Surfactant protein D regulates NF-kappa B and matrix metalloproteinase production in alveolar macrophages via oxidant-sensitive pathways

Targeted ablation of the surfactant protein D (SP-D) gene caused progressiv e pulmonary emphysema associated with pulmonary infiltration by foamy alveo lar macrophages (AMs), increased hydrogen peroxide production, and matrix m etalloproteinase (MMP)-2, -9, and -12 expression. In the present study, the mechanisms by which SP-D influences macrophage MMP activity were assessed in AMs from SP-D-/- mice. Tissue lipid peroxides and reactive carbonyls wer e increased in lungs of SP-D-/- mice, indicating oxidative stress. Immunohi stochemical staining of AMs from SP-D-/- mice demonstrated that NF-kappaB w as highly expressed and translocated to the nucleus. Increased NF-kappaB bi nding was detected by EMSA in nuclear extracts of AMs isolated from SP-D-/- mice. Antioxidants N-acetylcysteine and pyrrolidine dithiocarbamate inhibi ted MMP production by AMs from SP-D-/- mice. To assess whether increased ox idant production influenced NF-KB activation and production of MMP-2 and -9 , AMs from SP-D-/- mice were treated with the NADPH oxidase inhibitors diph enylene iodonium chloride and apocynin. Inhibition of NADPH oxidase suppres sed NF-kappaB binding by nuclear extracts and decreased production of MMP-2 and 9 in AMs from SP-D-/- mice. SN-50, a synthetic NF-kappaB-inhibitory pe ptide, decreased MMP production by AMs from SP-D-/- mice. Oxidant productio n and reactive oxygen species were increased in lungs of SP-D-/- mice, in t urn activating NF-kappaB and MMP expression. SP-D plays an unexpected inhib itory role in the regulation of NF-kappaB in AMs.