# CC16: A Link between Airway Infection and Obstructive Lung Disease

> **NIH NIH R01** · UNIVERSITY OF ARIZONA · 2020 · $502,989

## Abstract

PROJECT ABSTRACT
Asthma and COPD are the most commonly diagnosed chronic lung diseases in the United States. Studies have
shown that asthma is the most important risk factor for COPD that develops through a course of low lung function
from school age that tracks into adulthood. However, there is a fundamental gap in understanding the basic
underlying mechanisms of this progression. Club cell secretory protein (CC16) has been described for its
potential as a biological marker of lung epithelial cell injury and recent studies by our group concluded that low
circulating CC16 levels predict impaired lung function growth in childhood and increased risk of asthma or COPD
in adult life. In our cohort, adults with asthma with low serum CC16 levels and elevated levels of antibodies
against M. pneumoniae (Mp) have a striking 8-fold increase in their odds of developing airflow limitation.
These studies highlight the critical need for an intact immune system that protects against lung function decline
and provide evidence that persistent early life infections may be a previously overlooked link in understanding
progression of asthma into severe asthma with fixed airflow limitation. We developed a mouse model of early
life exposure to Mp in which WT or CC16 deficient mice are infected pre-weaning and assessed for lung function
in adulthood and found that CC16-/- mice have persistent airway inflammation and a striking >1000% over
baseline airways resistance as compared to WT controls, which is likely attributed to inflammation and airway
remodeling. The overall hypothesis is that CC16 plays a protective role during Mp-driven inflammation that is
dependent on binding to its newly discovered receptor, the integrin VLA-4. The action of CC16 attenuates lung
inflammation, remodeling and airway hyperresponsiveness. This hypothesis will be tested by pursuing three
specific aims: 1) Determine the impact of CC16 deficiency on pulmonary inflammation, remodeling and lung
function using M. pneumoniae infection mouse models that include comparisons between an early life and adult
infections, 2) Determine if the mechanism by which CC16 protects against inflammation, remodeling and loss of
lung function is dependent on the VLA-4 receptor, and 3) Determine the impact of CC16 deficits in association
with Mp infection on inflammation, remodeling factors and lung function using data and samples from multiple
human longitudinal cohorts. This proposal is innovative in that we have identified a previously unknown
receptor for CC16, adhesion molecule VLA-4 and we employ a novel translational approach to test our
hypothesis using ex vivo studies, animal models, and human samples from well-characterized local and
international cohorts. The proposed research is significant in that these findings will describe a new mechanism
by which CC16 functions in a protective manner and may be immediately applicable to other pulmonary
pathogens. Since CC16 is an informative and predictive biomarke...

## Key facts

- **NIH application ID:** 10002121
- **Project number:** 5R01HL142769-02
- **Recipient organization:** UNIVERSITY OF ARIZONA
- **Principal Investigator:** Julie Gunnells Ledford
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $502,989
- **Award type:** 5
- **Project period:** 2019-09-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10002121

## Citation

> US National Institutes of Health, RePORTER application 10002121, CC16: A Link between Airway Infection and Obstructive Lung Disease (5R01HL142769-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10002121. Licensed CC0.

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