The Role of Airway Mucus in Infection and Inflammation

Project Summary / Abstract
Abnormal mucociliary clearance (MCC) is a critical component of cystic fibrosis (CF) lung disease, and is
postulated to contribute to the high incidence of chronic pulmonary infections in this patient population; in turn
the presence of chronic infection is thought to worsen the MCC defect, creating a cycle of mucus obstruction,
infection, and inflammation that is difficult to interrupt or reverse. However, the mechanisms and interactions
responsible for this phenomenon are not well understood. New animal models, such as the CF rat, developed
at our institution, have been useful in identification of key factors that lead to chronic infection with the
pathogen Pseudomonas aeruginosa in the CF airway. This animal model develops the MCC defect
progressively, providing a model with which to study patients with early disease as well as late disease. In this
model of CF, mucus must be abnormal before exposure to Pseudomonas aeruginosa to convert the infection
to a chronic phenotype. CF rats exposed before the mucus abnormality develops are able to clear the
infection. A new rat model harboring a humanized G551D-CFTR genomic insert respond to FDA-approved
CFTR modulators that treat the fundamental defect of CF disease. Using the innovative Micro-Optical
Coherence Tomography (µOCT), a high-resolution reflectance imaging modality that can simultaneously and
non-invasively evaluate airway hydration, ciliary beating and mucus transport and viscosity in situ, we can
analyze aspects of the mucus defect in both the CF rat model before and after infection, with or without CFTR
modulators. Using these tools, this proposal will seek to investigate the mechanisms that cause patients with
CF to transition acute infections into chronic ones, with the following independent but complimentary aims:
1. Determine if Muc5b is the specific component of mucus that promotes chronic Pseudomonas aeruginosa
infection.
2. Determine if inflammation is necessary and sufficient to accelerate the mucus defect, predisposing the
airway to chronic P. aeruginosa infection.
3. Determine if new highly effective CFTR modulators promote clearance of P. aeruginosa by normalizing
abnormal mucus in the airway.
This proposal will determine the early events that lead to infection and progression in CF pulmonary disease
and how this relates to the conversion of P. aeruginosa from intermittent to chronic in this patient population,
using a highly relevant animal model. The studies will provide new fundamental observations that will inform
our understanding of the CF respiratory pathology and help identify robust therapeutic targets suitable for
intervention.

Grant Number: 5R01HL153079-05
NIH Institute/Center: NIH
Principal Investigator: Susan Birket