(Chest. 2000;117:260S-262S.)
© 2000
American College of Chest Physicians
Morphometry Explains Variation in Airway Responsiveness in Transgenic Mice Overexpressing Interleukin-6 and Interleukin-11 in the Lung*
Charles Kuhn, MD;
Robert J. Homer, MD, PhD;
Zhou Zhu, MD, PhD;
Nicholas Ward, MD and
Jack A. Elias, MD
*
From the Department of Pathology (Dr. Kuhn), Brown University School of Medicine, Providence, RI; and the Departments of Pathology (Dr. Homer) and Pulmonary and Critical Care Medicine (Drs. Zhu, Ward, and Elias), Yale University, New Haven, CT.
Correspondence to: Charles Kuhn, MD, Pathology Department, Memorial Hospital of Rhode Island, Pawtucket, RI 02860
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Introduction
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Abbreviations: AA = alveolar wall
attached; AHR = airway hyperreactivity; CC10 = Clara cell 10-kd
protein; IL = interleukin; S/V = surface/volume ratio
The
basis for airway hyperreactivity (AHR) accompanying COPD is poorly
understood. Structural changes may play a role. We have generated
transgenic mice that overexpress related cytokines, interleukin (IL)-6
and IL-11, in their airways, which were controlled by the Clara cell
10-kd protein (CC10) promoter. Despite some similar structural
abnormalities, their airway physiology differed. CC10-IL-6 mice had
normal expiratory flow and decreased reactivity to
methacholine,1
while CC10-IL-11 mice had airflow
obstruction and hyperreactivity.2
To clarify this
difference, a morphometric study was undertaken of the lung parenchyma
and bronchioles of the two transgenic strains and littermate controls.
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Materials and Methods
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The production of the transgenic mice has been
described.1
2
Lungs from mice (age, 1 to 2 months) were
fixed by intratracheal instillation of glutaraldehyde at a pressure of
25 cm of fixative. Two measures of airspace size, the mean cord length
and surface/volume ratio (S/V) of the gas-exchanging parenchyma, were
determined by a computerized method that has been described
previously.3
The bronchiolar lumen, the external diameter
of the bronchioles, and the total thickness of the bronchiolar wall and
thickness of the wall internal to the smooth muscle were measured with
a calibrated eyepiece reticle. To determine the density of alveolar
walls attached (AAs) to the bronchioles (alveolar attachments per unit
length of the bronchiolar perimeter), we measured both the long and
short axis of elliptically shaped bronchiolar profiles and counted the
number of AAs. The perimeter of the bronchiole,
P, was calculated from the measured axes using the
approximate formula for the perimeter of an ellipse,
P = 2
,
where a and b are the semi-major and semi-minor
axes, respectively. Knowing the calculated value for P, the
value of the density of AA then is AA/P.
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Results
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The morphometric results are summarized in Table 1
. Both transgenic strains of mice had emphysema-like airspace
enlargement that was of identical severity by three morphometric
measures: cord length, S/V, and AA/P. This
enlargement is thought to be the result of the failure of septation in
both strains, although it has only been proven for the CC10-IL-11
mice.3
Both had lymphocytic nodules in airways and airway
wall thickening with increased fibrosis and smooth muscle. Compared
with controls, hyporeactive CC10-IL-6 mice had a 50% increase in the
caliber and external diameter of their airways. When the wall
thickening was normalized to the diameter of the airway, it was
proportional to the increased airway size. In contrast, the CC10-IL-11
strain showed submucosal thickening, increased muscle, and fibrosis in
airways with normal external and luminal diameters. Their wall
thickening was disproportionate to airway size.
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Discussion
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The structural changes that lead to AHR have been modeled and
studied in detail.4
5
6
Airway narrowing in response to
agonists results from smooth muscle shortening working against the
passive load of the recoil of the surrounding parenchyma. Emphysema,
with its attendant loss of recoil and smooth muscle hypertrophy, which
increases the force of contraction, will exaggerate the response to a
given dose of agonist. Thickening of the bronchiolar wall internal to
the smooth muscle also exaggerates airway narrowing,4
while thickening of the adventitial sheath may uncouple the
interdependence of the airways and parenchyma, thereby decreasing the
effect of parenchymal recoil. Hence, the airway remodeling and
emphysema-like parenchymal changes both contribute to the airflow
obstruction and AHR seen in the IL-11-expressing mice. The
IL-6-expressing mice had equally severe emphysema and also had airway
wall thickening, but their bronchioles were 50% larger than those of
either their littermates or the IL-11-expressing strain, and their
airway wall thickening was proportional to airway size. Evidently, the
increased lumen diameter overrode the effect of the emphysema and
airway remodeling and resulted in relatively large airway diameter even
after agonist inhalation. We conclude that airway remodeling and
emphysema sometimes lead to AHR, but baseline airway size and caliber
also determine airway responsiveness.
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References
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DiCosmo, BF, Geba, GP, Picarella, D, et al (1994) Airway epithelial cell expression of interleukin-6 in transgenic mice: uncoupling of airway inflammation and bronchial hyperreactivity. J Clin Invest 94,2028-2035
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Tang, W, Geba, GP, Zheng, T, et al (1996) Targeted expression of IL-11 in the murine airway causes lymphocytic inflammation, bronchial remodelling and airways obstruction. J Clin Invest 98,2845-2853[ISI][Medline]
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Ray, R, Tang, W, Wong, P, et al (1997) Regulated overexpression of interleukin-11 in the lung: Use to dissociate development-dependent and -independent phenotypes. J Clin Invest 100,2501-2511[ISI][Medline]
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Wiggs, BR, Bosken, C, Paré, PD, et al (1992) A model of airway narrowing in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 145,1251-1258[ISI][Medline]
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Lambert, RK, Wiggs, BR, Kuwano, K, et al (1993) Functional significance of increased airway smooth muscle in asthma and COPD. J Appl Physiol 74,2771-2781[Abstract/Free Full Text]
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Paré, PD, Bai, TR (1996) Airway wall remodelling in chronic obstructive pulmonary disease. Eur Respir Rev 6,259-263
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Introduction
Materials and Methods
