Time course of chemotactic factor generation and neutrophil recruitment in the lungs of dust-exposed rats.

The time course of neutrophil recruitment into the lung, neutrophilic chemotactic activity, and the gene expression of neutrophilic chemokines by lavaged cells was determined after intratracheal instillation of various particles. Low-toxicity, low-solubility dusts such as titanium dioxide (TiO2) particles, as well as fibrogenic crystalline silica and nonfibrogenic amorphous silica particles were instilled into the lungs of rats. Results showed that all three dusts induced neutrophilic inflammation as early as 5 h after exposure. Both crystalline and amorphous silica elicited higher degrees of pulmonary inflammation when compared with TiO2 particles. Maximal infiltration of neutrophils into the lungs occurred 5 to 6 h after intratracheal instillation of the dusts. The inflammatory response was transient for TiO2 and amorphous silica, i.e., evident at 2 days after exposure but not different from controls at 10 days after exposure. In contrast, inflammatory effects were sustained through a 10-day period following exposures to crystalline silica. Chemotactic activity for neutrophils was detected directly in bronchoalveolar lavage (BAL) fluids of dust-exposed rats within 2 h after exposure, but not in the BAL fluids of saline- or unexposed rats. The chemotactic activity was correlated with the influx and disappearance of neutrophils into alveolar regions of the lung in TiO2- and amorphous silica-exposed rats. The mRNA expression of two known neutrophil chemotactic cytokines in BAL cells, macrophage inflammatory protein-2 (MIP-2) and KC, also correlated with chemotactic activity and acute and pulmonary inflammatory responses. MIP-2 mRNA was expressed prior to the detection of chemotactic activity in BAL fluids. However, the mRNA expressions of MIP-2 and KC were transient for rats that were exposed to these dusts as KC and MIP-2 message were no longer detectable in BAL cells after 2 days of recovery. Although both neutrophilic chemotactic activity and inflammation remained prominent 10 days after exposure to crystalline silica, MIP-2 expression could not be detected in BAL cells. Thus, we conclude that MIP-2 is likely to be only one of several cytokines involved in mediating neutrophilic inflammation following a single instillation of crystalline silica.