Inhaled irritants, such as cigarette smoke, activate epithelial cells and macrophages to release multiple cytokines, including growth factors such as TGF-β and FGFs, which stimulate fibroblast proliferation, resulting in fibrosis in the small airways. These cells also secrete the proinflammatory cytokines TNF-α, IL-1β, and IL-6, all of which amplify inflammation, and several chemokines that attract circulating cells into the lungs. CCL2 acts via CCR2 to attract monocytes (which differentiate into macrophages in the lungs); CXCL1 and CXCL8 act via CXCR2 to attract neutrophils and monocytes; and CXCL9, CXCL10, and CXCL11 act via CXCR3 to attract Th1 cells and Tc1 cells, both of which release IFN-γ, which in turn stimulates the release of more of these CXCR3-binding chemokines. Mucus hypersecretion is stimulated by EGF and TGF-α. CTGF, connective tissue growth factor. Adapted with permission from Nature Publishing Group (1).