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.
Pulmonary fibrosis (PF) is a rare degenerative disease characterized by progressive lung stiffening, and punctuated by intermittent inflammatory episodes of unknown cause, termed ?acute exacerbations?. Both genetic and environmental triggers are linked to disease pathogenesis and progression. Mutations of the epithelial cell-specific gene encoding for the surfactant protein-C (SP-C) are linked to clinical PF. To longitudinally examine endpoints relevant to PF, we developed a novel murine model that leverages the most common human mutation in the SP-C gene. The ubiquitous air pollutant ozone (O3) represents a major environmental contributor to disease exacerbation in vulnerable populations, including PF. Monocytes and macrophages are centrally involved in ozone toxicity and represent a predictor in PF severity. This project aims to functionally link monocyte/macrophage populations as central players in the exacerbation of PF resulting from ozone exposure of the SP-C mutant mice. Ultimately, we hope to identify a unique subset of monocyte- derived cells responsible for tissue damage, and thus develop a cell specific approach to improve health of PF patients.
