Alveolar clearance and retention of inhaled insoluble particles in rats simulated by a model inferring macrophage particle load distributions

Abstract

This paper presents the description of a revised, physiology-oriented compartmental kinetics (“POCK”) model of alveolar clearance and retention of biologically insoluble, respirable particles. By postulating a deposit-activated maximum macrophage recruitment rate leading to a quasi-steady state of the alveolar macrophage population on the alveolar epithelial surface, the model uses a theoretical derivation of an exposure-dependent distribution of particles in the alveolar macrophage population to determine the total load in mobile and immobilized macrophages. For this, the model assumes an invariant maximum volume capacity of the macrophages for particle uptake and a material-dependent critical load of the macrophages that causes total loss of their inherent mobility. Prior to a gradual onset of mobility decrease, there is a material-dependent range of low macrophage burdens without mobility impairment. Using independently determined physiological data for classical clearance rate coefficients, as well as for the lifetime of the alveolar macrophages and their particle turnover by phagocytosis, the model seems to be applicable to experimental results obtained for rats. A constant set of model parameters and a minimum of three material-dependent, physiologically meaningful model variables were sufficient to simulate the alveolar lung burden and available lymph node load data of 15 different subchronic or chronic exposures of Fischer 344 rats to diesel soot, carbon black or xerographic toner. For constant deposition rates, the model predicts the establishment of quasi-steady states for the total load of the alveolar macrophage pool. The final load would increase with increasing deposition rate and, particularly under overload conditions, i.e. at high deposition rates, the number of immobilized macrophages would grow significantly. According to the model, overload does not cause an excessive growth of the total burden of the macrophage pool, but leads to a tremendous increase of the particulate burden of the interstitial space. This compartmental burden is not available for macrophage-mediated classical clearance. Except for partial removal to the lymph nodes, the interstitial burden will persist even when exposures are discontinued and the alveolar macrophage population recovers to full mobility. Subchronic exposure studies seem to bear this out, but due to lack of experimental data for the burdens in most of the alveolar subcompartments of the model, the corresponding predictions cannot be validated at the present time.