An increased airway response to various bronchoconstricting agents is one of the hallmarks of asthma. An interdependence of heredity and environment appears to determine this nonspecific hyperreactivity of the airways. The present study describes the patterns of inheritance of the airway response to a direct mediator of smooth muscle contraction (acetylcholine) in A/J and C3H/HeJ inbred mice and their offspring. The mean airway response to acetylcholine was greater than sixfold higher in A/J mice as compared with C3H/HeJ mice. Two phenotypes were easily distinguished on the basis of airway responses to acetylcholine in the progeny of A/J and C3H/HeJ mice. These two phenotypes were termed HYPERREACTIVE (after the A/J strain) and HYPOREACTIVE (after the C3H/HeJ strain). The observed frequencies of HYPERREACTIVE and HYPOREACTIVE phenotypes in the (A/J x C3H/HeJ) F1; (C3H/HeJ x A/J) F1 x C3H/HeJ (C3H/HeJ backcross); and the [(A/J x C3H/HeJ) F1 x (C3H/HeJ x A/J) F1] F2 are consistent with a single autosomal recessive gene primarily controlling acetylcholine-mediated airway responses. This single gene difference in airway response is completely inhibited by atropine and therefore mediated entirely by the muscarinic acetylcholine receptor.

How normal airway dimensions change with lung volume is of great importance in determining flow limitation during the normal forced vital capacity maneuver as well as in the manifestation of obstructive lung disease. The literature presents a confusing picture, with some results suggesting that airway diameter increases linearly with the cube root of lung volume and others showing a highly nonlinear relation. The effect of smooth muscle contraction on lung-airway interdependence is even less well understood. Recent morphological work explicitly assumes that airway basement membrane is nondistensible, although the lung volume at which this maximal airway size is reached is unknown. With smooth muscle contraction, folding of the epithelium and basement membrane accounts for the changes in luminal area. In this study, we measured the effect of lung inflation on relaxed and contracted airway areas by using high-resolution computed tomography at different transpulmonary pressures, each held for 2 min. We found that fully relaxed airways are quite distensible up to a pressure of 5-7 cmH2O (P < 0.001), where they reach a maximal size with no further distension up to an airway pressure of 30 cmH2O (P = 0.49). Thus relaxed airways clearly do not expand isotropically with the lung. With smooth muscle tone, the airways in different animals responded differently to lung inflation, with some animals showing minimal airway dilation up to an airway pressure of 20 cmH2O and others showing airways that were more easily dilated with lung expansion. However, maximal diameter of these moderately constricted airways was not usually achieved even up to an airway pressure of 30 cmH2O. Thus a transient deep inspiration in vivo would be expected to have only a small effect on contracted airways.

The ability to successfully intubate the trachea of mice and control their ventilation is important for longitudinal studies requiring recovery from anesthesia and repeated pulmonary function measurements or other evaluations, such as the use of radiological imaging (e.g., computed tomography or magnetic resonance imaging). We describe a method for rapid and repeated intubation of mice, with subsequent pulmonary function measurements at baseline and after an agonist challenge. We describe a simply constructed metal blade used as a laryngoscope to facilitate oropharyngeal exposure, transillumination of the neck to facilitate visualization of the trachea through the oropharynx, readily available polyethylene tubing to intubate the trachea, and a simple solenoid ventilator to maintain physiological ventilation and assess respiratory resistance and compliance. Brief infusions of acetylcholine through a needle into the jugular vein are used to assess the responsiveness of the airway smooth muscle.

Xe gases were measured in the lungs of rabbits with elastase-induced emphysema and correlated against the mean chord length from lung histology. In vivo measurements were performed at baseline and 2, 4, 6, and 8 wk after instillation of elastase (mild and moderate emphysema groups) or saline (control group). ADCs were determined from acquisitions that used two b values. To investigate the effect of b value on the results, b-value pairs of 0 and 1.6 s/cm 2 and 0 and 4.0 s/cm 2 were used for 3 He, and b-value pairs of 0 and 5.0 s/cm 2 and 0 and 10.0 s/cm 2 were used for 129 Xe. At 8 wk after instillation, the rabbits were euthanized, and the lungs were analyzed histologically and morphometrically. ADCs for the rabbits in the control group did not change significantly from baseline to week 8, whereas ADCs for the rabbits in the emphysema groups increased significantly (P Ͻ 0.05) for all gas and b-value combinations except 129 Xe with the b-value pair of 0 and 5.0 s/cm 2 . The largest percent change in mean ADC from baseline to week 8 (15.3%) occurred with 3 He and the b-value pair of 0 and 1.6 s/cm 2 for rabbits in the moderate emphysema group. ADCs (all b values) were strongly correlated (r ϭ 0.62-0.80, P Ͻ 0.001) with mean chord lengths from histology. These results further support the ability of diffusion-weighted MRI with hyperpolarized gases to detect regional and global structural changes of emphysema within the lung.hyperpolarized gas magnetic resonance imaging; elastase MORE THAN 3,100,000 Americans suffer from emphysema, which is a component of chronic obstructive pulmonary disease (COPD). COPD and other forms of lower respiratory diseases, excluding asthma, represented the fourth-leading cause of death in the United States in 2002, claiming the lives of Ͼ124,000 people (1, 2). Pulmonary function tests are frequently used for the detection and assessment of emphysema. Patients with emphysema have a decreased expiratory flow rate, but 30% of lung capacity can be lost before changes appear in pulmonary function tests (22). Furthermore, the measurements are effort dependent, resulting in a relatively large intraindividual variability. High-resolution CT has been used to assess emphysematous change in the lung. In fact, CT was able to detect a decrease in the rate of decline of lung function in patients with ␣ 1 -antitrypsin deficiency who were treated with ␣ 1 -antitrypsin, whereas no significant change was seen with spirometry (20). Thus CT has been proposed as a potential biomarker for emphysema (3). Because of the tissue destruction that occurs in emphysema, emphysematous regions of the lung have less lung tissue per unit volume than normal lung, so they exhibit lower attenuation on CT. However, other processes in the lung can reduce CT attenuation, including reduced perfusion and air trapping (23). Furthermore, the relatively high radiation dose of a chest CT scan may limit its use for repeated scans in longitudinal studies and clinical trials (4). Hyperpolarized 3 He and 129 Xe are gaseous contrast agent...

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