 |
Research | FERKOL LAB
PULMONARY INFECTION AND
INFLAMMATION IN CYSTIC FIBROSIS
The respiratory epithelium is the first line of defense in the
lung, and it is constantly exposed to innumerable inhaled
pathogens, aeroallergens, and other noxious agents. Innate host
defenses have evolved to prevent acute pulmonary injury, relying
on complex interactions that occur between effector cells present
in the respiratory tract. An important feature of pulmonary
immunity is the host’s ability to protect itself from such stimuli
while govern the inflammatory response to avoid airway injury and
destruction. This regulation of the inflammatory response and
interaction between the respiratory epithelium and inflammatory
cells is perturbed in the lung of a cystic fibrosis (CF) patient.
In CF, defective function of the cystic fibrosis transmembrane
conductance regulator (CFTR) in airway epithelial cells and
submucosal glands results in chronic involvement of the
respiratory tract, clinically manifested by airway obstruction and
recurrent sinopulmonary infections with Pseudomonas aeruginosa.
Although infection contributes to the morbidity of patients with
CF, the intense host inflammatory response largely accounts for
the progressive, suppurative lung disease, which leads to death.
Indeed, several lines of evidence suggest that this inflammatory
response is excessive and disproportionate to the threat posed by
the infection. Yet, the precise mechanism in which the abnormal
CFTR actually leads to pulmonary infection and inflammation
remains unclear.
Research in our laboratory has focused on developing cell and
animal models to study pulmonary inflammation characteristic of
CF. We have characterized a murine model of lung infection with
Pseudomonas aeruginosa, and used this approach to examine the
inflammatory response of CF and wild-type mice. The mortality of
CF mice challenged with Pseudomonas-laden beads was greater than
wild-type animals. Moreover, concentrations of inflammatory cells
and mediators in bronchoalveolar lavage fluid was elevated in both
cohorts of mice inoculated with Pseudomonas, with markedly higher
levels seen in the CF mice as compared to normal littermates.
This striking difference in survival and inflammation between
normal and CF mice challenged with the same Pseudomonas represents
the first model in which CF mice display special vulnerability to
the most common and important CF pathogen. We are currently using
this model to define factors in the CF mouse that may lead
patients to develop chronic endobronchial infection and
inflammation, as well as non-invasive measures of neutrophil
influx into the airways (e.g., PET). Moreover, with our
collaborators, we have created cell model systems that should
allow us to examine the effects of bacterium-epithelium
interaction in the CF airway.
Suppression of airway inflammation has become a therapeutic goal
for CF, and anti-inflammatory agents have been shown to effect the
course of both diseases. Unfortunately, systemic administration
of anti-inflammatory agents is inefficient, and these therapies
have had dose-limiting toxicities. Also, an airway’s response to
stimuli and inflammatory mediators is highly compartmentalized,
and it is likely that any attempt to reduce airway inflammation
may need to be directed to the microenvironment of the airway
surface. Inhalation of anti-inflammatory agents should permit
direct delivery to the airways, but deposition of aerosolized
particles to the diseased lung is uneven and puts the drug atop
the mucus blanket rather than the critical site at the surface of
the cell. We are testing novel approaches for anti-inflammatory
treatment for CF, including gene therapy, and have developed an
innovative strategy to deliver reagents to the respiratory
epithelial cell surface directly by exploiting properties of the
polymeric immunoglobulin receptor (pIgR). We have shown that
fusion proteins containing a single-chain Fv antibody directed at
the pIgR can be transported specifically from the basolateral
surface of epithelial cells to the apical surface in vitro and in
vivo. This approach allows us to deliver anti-inflammatory agents
directly to the epithelial surface, and we are examining its
therapeutic potential for CF.
Related Links
Contact Information
Thomas W. Ferkol, M.D.
Department of Pediatrics
Division of Pediatric Allergy and Pulmonary Medicine
at St Louis Children’s Hospital
Washington University School of Medicine
4905 Children’s Place, Box 8116
St. Louis, Missouri 63110 e-mail address:
|
|
SCHOOL OF MEDICINE
