# Mechanisms driving airway inflammation in chronic lung disease

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

In the current funding period, we showed that acquired defects in mucosal immunity in small airways are a
central feature of chronic obstructive pulmonary disease (COPD). We now propose to investigate mechanisms
by which impairment of this first line of host defense leads to persistent activation of subsequent lines of host
defense (innate and adaptive immunity), thus driving COPD progression. Although it has been clear for
several years that COPD pathology begins in the small resistance airways, the mechanisms linking small
airway and parenchymal pathology have been obscure. The small airway epithelium generates mucosal host
defense by a variety of mechanisms, including transporting immunoglobulins to the airway surface. Down-
regulation of polymeric immunoglobulin receptor (pIgR) expression, which is required for transport of dimeric
IgA from the basolateral to luminal surface of the airway, is selectively reduced in COPD and impairs
generation of the secretory IgA (SIgA) barrier on the airway surface. In individual small airways of COPD
patients, reduced SIgA is associated with bacterial invasion into the epithelial layer, activation of NF-κB, and
influx of inflammatory/immune cells. These pathogenic features can be modeled in pIgR deficient (pIgR-/-)
mice, which lack SIgA on mucosal surfaces. Like COPD patients, these mice develop progressive
emphysema and small airways remodeling, along with evidence of bacteria within the airway epithelial layer,
epithelial NF-κB activation, and an influx of inflammatory/immune cells. Raising pIgR-/- mice in germ-free
conditions, treatment with broad spectrum oral antibiotics, and neutrophil depletion reduce lung pathology. In
addition, pIgR-/- mice develop lymphocyte accumulation, including increased CD4+ and Th17+ T cells, and
tertiary lymphoid structures in the lungs, particularly with advanced age (similar to humans with severe COPD),
along with a shift in the dendritic cell population towards increased monocyte-derived dendritic cells.
Lymphocyte depletion reduces COPD-like pathology in pIgR-/- mice and treatment with broad spectrum
antibiotics normalizes DC populations, reduces T cell influx, and eliminates accumulation of tertiary lymphoid
structures, thus implicating both innate and adaptive immunity in the COPD-like pathology in this model.
Together, available data suggests that each layer of the multi-layered airway host defense structure, which
evolved to protect vulnerable mucosal surfaces, becomes dysfunctional in COPD. Therefore, we hypothesize
that disruption of the SIgA immune barrier in small airways results in inflammatory signaling in epithelial cells,
leading to persistent recruitment and activation of innate immune cells and pathologic activation of adaptive
immunity, which synergize to drive airway remodeling and emphysema. Specific Aims are: 1) to investigate
the role of epithelial NF-κB in driving innate and adaptive immune activation in mice with mucosal immune
deficiency, 2) to ide...

## Key facts

- **NIH application ID:** 10477197
- **Project number:** 5I01BX002378-07
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Timothy S. Blackwell
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2014-04-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10477197

## Citation

> US National Institutes of Health, RePORTER application 10477197, Mechanisms driving airway inflammation in chronic lung disease (5I01BX002378-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10477197. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*