Mechanisms of wool and dust-mediated inflammation and leukocyte activation in the rat lung

A previous IOM study to investigate the effects of wool dust in the rat lung showed that inflammation was evident following intratracheal instillation of dust collected from the air of wool mills. Grain dust also produced inflammation. The present study has confirmed that organic dust can produce recruitment of inflammatory cells, activation of alveolar macrophages, stimulation of immune cells and the complement system activation of cell adhesion molecules, fibrosis of small airways and destruction of lung parenchyma in a rat model of lung injury.In toxicity experiments, no direct injury was evident towards alveolar epithelial cells or alveolar macrophages. This does not preclude sub-lethal effects, where stimulation of the cells could occur, resulting in activation and secretion of pro-inflammatory mediators.Activation was confirmed in in vitro experiments where organic dusts and dust leachates produced secretion of TNF from alveolar macrophages. A large part of the cell stimulation was due to the presence of endotoxin on the dusts and in the dust leachates, confirmed when endotoxin was depleted from the samples. The dusts also produced activation of cell adhesion molecules, manifest as homotypic aggregations of macrophages. An important consequence of macrophage activation could be increased adhesion of macrophages to epithelial cells leading to epithelial cell injury but this was not investigated.The possible involvement of the immune system was demonstrated in experiments where the lymph node lymphocytes from dust-treated rats were shown to be in a primed state. Priming could arise from mechanisms where activated macrophages could migrate from the lung to the lymph nodes and secrete pro-inflammatory cytokines, particularly TNF, although other molecules may be important.Persistence of dust in the lung resulted in the formation of granuloma. These changes were evident 14 days post dust-instillation and after 3 months there was fibrosis of small airways, destruction of lung parenchyma and the presence of aggregates in the airspaces. These events, singly or in concert could provide the starting point for inflammation and for changes in lung function and pathology, which may be relevant in workers exposed to organic dust.Suggestions for further work are outlined in Section 5.11.