Developmental Origins of COPD

Abstract
Emerging data indicate that up to 50% of Chronic Obstructive Pulmonary Disease (COPD) results from failure
to attain maximal lung function in early adulthood, rather than accelerated decline in lung function later in life.
Because lung function trajectories are established soon after birth, deficits in lung function in infancy may
persist and predispose to COPD in adulthood. Many preterm infants are born with lungs in the saccular stage
of development. Lung inflammation in these infants can lead to bronchopulmonary dysplasia (BPD), a
complication of prematurity characterized by altered development with dilated and fewer airspaces in the distal
lung. Along with respiratory morbidity during childhood, patients with BPD are at risk for reduced peak lung
function in their adult years and may develop COPD. To understand mechanisms connecting aberrant early
lung development to long-term abnormalities in lung growth and function, we developed a transgenic model in
which IKKβ, an upstream activator of NF-κB, can be expressed in the lungs in a developmental-stage specific
manner. Using this model, we found that transient inflammation in the saccular stage (but not the alveolar
stage) reduced expression of fibulin-5, a critical elastin assembly component, and resulted in altered elastic
fiber organization and dilated terminal airspaces. Remarkably, mice with saccular stage inflammation
demonstrated persistent abnormalities in lung elastic fiber organization and developed a COPD-like phenotype
with emphysema and loss of alveolar attachments that progressed from 2 to 24 months of age. Neutrophil
depletion during the saccular stage rescued the lung phenotype in these mice. Further, we found that
neutrophil elastase downregulates fibulin-5 expression by mouse lung fibroblasts and alters saccular stage
elastin assembly ex vivo, potentially through activation of epidermal growth factor receptor signaling. These
findings support the hypothesis that neutrophil elastase downregulates fibulin-5 expression and alters elastic
fiber assembly in the saccular stage lung, thereby predisposing to COPD in adulthood. Specific aims are
designed to: 1) delineate the mechanisms by which neutrophils impair elastic fiber assembly in the saccular
stage, 2) determine the role and regulation of mesenchymal-derived fibulin-5 in elastic fiber assembly during
lung development, and 3) investigate the long-term effects of impaired elastic fiber assembly in the lung.
Collectively, proposed studies will determine the impact of inflammation during a critical developmental window
on both neonatal and adult lung disease. A mechanistic understanding of the developmental origins of COPD
will empower future investigations to prevent and/or treat this debilitating disease.

Grant Number: 7R01HL157373-05
NIH Institute/Center: NIH
Principal Investigator: JOHN BENJAMIN