Why More Research into Molecular and Cellular Mechanisms of COPD Is Needed - Chronic Obstructive Pulmonary Disease - page 5

ease is unknown, but may reflect a response to chronic bacterial coloniza-
tion and acute exacerbations of inflammation. The mechanisms of fibrosis
around the airway are not yet understood, but are likely to represent an
attempt to repair chronic inflammation. The role of specific growth factors,
such as transforming growth factor- b (TGF- b ) which shows increased
expression in peripheral airways (24,25) and connective tissue growth factor
(CTGF), are not yet known. TGF- b may induce fibrosis via the release of
CTGF which may stimulate collagen deposition in the airways (26,27). A
major barrier to understanding the contribution of small airway obstruction
is the difficulty in quantifying small airway obstruction in patients using
measurements of airflow due to the high variability and poor reproducibility
of measurements (28).

C. Alveolar Destruction

Both panacinar and centrilobular emphysema may occur in smokers (29).
The role of emphysema in causing airflow obstruction in COPD has been
examined by measuring macroscopic emphysema in resected lung or on
computerized tomography (CT) scans in relation to tests of lung function,
or by measuring static transpulmonary pressure (P L ) as a measurement of
alveolar disease. Many studies have shown significant, albeit weak, correla-
tions between the grading of macroscopic emphysema and various tests of
lung function (30,31). However, the assessment of macroscopic emphy-
sema is dominated by destroyed or poorly functioning lung, whereas lung
function tests reflect predominantly the function of the best surviving lung.
In the extreme case of non-ventilated emphysematous bullae surrounded
by normal lung, the two assessments are virtually independent, with lung
function tests measuring only the reduced volume of surviving lung. In
more common types of emphysema, a simple two-compartment model
does not apply, but usually there will be greater heterogeneity of disease
with more and more units becoming poorly functional as disease pro-
gresses, resulting in a rise in residual volume and a fall in vital capacity.
Thus the strength of the correlation between assessment of gross emphy-
sema and lung function will depend on the severity and homogeneity
of ''microscopic'' disease in the less affected lung which is not often
measured.
P L (measured using an esophageal catheter) is plotted against airflow
conductance or maximal expiratory flow at different lung volumes to indi-
cate the contribution of alveolar disease (and by implication emphysema)
to airflow limitation, with the assumption that the rest is due to intrinsic air-
way disease (32-34). However, it is not certain that the magnitude of decline
in P L accurately reflects the severity of emphysema and its effects on the
airways. Reduction in P L is likely to be largest with relatively uniform
emphysema, as occurs in panacinar emphysema (e.g., a 1 -antitrypsin