Overload of Lung Clearance Is Associated with Activation of Alveolar Macrophage Tumor Necrosis Factor and Fibronectin Release

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Abstract
This report summarizes recent findings on the relationships among overloaded lung clearance, activation of alveolar macrophages (AM) release of inflammatory mediators and the development of fibrosis using Ti02 as a model nuisance type dust. Briefly rats were intratracheally instilled with 2-100 mg Ti02/kg body weight and AM tumor necrosis factor or fibronectin release determined ex vivo 1, 7, 14 and 28 days after exposure. Lung dust burdens were determined 1 and 28 days after exposure. Histopathology was assessed 28 and 90 days after exposure. Intratracheal instillation of ≥50 mg/kg Ti02 resulted in overloaded lung clearance. Ti02 doses ≥50 mg/kg stimulated transient increases in AM TNF release and a persistent increase in AM fibronectin secretion. Histopathology demonstrated dose-related interstitial inflammation with fibrosis developing only after treatment with ≥50 mg/kg Ti02. Results from these studies suggest activation of AM secretory activity may play a key role in adverse pulmonary responses to high dust burdens of relatively innocuous materials. Studies investigating in vitro responses of AM to dust indicated that direct Ti02:AM interaction does not stimulate release of TNF or fibronectin, however, pre-exposure to γ-interferon can render AM responsive to Ti02 with respect to increased TNF release.