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Though considered as an inflammation marker, exhaled nitric oxide (FENO) was shown to be sensitive to airway caliber changes to such an extent that it might be considered as a marker of them. It is thus important to understand how these changes and their localization mechanically affect the total NO flux penetrating the airway lumen (JawNO), hence FENO, independently from any inflammatory status change. A new model was used which simulates NO production, consumption and diffusion inside the airway epithelium wall, then, NO excretion through the epithelial wall into the airway lumen and, finally, its axial transport by diffusion and convection in the airway lumen. This model may also consider the presence of a mucus layer coating the epithelial wall. Simulations were performed that showed the great sensitivity of JawNO to peripheral airways caliber changes. Moreover, FENO showed distinct behaviors depending on the location of the caliber change. Considering a bronchodilation, absence of FENO change was associated with dilation of central airways, FENO increase with dilation up to pre-acinar small airways, and FENO decrease with intra-acinar dilation due to amplification of the back-diffusion flux. The presence of a mucus layer was also shown to play a significant role in FENO changes. Altogether, the present work provides theoretical evidences that specific FENO changes in acute situations are linked to specifically located airway caliber changes in the lung periphery. This opens the way for a new role for FENO as a functional marker of peripheral airway caliber change.