NiO and Co3O4 nanoparticles induce lung DTH-like responses and alveolar lipoproteinosis

Lung exposure to metal oxide nanoparticles (NPs) comprising soluble metal haptens may produce T-helper cell type 1 (Th1)-and Th17-associated delayed-type hypersensitivity (DTH) responses and pulmonary alveolar proteinosis (PAP). In order to study this, haptenic metal oxide NPs (NiO, Co3O4, Cr2O3 and CuO) were instilled into the lungs of female Wistar rats, and the immunoinflammatory responses were assessed at 24 h and 4 weeks post-instillation. Primary culture of alveolar macrophages from Wistar rats was used to evaluate the effect of the NPs on the ability to clear surfactant. NiO NPs induced chronic interstitial inflammation and pro-inflammatory Th1 and Th17 immune responses characterised by increases in the cytokines monocyte chemotactic protein (MCP)-1/CCL2, interleukin (IL)-12 p40, interferon-c and IL-17A, whilst similar pathological responses induced by Co3O4 NPs were associated with increases in MCP-1/CCL2 and IL-12 p40. However, neither Cr2O3 nor CuO NPs elicited immunoinflammatory reactions. PAP was induced by both NiO and Co3O4 NPs during the chronic phase. PAP was associated with over-production of surfactant by proliferation of type II cells and impaired clearance of surfactant by macrophages. These findings have implications for the risk management of occupational NP exposure and provide evidence that haptenic metal oxide NPs can induce chronic progressive lung immune responses via a DTH-like mechanism.