Volumetric Loading of Alveolar Macrophages (AM): A Possible Basis for Diminished AM-Mediated Particle Clearance

Abstract

Using intratracheal instillation of radioactively labeled plastic microspheres of 3.3 and 10.3 μm diameter at two dose levels, this 7-month study in male Fischer 344 rats was designed to test a volumetric particulate burden hypothesis that has been proposed as a mechanistic basis for the condition of dust overloading of the lungs with highly insoluble particles of very low toxicity and to explain the prolongation of pulmonary particle retention. The study utilized airway and deep lung lavage techniques, scanning electron and optical microscopy of lavaged cells and lungs of sacrificed animals, particle distribution in alveolar macrophages (AM), fecal recovery of radioactive particles, and lung retention measurements by external counting. Microscopic assessments revealed that essentially all of the 3.3- and 10.3-μm-diameter particles were phagocytized by AM within 24 h postinstillation. One phagocytized 10.3μm particle is capable of producing the hypothesized 600-μm³/AM overload criterion for virtual AM immobilization. Neither the number nor the volume of 3.3-μm-diameter particles instilled was large enough to produce volumetric overloading assuming uniform distribution of the particles in the lung. In contrast to the 3.3-μm particles, the 10.3-μm particles were apparently sequestered to a greater extent and capable of greatly prolonging AM-mediated clearance of particles from the pulmonary region. The measured pulmonary retention half times for the small and large particles were 86–109 days and 870–1020 days, respectively. Fecal recovery data closely complemented pulmonary clearance data for both particle sizes. The two-particle approach was found supportive of the volumetric overload hypothesis.