Role of Pulmonary Inflammation in Altered Airway Responsiveness in Three Sheep Models of Acute Lung Injury

Pulmonary inflammation may contribute to increased airway responsiveness in experimental models of acute lung injury. Infusions of endotoxin, phorbol myristate acetate (PMA), or zymosan-activated plasma (ZAP) all result in the accumulation of polymorphonuclear leukocytes (PMNs) in the lung and alterations in lung mechanics. These three interventions have strikingly different effects on airway responses to aerosol histamine: ZAP does not increase airway responsiveness, whereas endotoxin causes a greater Increase in airway responsiveness than does PMA. The present histologic study examines the question of whether the pattern and severity of PMN and mast cell accumulation in large- and medium-sized airways and lung periphery could contribute to the differences in airway responsiveness to histamine. Minimally instrumented sheep were given either an infusion of endotoxin (0.5 µg/kg over 20 min), a bolus injection of PMA (5 µg/kg), or repetitive boluses of autologous ZAP (5 ml). Four and a half hours later, the animals were killed, and the left lung was removed and fixed in the distended state. Three levels of the left lung were examined by light microscopy: the large hilar bronchus, a medium-sized bronchus, and peripheral lung. The number of PMNs and mast cells in the airway wall were expressed as cells/mm length of airway circumference and In the lung periphery as cells/100 alveolar profiles. Both endotoxin and PMA caused a significant 2- to 3-fold increase in number of PMNs/mm of large airway circumference, the majority of PMNs being in the blood vessels of the lamina propria and submucosa; ZAP caused only minimal PMN accumulation in the blood vessels of the submucosa. Similarly, endotoxin and PMA caused at least a 3-fold increase in number of PMNs in the submucosal blood vessels of middle-sized bronchi and a 2- to 3-fold increase in their number/100 alveolar profiles. Mast cell numbers were unchanged by any of the interventions. The significant increases in PMNs after endotoxin, PMA, and ZAP grossly parallel the changes in airway responsiveness noted with these same agents. On the other hand, absolute numbers of PMNs in large and medium airways and peripheral lung were not statistically different between these interventions. Such findings underscore the difficulty in establishing a cause-and-effect relationship between inflammation and airway responsiveness.