MORPHOMETRY OF METHACHOLINE-INDUCED BRONCHOCONSTRICTION IN THE RAT

It has been suggested that parenchymal viscoelasticity accounts for a large proportion of resistive pressure losses induced by smooth muscle agonists. We used morphometric methods to evaluate the relative contributions of parenchyma and airways to mechanical changes during methacholine- (MCh) induced bronchoconstriction. We measured tracheal pressure and tidal volume in 17 open-chest mechanically ventilated Sprague-Dawley rats (frequency = 1.5 Hz, tidal volume = 2 ml, positive end-expiratory pressure = 5 cmH2O) after saline (n = 7, C), 16 mg/ml MCh (n = 5, L), and 256 mg/ml MCh (n = 5, H) aerosols. We calculated pulmonary resistance (RL) and elastance (EL) by fitting the equation PL = VRL + VEL + K, where PL is transpulmonary pressure, V is flow, and V is volume. V was obtained numerically from V. Lungs were rapidly frozen in liquid N2 30 s after aerosolization and processed with freeze substitution. Using midsagittal slices of left lung, we measured airway narrowing as the ratio of lumen area (a(BM)) subtended by the basement membrane perimeter (L(BM)) to predicted maximal lumen area (A(BM) = L(BM)2/4pi). Air space size was estimated as mean linear intercept (L(m)) and parenchymal distortion as standard deviation of linear intercepts (SD(i)). L(m) was increased in L and H animals, reflecting hyperinflation; a(BM)/A(BM) in 0.17- to 0.43-mm-diam airways decreased progressively from C to L to H animals, reflecting bronchoconstriction. By use of stepwise multiple linear regression, the contribution of L(m) to variance in mechanics was found to consistently exceed or equal that of a(BM)/A(BM). SD(i) contributed little once L(m) was taken into account. These results support the notion that viscoelastic pressure losses associated with parenchymal distortion are important determinants of mechanics after MCh exposure.