Project Summary/Abstract:
Pulmonary fibrosis (PF) is a rare degenerative disease characterized by progressive lung stiffening, resulting in
death within 3-5 years of diagnosis. Compelling clinical evidence show that mutations of the epithelial cell-
specific gene encoding surfactant protein-C (SP-C), are linked to a particularly extreme lung phenotype.
Progression of PF in humans is often punctuated by inflammatory bursts, clinically termed “acute exacerbations”,
that drastically accelerate the disease and reduce life expectancy. In accord with this notion, monocyte
mobilization and the persistence of monocyte-derived macrophages in the lung are strong predictors of PF
severity. Several environmental factors have been proposed to promote and accelerate acute inflammatory
exacerbations of PF; however, the exact mechanisms have not been interrogated. The ubiquitous air pollutant
ozone (O3) represents a major, and unavoidable, environmental contributor to pulmonary disease through
oxidative stress and monocyte/macrophage rich inflammation. To closely mimic causes of human PF, we
developed a novel mouse model that develops spontaneous lesions over time, as a result of inducible ectopic
expression of the most common PF-linked SP-C mutation (SP-CI73T). This preclinical model provides a unique
platform to decipher mechanisms of PF progression and specifically the roles of acute exacerbations (induced
by O3), infiltrating monocytes, and monocyte-derived macrophages in promoting PF. Our published work showed
that SP-C mutation is accompanied by a dynamic monocyte/macrophage inflammatory response, initiated by
the epithelium. Preliminary evidence confirm that O3 exposure amplifies inflammatory cell influx and pro-
inflammatory signaling in SP-C mutant mice, worsening PF. Assessment of the proposed paradigm will provide
fundamental data to define the responses of the healthy, acutely inflamed, and fully fibrotic lung to environmental
exposure. Our hypothesis is that O3-induced acute exacerbation of PF driven by SP-C mutation enhances the
recruitment and activation of inflammatory monocytes, triggering a monocyte-derived macrophage pro-fibrotic
response. Our Specific Aims are to: 1) Define monocyte dynamics following O3-induced pulmonary inflammation
and PF. 2) Investigate the role of monocyte-derived macrophages and O3-induced exacerbation of PF; and 3) :
Establish the role of monocyte subpopulations in the PF phenotype.
