EMT, COPT, HDAC-2, S100A4, MMP-9,EGFR, airway remodelling
Additional Information:

“The publishers of the paper comprising Chapter 1 and Chapter 4 hold the copyright
for that content, and access to the material should be sought from the respective
journals. The remaning non published content of the thesis may be made avalaible
for loan and limited copying in accordance with copyright Act 1968.”

Copyright © the Author

Date Deposited: 09 May 2011 00:44
Last Modified: 11 Mar 2016 05:53
Item Statistics: View statistics for this item

Actions (login required)

Item Control Page Item Control Page