Surfactant protein D (SP D) is a constituent of the innate immune system that plays a role in host defense against lung pathogens and in modulating inflammatory responses. While SP-D has been detected in extra-pulmonary tissues, little is known about its expression and function in the vasculature. Immunostaining of human coronary artery tissue sections demonstrated immunoreactive SP D protein in smooth muscle cells (SMC) and endothelial cells. SP D was also detected in isolated human coronary artery smooth muscle cells (HCASMC) by PCR and immunoblot analysis. Treatment of HCASMC with endotoxin (LPS) stimulated the release of IL-8, a pro-inflammatory cytokine. This release was inhibited > 70% by recombinant SP D. Overexpression of SP-D by adenoviral-mediated gene transfer in HCASMC inhibited both LPS- and TNF-induced IL-8 release. Overexpression of SP-D also enhanced uptake of Chlamydia pneumoniae elementary bodies into HCASMC while attenuating IL-8 production induced by bacterial exposure. Both LPS and TNF increased SP D mRNA levels by 5- to 8-fold in HCASMC, suggesting that inflammatory mediators up-regulate expression of SP-D. In conclusion, SP-D is expressed in human coronary arteries and functions as an anti-inflammatory protein in human coronary artery SMC. SP-D may also participate in host defense against pathogens that invade the vascular wall.