Alveolar Macrophage-Particle Relationships During Lung Clearance

Abstract

Retention kinetics for insoluble particles that deposit in the lung oftentimes resemble a multicomponent process during alveolar clearance, with each component appearing to follow simple first-order kinetics. Inasmuch as alveolar macrophages (AM) are thought to play an important role in particle removal from the lung, a study was undertaken to examine particle-AM relationships during the clearance of particles to obtain information on potential AM mechanisms that could provide the underlying bases for the lung retention kinetics of the particles. Adult, Fischer 344 rats were intratracheally instilled with 1.6 × 107 (∼86 µg) polystyrene microspheres (∼2 µm diam). On Days 7, 14, 57, 85, and 176 thereafter, subgroups were killed, their lungs were lavaged, recovered cells (>95% AM) were counted, the frequency distribution of the particles among the AM was determined (e.g., zero, 1 to 2, 3 to 4 particles/AM), and the total numbers of particles lavaged were estimated. The lavaged lungs were solubilized, and unlavaged particles were also counted. The sums of the lavaged and unlavaged particles were used to estimate retained lung burdens at each postinstillation time. The lung retention data followed a pattern consistent with the sum of two negative exponential components, i.e., an earlier, more rapid component and a slower, longer term component. The rates at which the AM disappeared from a given particle category also were biphasic for AM that contained up to 14 microspheres. The rates of both the earlier and longer term components of such disappearance were found to increase with increasing AM burdens. Over an AM burden range of 1 to 10 microspheres, the proportion of AM that disappeared via rapid components also increased as the particle burden defining an AM category increased. At higher particle burdens, the proportion of AM that disappeared by an early component appeared to markedly diminish; an early component for AM disappearance was no longer resolvable for AM that contained >15 microspheres. The net effect of these phenomena was that retained lung burdens over time became progressively contained in AM with lesser burdens of particles. The results from this study suggest that the rate(s) of translocation of particle-containing AM from the lung during lung clearance may be related to their individual particulate burdens. These findings, however, are also consistent with a gradual redistribution of particles among the lung's AM population over time concurrent with AM removal from the lung. Regardless, the biphasic nature of the lung retention data qualitatively was generally evident for particle-containing AM as well.