MSc Exit Seminar – Iram Sobia Khan (Terebiznik lab)

MSc Exit Seminar

Monday June 27^th, 2:10 pm – Room MW 229, University of Toronto at Scarborough

Iram Sobia Khan (Terebiznik lab)

“Biogenesis and Maturation of Asbestos-containing Phagosomes in Macrophages“

Abstract
Exposure to asbestos has been associated with many pathogenic effects, including the development of malignant mesothelioma and bronchogenic carcinoma. Fibres are inhaled and circumvent the ciliated airways, depositing in areas of the lungs such as the alveoli and pleura where they become targets for removal via phagocytosis. The field of fibre toxicology has proposed a model, termed the fibre pathogenicity structure: activity paradigm, to explain the pathogenicity of asbestos and other respirable fibres. This model identifies length as being critical to toxicity and states that fibres exceeding 15 μm are problematic for removal by macrophages, purportedly causing frustrated phagocytosis. This pro-inflammatory condition stimulates cells to release inflammatory mediators and damaging reactive oxygen species, contributing to fibrosis and tissue damage. Although frustrated phagocytosis is widely accepted as being an explanation for asbestos-induced toxicity, the cellular mechanisms involved in this process are not well understood. To study the mechanisms involved in this phenomenon, we followed the phagocytosis of asbestos fibres in cultured and primary human and murine macrophages.

Our results demonstrate that the fibre length internalized by macrophages easily surpasses the threshold length proposed by the paradigm, and that the time required for uptake is length-dependent. Following phagosome formation, maturation progresses to different stages based on the cell type, with maturation stalling at early stages in human and primary murine cells. In contrast, the maturation of asbestos-containing phagosomes proceeds in RAW 264.7 cultured murine macrophages, as evidenced by the fusion of endosomes with these compartments and the subsequent acquisition of characteristics of a maturing phagosome. In all cells, however, phagosomes containing asbestos fail to acidify, suggesting a defect in phagosomal maturation that may contribute to fibre pathogenicity.

Altogether, our results indicate that fibre length is not the primary factor in asbestos-induced toxicity and suggest that surface chemistry may contribute to a greater extent to the development of asbestos-related diseases.