Neurokinin 1 receptors (NK1Rs) in alveolar macrophages (AMs) are overexpressed by cigarette smoke (CS) in vivo and substance P (SP) in vitro. Because CS could stimulate pulmonary C-fibers (PCFs) to release SP, we asked whether this neurogenic SP was responsible for AMs' NK1R overexpression during CS. We compared pulmonary SP and AMs' NK1R gene and protein levels in intact and PCF-degenerated mice exposed to filtered air (FA) and CS. Pulmonary SP was increased by CS but almost eliminated by PCF degeneration, which closely correlated to the changes in AMs' NK1R expression. Moreover, SP was higher in the PCF-degenerated mice exposed to CS than FA. To evaluate the direct effects of CS and SP on the NK1R expression and the involvement of nuclear factor (NF)-kappaB, macrophages were exposed to CS condensate (CSC) and/or SP without or with blocking NK1R or inhibiting NF-kappaB activation in vitro. CSC itself induced a moderate secretion of SP from macrophages, and amplified NK1R responses to SP that were completely eliminated by blocking NK1R, and substantially reduced after inhibiting NF-kappaB. Our results suggest that CS produces AMs' NK1R overexpression primarily by both promoting neurogenic SP release and synergizing NK1R response to neurogenic SP largely via activating NF-kappaB pathway.