Alveolar macrophages (AM) play an important role in clearing inhaled particles from the lung. The mechanisms through which macrophages identify particles that have been deposited in the alveolar regions is not well understood, although macrophage motility and phagocytic functions appear to be prerequisites for efficient clearance of inhaled materials. In previous studies, we assessed the mechanisms of macrophage-mediated clearance of inhaled particles using a rat model. In this regard, it appears that one mechanism by which rat alveolar macrophages are recruited to sites of particle or fiber deposition is through complement activation and consequent generation of chemotactic factors by the inhaled particulates. Whether this mechanism is operative in other rodent species remains an unanswered question. The current studies were undertaken to compare pulmonary clearance responses in several rodent species exposed to carbonyl iron (CI) particles. In vitro and in vivo pulmonary clearance responses were evaluated using one strain each of mouse, hamster, rat, and guinea pig. In vitro studies showed that hamster AM had the greatest phagocytic activity and that rat AM migrated best to complement-dependent chemotactic factors. Subsequently, groups of animals from each species were exposed to CI particles for 1 or 6 hr at aerosol concentrations of 100 mg/m3. Particle depositions patterns in the distal lung were nearly identical for all species, although enhanced numbers of CI particles were deposited on alveolar duct bifurcations of either rats or mice compared to hamsters, and particle deposition in guinea pigs was substantially lower. Time course studies showed that enhanced numbers of rat AM migrated to deposition sites and phagocytized particles, and this correlated with increased numbers and percentages of phagocytic macrophages recovered by lavage (P < 0.01). In vivo phagocytic rates were the lowest in the mouse, and this correlated with reduced phagocytic rates in vitro. It is concluded from these studies that the rat may be the most efficient rodent species in clearing inhaled iron particles. In addition, it is conceivable that hamster AM are recruited to sites of particle deposition by a noncomplement-mediated mechanism.
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.
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.
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