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 x 10(7) (approximately 86 micrograms) polystyrene microspheres (approximately 2 microns diam). On Days 7, 14, 57, 85, and 176 thereafter, subgroups were killed, their lungs were lavaged, recovered cells (greater than 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 greater than 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.

Pulmonary and thoracic macrophage subpopulations and clearance of particles from the lung.

“…Otherwise, the process ofphagocytosis, i.e., particle encounters and engulfment by AM, seemingly would have to be accomplished with complete efficiency within a post-depositional time span that would preclude particle uptake by the type I cells. The above extension ofthe Adamson and Bowden postulate is consistent with numerous reports that particles appear in the regional lymph nodes even when they are deposited at relatively low lung burdens (105,106,118,132). Assuming particle phagocytosis by AM is not perfectly efficient and sufficiently rapid, increasing numbers of particles would be expected to gain entry into type I cells essentially continuously during chronic aerosol exposures even ifthe phagocytic capacities of alveolar phagocytes have not been ex- FIGURE 15.…”

“…Moreover, the conclusions drawn in these studies would have gained further support ifcomparisons ofthe frequency distributions ofparticles in the lung free-cells and lung lymph nodes had been shown to be similar. Nevertheless, the above studies collectively seem to suggest that particle-containing AM may indeed make their way as one approach to obtain information on potential AM-related mechanisms that could form the underlying bases for conventional depictions of alveolar clearance (132). Briefly, the apparent overall rate(s) ofdisappearance of AM from the total AM population over time was found to increase with increasing particle burdens contained in the AM (Fig.…”

“…Histologically, clusters or aggregates of particle-laden AM are typically ob- FIGURE 10. Over time, the percentage of a retained lung burden of polystyrene microspheres was found to be progressively contained in alveolar macrophages with low particle loads (132).…”

“…Additionally, as particles are gradually released on a continual basis by alveolar phagocytes that initially engulfed them (64,130,132), a fraction of these free particles may also undergo passage from the alveolar surface into the type I cells at times well after initial particle deposition.…”

Intracellular Particle Dissolution in Alveolar Macrophages

“…Exhaustive total bronchalveolar lavages (BAL) in rodents up to half a year after particle administration (38,39) showed that more than 80% of the retained particles were still retained in AM on the epithelium. In large animals, partial BAL suggested particle retention in AM up to 500 days after inhalation (14,31,40,41).…”