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Airway inflammation in the evolution of airway fibrosis

Institution: University of California, San Francisco
Investigator(s): Stephen Nishimura, M.D.
Award Cycle: 2015 (Cycle 24) Grant #: 24RT-0020 Award: $421,284
Subject Area: Early Diagnosis/Pathogenesis
Award Type: Research Project Awards

Initial Award Abstract

Chronic obstructive lung disease (COPD) is the third leading cause of death in the United States. Chronic inflammation surrounding small airways is refractory to currently available therapies and is thought to be a major contributing factor leading to the symptoms of COPD.

Therapeutic antibodies are emerging as the leading innovative and fastest growing segment in the drug industry. This trend is driven by the improved half-life, specificity and safety of antibodies compared with small molecules. Yet these advances in antibody technologies have been slow to be tested in COPD clinical trials compared to other respiratory diseases (i.e. asthma). Of 315 open interventional COPD drug trials, less than 1% use monoclonal antibodies (, indicative of the high-thresholds for moving antibodies forward to treat COPD. These thresholds include the increasingly high state-of-the-art standards for therapeutic antibodies2, and “… inadequate in vivo models… inefficient physiological and clinical endpoints…”3. These factors make the cost of COPD drug development and chances of failure of trials among the highest of all disorders3.

Our laboratory is focused on developing more physiologically relevant COPD models to dissect the basic mechanisms of the airway disease component of COPD (a.k.a. airway remodeling) and to target these mechanisms therapeutically.  We have used human tissues and mechanistic studies in models to identify a cell surface molecule called integrin v8 as a COPD-relevant target.  We have recently used an antibody to v8 to prevent airway remodeling in these models. The integrin v8 (itgb8) is a critical activator of another important pro-inflammatory molecule called transforming growth factor- (TGF-). This work is promising, and inspires additional work to understand the cellular mechanisms and translational relevance to provide the evidence required to move v8 antibodies, or related antibodies into human COPD clinical trials.

In our efforts to understand v8/TGF--dependent airway remodeling, we have made a number of recent findings that have provided insights into the biochemical and cellular mechanisms that drive COPD pathogenesis. These insights include verifying a role for chronic inflammation in airway remodeling. We identified that the arm of the immune system represented by cells called dendritic cells (DCs) are essential to the chronic inflammation that drives airway remodeling. DCs are increased in COPD airways, and therefore may drive chronic inflammation and be critical upstream cellular mediators to airway remodeling in COPD. We used 3 methods alter DC function to confirm their critical role in airway remodeling. However, these experiments fall short in that the models used thus far are short-term models that do not recapitulate the chronicity and the microbial pathogenesis involved in human COPD.

Here to lay the foundation for using therapeutic antibodies in COPD clinical trials, we will establish highly physiologically relevant models of COPD in mice. We will confirm the efficacy of v8 antibodies and the critical role of DCs in airway remodeling, and will develop and establish an assay to measure the effect of v8 and other DC targeted therapeutics in living murine and human COPD lung tissue. These translational studies will encourage development of innovative therapeutic approaches to treat COPD.