ALLERGY & IMMUNOLOGY 08.01.

2011 2 COMMENTS

Cigarette Smoke Remodels Airways

in COPD

by Nancy Walsh
Staff Writer, MedPage Today

Cigarette smoke can directly alter lung tissue in ways that lead to
permanent airway remodeling in patients with chronic obstructive
pulmonary disease (COPD), Australian researchers reported.

Exposure of tissue samples from COPD patients to smoke extracts led to

an increase in fibronectin deposition in the extracellular matrix (P<0.05),
a phenomenon that did not occur in tissue samples from patients with
other lung diseases, according to Brian Oliver, PhD, and colleagues at the
University of Sydney.

The cellular processes underlying COPD include thickening of the airway

walls, which can occur through changes to the extracellular matrix, the
researchers explained online in the American Journal of Respiratory Cell
and Molecular Biology.
 The matrix can affect cellular activities such as inflammation and
proliferation, and fibroblast deposition in the extracellular matrix of the
lung has been shown to lead to airway remodeling in asthma.

To investigate whether cigarette smoke can directly cause permanent

airway changes in COPD, Oliver's group performed a series of in vitro
experiments using lung tissue samples from 33 patients undergoing
resection for severe pulmonary disease.

The experiments involved stimulating cell cultures with cigarette smoke

extracts and using transforming growth factor (TGF)-β1, a protein that
helps mediate cell growth, as a control.

They found that in COPD samples, exposure to cigarette smoke

upregulated the deposition of perlecan, a proteoglycan that links various
components of the extracellular matrix, and contributes to tumor growth
(P<0.05).

And although TGF-β1 increased perlecan deposition in fibroblasts from

non-COPD samples, cigarette smoke extract had no effect on perlecan
deposition in the non-COPD tissues.

The researchers also determined that cigarette smoke activates the NF-
ΚB pathway, which controls DNA transcription and is involved in
inflammatory events, cancer, and autoimmunity, by showing that
addition of an NF-ΚB inhibitor (BMS-345541) prevented fibronectin
deposition (P<0.01).

They further demonstrated that levels of the chemokine interleukin-8,

which is central to the inflammatory response, was significantly higher in
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COPD tissues compared with non-COPD tissues (P<0.01) after cigarette
ADVERTISEMENT smoke exposure.

This increase was also attenuated by the addition of the NF-KB inhibitor.

The researchers reported that the extracellular matrix was functionally

The researchers reported that the extracellular matrix was functionally
different after exposure to smoke, in that it exhibited proliferative
effects. This was an unexpected observation, they noted, because
previous work suggested that smoke exposure inhibited proliferative
actions.

This finding that the extracellular matrix was functionally altered helps
to explain why the pathologic processes of COPD can continue even
without further cigarette smoke exposure, they explained.

It has long been known that lung fibrosis is irreversible in COPD, and
while more research will be needed to fully clarify the functional changes
in the matrix, these findings "may provide insight into the mechanisms
by which decreased lung function never completely recovers in patients
with COPD who have quit smoking," the researchers wrote.

Cigarette smoke contains thousands of chemical compounds, and it is

not known which mediate the changes in matrix structure and function.

Most likely a host of molecules and signaling pathways are involved in

the upregulation of the extracellular matrix, they suggested.

Genetic susceptibility also may contribute, although with enough smoke

exposure, almost all smokers ultimately develop the pulmonary cellular
changes associated with COPD.

Further research into these changes and how the pathophysiology of

COPD differs from other lung diseases "may result in viable therapeutic
targets for reducing the detrimental airway changes underlying COPD,"
they concluded.

No disclosures were provided.

Reviewed by Robert Jasmer, MD

Associate Clinical Professor of
Associate Clinical Professor of
Medicine, University of California, San
Francisco and Dorothy Caputo, MA,
RN, BC-ADM, CDE, Nurse Planner

Primary Source
American Journal of Respiratory Cell and Molecular Biology
Source Reference: Krimmer D, et al "Matrix proteins from smoke exposed fibroblasts are pro-
proliferative" Am J Respir Cell Mol Biol 2011; DOI: 10.1165/rcmb.2010-0426OC.

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