MISSION

ability to detect early emphysematous changes in the lung. This is especially important for exposure to
SHS because oftentimes the level of exposure is subtler than what active smokers receive and, therefore,
much more sensitive detection methods are needed. A highly sensitive, noninvasive image-based detection
method will not only transform one’s ability to detect and follow treatment of the disease process, but may
be the only way to detect early emphysematous disease.
FAMRI Supported Publications
Patz S, Muradian M, Hrovat MI, Hersman, FW, Hatabu H, Butler JP. Xenon MRI of the lung. In:
Kauczor HU, ed. MRI of the Lung. Springer Verlag, 2009.
THE ROLE OF BRONCHIO-ALVEOLAR STEM CELLS IN CIGARETTE SMOKE-RELATED EMPHYSEMA
Shivraj Tyagi, PhD; Brigham and Women’s Hospital; CIA 2008
COPD is a complex human disease mainly influenced by active tobacco exposure and SHS. A greater
understanding of pathways contributing to lung maintenance and repair is needed to identify mechanisms
contributing to COPD. It is believed that following smoke-induced injury to the lung, reparative mechanisms
are active and may contribute to individual variability in exposure-related disease susceptibility.
Peroxisome proliferator-activating receptor (PPAR)-gamma is a well-known regulator of cellular differentiation
and tissue homeostasis/inflammation. Their laboratory has shown that deficiency in PPARgamma
specifically within airway epithelial cells leads to increased susceptibility to the development of emphysema
in response to chronic cigarette smoke exposure. Recent studies have discovered a population of airwayderived
progenitor cells capable of repairing the airway and airspace, bronchioalveolar stem cells (BASCs),
which are identified by co-expression of Clara cell secretory protein (CCSP) and surfactant protein C
(SPC). In vitro, these cells show characteristics including self-renewal and multi-potency, such as the ability
to generate both Clara cells and type II pneumocytes. It is reasoned that BASCs may play a role in repairing
cigarette smoke-related lung damage in the setting of emphysema. Since airway epithelial cell-targeted
PPARgamma deficiency leads to increased susceptibility to smoke-related emphysema-like pathology, it is
suggested that PPARgamma function in BASCs can modify this response by contributing to the regulation
of BASC differentiation and progenitor cell potential. They have verified PPARgamma expression within
BASC, and have confirmed targeting of this cell population in airway epithelial cell PPARgamma deficient
mice. They provide preliminary data describing changes in gene expression in BASCs in wild-type mice following
smoke exposure and in BASCs deficient in airway epithelial cell PPARgamma. They propose that
BASCs are necessary for lung repair in response to cigarette smoke exposure and that PPARgamma is capable
of modulating the progenitor potential of BASCs by controlling cell differentiation.
They will test these hypotheses by 1) investigating the effect of cigarette smoke exposure upon BASC
function in vivo and in vitro, and 2) defining the contribution of BASC proliferation and function to
increased susceptibility to smoke-related lung disease in PPARgamma-deficient mice. These studies will
extend understanding of the biological functions of BASCs, assess novel mechanisms contributing to cigarette
smoke-related lung injury and repair, and identify novel targets for therapeutic intervention in
patients with COPD.
HAEMOPHILUS INFLUENZAE TOLERANCE: A MECHANISM FOR CHRONIC COLONIZATION IN COPD
Tricia D. LeVan, PhD; University of Nebraska; CIA 2008
COPD is the fourth leading cause of mortality worldwide and is characterized by chronic airway inflammation
and nonreversible airflow limitation. While tobacco smoking is the leading risk factor for COPD,
even secondary causes of COPD, such as SHS exposure, are a major public health concern. Each year the
proportion of patients with COPD who are life-long never smokers rises.
In addition to tobacco smoke being the main etiological factor of COPD pathogenesis, recent studies
have found that tobacco exposure is a major risk factor for respiratory tract infections. Studies also show
that cigarette smoke reduces bacterial clearance by impairment of mucociliary clearance, changes in
pathogen adherence, and disruption of the bronchial epithelium. The bronchial epithelium is in a key position
to regulate inflammation, but it remains unknown whether the epithelium becomes hypersensitive or
tolerant to the chronic presence of bacteria. Nontypeable Haemophilus influenzae (NTHi), the most common
pathogenic bacteria isolated from the airways of patients with COPD, are recognized by bronchial
epithelial cells by directly interacting with toll-like receptor 2 (TLR2).The overall hypothesis of this study
is that chronic exposure of bronchial epithelial cells to cigarette smoke and/or NTHi induces innate
immune dysfunction characterized by bronchial epithelial tolerance that perpetuates chronic colonization
in individuals with COPD.
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