Cigarette
smoke-induced
emphysema and
small airway remodeling are the anatomic bases of
chronic obstructive pulmonary disease (
COPD), but the pathogenesis of these changes is unclear, and current treatments for
COPD are minimally effective. To evaluate the role of signal transducer and activator of transcription (STAT)-4 in cigarette
smoke-induced
small airway remodeling, we used C57BL/6J (wild type [WT]) and STAT4-/- mice exposed to air or cigarette
smoke for 6 months and isolated airway and parenchymal fibroblasts. We also compared the results with those obtained with human fibroblasts. We found that STAT4-/- mice were protected against
smoke-induced
small airway remodeling but not
emphysema. STAT4 is abundantly expressed in airway compared with parenchymal-derived fibroblasts isolated from normal human and murine lung. WT airway fibroblasts proliferate faster than STAT4-/- airway fibroblasts, whereas there is no difference between strains for parenchymal fibroblasts.
IL-12 is up-regulated in the lung after
smoke exposure, and
IL-12 receptor B2 is expressed on airway and parenchymal fibroblasts in mouse and human lung. Treatment with
IL-12 causes phosphorylation of STAT4 in WT airway fibroblasts. Exposure of WT airway, but not parenchymal, fibroblasts to
IL-12 causes increased expression of
collagen 1α1 and
transforming growth factor β1, factors involved in
small airway remodeling, whereas STAT4-/- fibroblasts are unresponsive to
IL-12. These results indicate that
IL-12 can drive
small airway remodeling via STAT4 signaling and suggest that treatment with clinically available anti-IL-12p40 drugs might provide a new approach to preventing
small airway remodeling in cigarette smokers.