Surfactant protein-D (SP-D) is a member of the collectin family of collagenous proteins with lectin activity. SP-D is expressed in numerous tissues, primarily in type II alveolar cells in the periphery of the lung. SP-D plays an important role in host defense of the lung. To evaluate the importance of SP-D in vivo, transgenic mice lacking SP-D (SP-D-/- mice) have been generated. Lipid accumulation and airspace enlargement were observed in the lungs of SP-D-/- mice within 3 weeks after birth, and progressed with advancing age. Airspace enlargement and abnormalities in elastin fibers supported the concept that SP-D was required to inhibit destruction of the alveoli. Alveolar macrophages from SP-D-/- mice produced more H2O2 and matrix metalloproteinases (MMP)-2, -9, and -12 compared with wild-type mice. In vitro studies demonstrated that oxidants derived in part from NADPH oxidase enhanced NF-kappaB activation and MMP production in alveolar macrophages from SP-D-/- mice. A specific inhibitor of NF-kappaB reduced MMP production by alveolar macrophages from SP-D-/- mice. Taken together, these data demonstrated oxidant-dependent activation of NF-kappaB and enhanced MMP expression by alveolar macrophages from SP-D-/- mice, a process likely to mediate airspace remodeling caused by SP-D deficiency. SP-D plays a critical role in regulating alveolar macrophage activation, oxidant production, and MMP activity that may influence the pathogenesis of various pulmonary disorders.