During the late-phase (LP) response to inhaled allergen, mediators from neutrophils and eosinophils are released within the airways, resembling what occurs during an asthma attack. We compared the distribution of obstruction and degree of reversibility that follows a deep inspiration (DI) during early-phase (EP) and LP responses in nine asthmatic subjects challenged with allergen. Heterogeneity of constriction was assayed by determining frequency dependence of dynamic lung resistance and elastance, airway caliber by tracking airway resistance during a DI, and airway inflammation by measuring inflammatory cells in induced sputum postchallenge. Despite a paucity of eosinophils in the sputum at baseline (<1% of nonsquamous cells), asthmatic subjects showed a substantial EP response with highly heterogeneous constriction and reduced capacity to maximally dilate airways. The LP was associated with substantial airway inflammation in all subjects. However, five subjects showed only mild LP constriction, whereas four showed more marked LP constriction characterized by heterogeneous constriction similar to EP. Bronchoconstriction during LP was fully alleviated by administration of a bronchodilator. These findings, together with the impaired bronchodilatory response during a DI, indicate a physiological abnormality in asthma at the smooth muscle level and indicate that airway inflammation in asthma is associated with a highly nonuniform pattern of constriction. These data support the hypothesis that variability in responsiveness among asthmatic subjects derives from intrinsic differences in smooth muscle response to inflammation.

Human emphysema is a progressive, destructive lung disease that produces morphologic and functional heterogeneity throughout its course. Consequently, the mature form of the disease is described by a broad range of anatomic, radiological, and physiologic patterns. This report describes the development and characterization of a sheep model of emphysema that represents many of the essential features of both homogeneous and heterogeneous emphysema. Emphysema was produced by two different techniques of papain exposure: (1) aerosol (75 IU/kg) given weekly for 4 treatments (HM) or (2) aerosol (75 IU/kg) weekly for 3 treatments following subsegmental intrabronchial instillations, 75 IU (in 10 saline) per lobe in 6 lobes (HT). Dexamethasone (0.06 mg/kg iv) was administered prior intrabronchial instillations only. On computed tomography, the HM group had homogeneous emphysema, the HT group gross nonuniformity of disease and bullae formation. Both groups demonstrated a significant (p < 0.05) increase in residual volume (HM, +38%; HT, +30%). There was a significant increase (p = 0.002) in total lung capacity per kilogram for the HM group. Emphysema had no effect on active or passive chest wall compliances. Diffusion capacity was significantly (p < 0.05) reduced in both groups. Both elastic (p = 0.066) and resistive (p = 0.025) components of impedance were increased in the HT, and airway resistance increased significantly in the HM groups. The HM model demonstrated gas trapping, a characteristic feature of emphysema, but failed to replicate the alterations in lung dynamics observed in the human form of this disease. The HT model demonstrated less static hyperinflation but significant frequency dependence and hence appeared to better represent the dynamic characteristics of human emphysema.

Human emphysema is a progressive, destructive lung disease that produces morphologic and functional heterogeneity throughout its course. Consequently, the mature form of the disease is described by a broad range of anatomic, radiological, and physiologic patterns. This report describes the development and characterization of a sheep model of emphysema that represents many of the essential features of both homogeneous and heterogeneous emphysema. Emphysema was produced by two different techniques of papain exposure: (1) aerosol (75 IU/kg) given weekly for 4 treatments (HM) or (2) aerosol (75 IU/kg) weekly for 3 treatments following subsegmental intrabronchial instillations, 75 IU (in 10 saline) per lobe in 6 lobes (HT). Dexamethasone (0.06 mg/kg iv) was administered prior intrabronchial instillations only. On computed tomography, the HM group had homogeneous emphysema, the HT group gross nonuniformity of disease and bullae formation. Both groups demonstrated a significant (p < 0.05) increase in residual volume (HM, +38%; HT, +30%). There was a significant increase (p = 0.002) in total lung capacity per kilogram for the HM group. Emphysema had no effect on active or passive chest wall compliances. Diffusion capacity was significantly (p < 0.05) reduced in both groups. Both elastic (p = 0.066) and resistive (p = 0.025) components of impedance were increased in the HT, and airway resistance increased significantly in the HM groups. The HM model demonstrated gas trapping, a characteristic feature of emphysema, but failed to replicate the alterations in lung dynamics observed in the human form of this disease. The HT model demonstrated less static hyperinflation but significant frequency dependence and hence appeared to better represent the dynamic characteristics of human emphysema.