Permeability of human isolated airways increases after hydrogen peroxide and poly-L-arginine

In asthma, the airway epithelium may be damaged by oxidants and cationic proteins produced by eosinophils. The degree of epithelial damage correlates with the level of bronchial hyperreactivity. An increase in airway permeability to bronchoactive agonists may be one of the factors responsible for airway hyperresponsiveness in asthma. We investigated the effects of the oxidant hydrogen peroxide and the major basic protein (MBP) analogue poly-l-arginine on the permeability and morphology of nonasthmatic human peripheral airways. In addition, we examined whether airway permeability depends on airway size. Human airway tubes (generation 7 to 12) mounted in an organ bath were luminally perfused with Krebs-Henseleit buffer containing the hydrophilic tracer In-111-diethyletriamine pentaacetic acid (In-111-DTPA) or the lipophilic tracer C-14-antipyrine (C-14-AP). Permeability of the airways was calculated from the fluxes of the tracer molecules across the airway wall. After experiments, light- and electronmicroscopic examination of the airway epithelium was performed. Baseline permeability to C-14-AP was five times greater than to In-111-DTPA. Luminal exposure of the airways to 100 mmol/L H2O2 produced a significant, sixfold increase in permeability to In-111-DTPA but not to C-14-AP, indicating the opening of paracellular pathways. The H2O2-induced increase in permeability was partly reversible. Luminal exposure to polyarginine for 3 h and 16 h produced a significant 4.5- and 7-fold increase in permeability to In-111-DTPA, respectively. Histologic examination of epithelium exposed to H2O2 of poly-L-arginine showed focal loss of superficial cells with preservation of basal cells. Baseline airway permeability increased with decreasing airway size (rs = -0.75, p < 0.01). These results suggest that epithelial damage due to eosinophil products may increase airway permeability, and that this may at least partly explain the increased responsiveness to inhaled stimuli in asthma.