Deciphering Pathogenesis of Silica Nanoparticle-Induced Airway Remodeling and Fibrosis: Insights from a Human Patient Cohort and a Murine Model.

Occupational chronic obstructive pulmonary disease (O-COPD) represents a lung disorder attributable to occupational exposures that are characterized by early development of airway remodeling and pulmonary fibrosis. O-COPD is poorly recapitulated by existing preclinical models. This study aimed to perform comparative characterization of an O-COPD patient cohort exposed to industrial aerosols and to develop a relevant murine model that accurately mirrors the human pathology. In the patient cohort, it was shown that the O-COPD phenotype is associated with the chemical composition of industrial aerosols and mediated by a specific inflammatory pattern with predominant obstructive changes and increased bronchial reactivity upon exposure to metal particles, as well as irreversible fibrotic changes in the lungs upon exposure to silicon dioxide. In the murine model, silica nanoparticles (SiNPs) or magnetic nanoparticles (MNPs) were utilized. Repeated intranasal SiNP administrations have been shown to reflect one of the main features of O-COPD-progressive airway remodeling and fibrosis, observed even after elimination of SiNPs. Administration of MNPs in the same regimen did not result in fibrotic changes in the lungs, partially recapitulating the human pathology resulting from exposure to the complex composition of industrial aerosols as well as the specific properties of chemically synthesized nanoparticles. Thus, the integrative data from the human cohort and animal model provides a reflective platform to advance the investigation of O-COPD mechanisms and development of interventions for fibrotic lung pathology.