title: Time course of quartz and TiO(2) particle-induced pulmonary inflammation and neutrophil apoptotic responses in rats.
abstract: Apoptosis, or programmed cell death, has been reported to play an important role in the resolution of pulmonary inflammation. This study was undertaken to investigate the role of apoptosis in resolving particle-induced lung inflammatory responses in exposed rats, using a dose-response / time course experimental design. Groups of rats were exposed via intratracheal instillation to 0, 0.5, 1, 5, 10, or 50 mg/kg body weight of quartz (i.e., crystalline silica) particles or to 0, 0.5, 1, 5, 10, 20, or 50 mg/kg of pigment-grade titanium dioxide (TiO(2)) particles and evaluated for lung inflammation parameters and evidence of apoptosis of inflammatory cells at 24, 48, 72, or 168 hours post exposure. At each post exposure evaluation period, bronchoalveolar lavage (BAL)-recovered cells from control and particle-exposed rats were assessed for apoptosis using 4 different techniques. The results in silica-exposed rats demonstrated a significant dose-related increase in inflammation concomitant with apoptosis of pulmonary inflammatory cells at 24 to 48 hours post exposure. At later postexposure time points, both the silica-induced inflammatory responses and apoptotic levels of inflammatory cells at higher doses (i.e., >or= 5 mg/kg) were reduced but persisted through 1 week. TUNEL (TdT-mediated dUTP nick end-labeling) assay studies confirmed that the vast majority of apoptotic cells were neutrophils. In contrast, titanium dioxide particle exposures produced transient pulmonary inflammation but only small measurable and nonsignificant apoptotic responses at higher exposure concentrations. These results suggest that the sustained lung inflammatory response in rats exposed to >or= 5 mg/kg silica may be related to the ineffectiveness of the normal apoptotic mechanisms associated with resolution of inflammation. However, because quartz particles are known to be cytotoxic to alveolar macrophages and other lung cells, normal apoptotic mechanisms may have limited utility for resolving particle-induced inflammation, particularly because silica may not be representative of other particle-types. Alternatively, it seems unlikely that apoptosis served to promote silica-induced lung inflammatory responses because the initial increase of apoptosis in inflammatory cells was subsequently correlated with a reduction of the pulmonary inflammatory response in silica-exposed rats. The findings from this in vivo study demonstrate that the neutrophil, and not the alveolar macrophage, is the primary inflammatory cell-type that undergoes apoptosis in response to particles. Furthermore, at doses causing similar degrees of inflammation at 24 hours post exposure, the magnitude of apoptosis induced by silica is significantly larger than that induced by TiO(2), indicating that there are potency differences in lung inflammation as well as apoptotic responses among different particle-types.
authors.affiliation: DuPont Haskell Laboratory for Health and Environmental Sciences, Newark, Delaware, USA.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hartsky
authors.forename: David B
authors.initials: DB
authors.lastname: Warheit
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000494:pharmacology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D053938:DNA Fragmentation / Q000187:drug effects / Q000276:immunology*; D020287:In Situ Nick-End Labeling; D008297:Male; D009504:Neutrophils / Q000166:cytology* / Q000187:drug effects; D011014:Pneumonia / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D011791:Quartz / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011930:Reaction Time / Q000276:immunology; D012822:Silicon Dioxide; D013047:Specific Pathogen-Free Organisms; D014025:Titanium / Q000494:pharmacology*
chemical_list: D001672:Biocompatible Materials; D011791:Quartz; C009495:titanium dioxide; D012822:Silicon Dioxide; D014025:Titanium