Effect of histamine, albuterol and deep inspiration on airway and lung tissue mechanics in cynomolgus monkeys

Forced oscillation is a technique that has been used to measure airway and lung tissue impedance. To evaluate airway and lung tissue impedance in a colony of cynomolgus monkeys housed at Schering-Plough Research Institute, a forced oscillation technique was used to measure Newtonian resistance (RN), tissue damping (G), tissue elastance (H) and lung hysteresivity (η). Functional residual capacity (FRC) was also measured to correlate the lung impedance data with FRC. There was no difference in RN, G, H and η between Ascaris sensitive allergic monkeys (n=25) and a small cohort (n=5) of non-allergic monkeys under baseline conditions. However, a highly significant (p<0.0001) negative correlation (r=0.71) was found between FRC and H. Significant correlations were also found between FRC and G (r=0.53) and FRC and RN (r=0.50). Bronchoprovocation with aerosolized histamine increased RN, G, H and η and reduced FRC by 29±3% (n=30) from baseline. In monkeys that were hyperreactive to the histamine challenge, an exaggerated increase in lung tissue damping was seen whereas monkeys that were less reactive to the histamine showed greater increases in RN. Aerosolized albuterol (0.003–3mg/ml) produced a concentration-dependent reversal of the increases in RN, G, H and η induced by histamine with the greatest reversal seen on RN. Deep inspiration, performed after the aerosolized albuterol exposure, also reversed the histamine-induced changes in RN, G, and H with the complete reversal seen on the increase in H. These results demonstrate that significant correlations exist between airway and lung tissue impedance and FRC and that airway and lung tissue mechanics contribute significantly to inherent bronchoconstrictor reactivity and to the bronchodilator response to a beta-adrenergic agonist and deep inspiration in cynomolgus monkeys.