Preterm Lung Inflammation Linked to Early COPD Development

Preterm Lung Inflammation Linked to Early COPD Development
Neutrophilic inflammation may predispose preterm infants to adult lung disorders.

New findings from researchers at Monroe Carell Jr. Children’s Hospital at Vanderbilt suggest that neutrophilic inflammation-induced disruption of elastic fibers during preterm lung development may result in early-life predisposition to adult lung disorders, including chronic obstructive pulmonary disease (COPD).

While cigarette smoking has traditionally been the predominant risk factor for COPD, early-life events, such as bronchopulmonary dysplasia (BPD), a chronic respiratory disease of premature infants born in the saccular stage of lung development, have also been associated with reduced lung function in adults.

The researchers, John Benjamin, M.D., a neonatologist at Vanderbilt, Timothy Blackwell, M.D., director of the Division of Allergy, Pulmonary and Critical Care, and colleagues investigated the effects of transient inflammation during the saccular stage of lung development using an inducible transgenic mouse model. Findings published in the Journal of Clinical Investigation suggest preterm neutrophilic inflammation may be a key contributor to early COPD development.

“There has been a paradigm shift in the COPD literature,” Benjamin said. “Recent data suggests that up to 50 percent of adults develop COPD because normal maximal lung function is not achieved in young adulthood.”

From BPD to COPD

Preterm infants with BPD have reduced lung function in adolescence and young adulthood. Furthermore, CT scans from patients with a history of BPD have revealed abnormalities, such as air trapping and emphysema. The association between altered lung function trajectory and BPD suggests the saccular stage is a critical developmental window for early-life events that irreversibly impact lung structure and function, Benjamin says.

Benjamin and colleagues previously reported that in mice, perinatal activation of the master inflammatory transcription factor NF-κB in airway epithelial cells led to early postnatal death with disorganized elastic fiber formation, dilation of terminal saccules and hypoxemia.

“We hypothesized that transient NF-κB–induced inflammation during the saccular stage of lung development could disrupt formation of the elastin scaffold of the distal lung, resulting in permanently impaired lung function,” Benjamin explained.

“The findings define a critical window in saccular-stage lung development required to support distal lung structure and function throughout the lifespan.”

Modeling Lung Disease

In their current study, the researchers induced sublethal inflammation and injury during either the saccular or alveolar stage of mouse lung development. They found that epithelium-derived inflammation in the saccular, but not alveolar stage, resulted in an early BPD-like phenotype. The mice had disruption of the developing elastin meshwork in the distal lung, followed by emphysematous airspace dilation with decreased lung function that persisted through 24 months of age.

Mechanistic studies revealed neutrophil elastase downregulated expression of critical elastic fiber assembly components, particularly elastin and fibulin-5. Depleting neutrophils prevented lung injury.

“The findings define a critical window in saccular stage lung development for establishing the elastin scaffold required to support distal lung structure and function throughout the lifespan,” Benjamin said.

Future Directions

Based on these results, an important question for future studies is whether subtle inflammatory insults during the saccular stage, which are inadequate to cause BPD, can prompt enough disruption in elastin fiber assembly to restrict peak lung function and predispose patients to COPD.

“These and other questions will be addressed in future studies,” Benjamin said. “Our findings will enable better understanding of the developmental origins of COPD and other adult lung diseases.”