Respiratory tract responses to dust: Relationships between dust burden, lung injury, alveolar macrophage fibronectin release, and the development of pulmonary fibrosis

Abstract

A multidisciplinary approach was used to investigate the responses of the respiratory tract to silica (SiO 2) or titanium dioxide (TiO 2). Rats were intratracheally instilled with 5–100 mg/kg of dust and bronchoalveolar lavage fluid (BALF) lactate dehydrogenase (LDH) and total protein (TP) and ex vivo alveolar macrophage (AM) fibronectin release assessed on Days 7, 14, and 28 after exposure. Lung dust burdens were determined on Days 1, 7, and 28 after instillation. Both dusts elicited dose-related increases in BALF LDH and TP, a response which was more pronounced and progressive with SiO 2. All doses of SiO 2 elicited persistent increases in AM fibronectin release. TiO 2 stimulated persistent increases in AM fibronectin release at ≥ 50 mg/kg, with transient or no effect at ≤ 10 mg/kg. Increased SiO 2 retention was observed for all doses and TiO 2 retention was increased only at doses ≥ 50 mg/kg. In vitro exposure of naive AM to SiO 2 or TiO 2 did not stimulate AM fibronectin release. Histopathology demonstrated fibrosis at all SiO 2 doses; only TiO 2 doses ≥ 50 mg/kg resulted in fibrosis. These results reveal an association between increased dust retention, lung injury, activation of AM fibronectin release, and the development of fibrosis. The magnitude and temporal pattern of responses clearly differentiated SiO 2 from TiO 2. The correlation of BALF markers of lung injury and increased AM fibronectin release with the development of fibrosis supports the use of these parameters as predictive biomarkers of dust-induced interstitial lung disease.