A nonlinear pharmacologic model of the acute effects of ozone on the human lungs

A pharmacologic model describing the quantitative relationship between short-term exposure to ozone and pulmonary airway resistance is described. The model simulates the following processes: (1) removal of a fraction of inhaled ozone in the airways of the head; (2) ozone oxidation of membrane-bound fatty acids in the target tissue in the lower airways; (3) rupture of cell membranes, releasing inflammatory mediators into the intercellular space; (4) migration of inflammatory cells into the injured tissue, releasing additional mediators and thus amplifying the inflammatory effect of ozone in a positive feedback loop; (5) stimulation of irritant receptors by ozone directly and by inflammatory mediators leading to vagally mediated bronchoconstriction. Mathematically the model consists of a logistic equation determining losses in the head, and a set of four differential equations simulating the uptake of ozone in the target tissue and the ensuing inflammation and bronchoconstriction. The observed human response to ozone in chamber studies is nonlinear, and it was necessary to introduce a nonlinear feedback loop for inflammation in the model to replicate this. Despite limited data upon which to base the model, it successfully predicts the human response to ozone reported in a series of published short-term chamber studies and is superior to "effective dose" (the product of ozone concentration, minute ventilation, and exposure duration) used by other investigations to describe dose-response relationships. Nonlinear multicompartment pharmacologic models such as this one can exhibit very complex behavior making the estimation of model parameters difficult, but they hold promise because the physiologic processes under study are themselves complex nonlinear phenomena.