Two possible mechanisms could explain this observation. First, the decrease in Di and the shallower Sn with breath holding for SBWSM may both be explained by the common effect of small airway inflammation and/or regional loss of elastic recoil on intraregional convective dependent inhomogeneity, the interaction of convection and diffusion at peripheral branch points, or both phenomena . Second, the breath holding effects on Di and Sn may not necessarily have been causally linked to alterations in ventilation inhomogeneity as previously suggested to explain the effects of breath holding on Di in normal subjects . Rather, both may have been altered by time, but for different reasons. Sn may have been steeper in smokers because of increased peripheral ventilation inhomogeneity. Di may have been increased, at least in part, by an additional effect of an exaggerated serial gradient in alveolar-capillary diffusion in smokers, such that diffusion was preferentially reduced in the proximal versus distal region of the terminal respiratory unit. Without breath holding, such a gradient in diffusion within the acinus would have created a higher carbon monoxide concentration in proximal regions that emptied early in exhalation, accounting for the higher than expected carbon monoxide concentration early in exhalation (sample 1) and the lower than expected carbon monoxide concentration later in exhalation . However, with breath holding this serial gradient in carbon monoxide concentration within the acinus would have rapidly decreased over time because of cardiogenic and diffusive gas mixing within the air phase of the terminal respiratory unit. Early centrilobular emphysema could have caused such a preferential decrease in diffusion in the proximal (alveolar ducts), compared with the distal (alveole), regions of the terminal respiratory units, thus exaggerating the effects of breath holding on Di seen in normal subjects .