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 progressive pulmonary emphysema associated with pulmonary infiltration by foamy alveolar macrophages (AMs), increased hydrogen peroxide production, and matrix metalloproteinase (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 were increased in lungs of SP-D(-/-) mice, indicating oxidative stress. Immunohistochemical staining of AMs from SP-D(-/-) mice demonstrated that NF-kappaB was highly expressed and translocated to the nucleus. Increased NF-kappaB binding was detected by EMSA in nuclear extracts of AMs isolated from SP-D(-/-) mice. Antioxidants N-acetylcysteine and pyrrolidine dithiocarbamate inhibited MMP production by AMs from SP-D(-/-) mice. To assess whether increased oxidant production influenced NF-kappaB activation and production of MMP-2 and -9, AMs from SP-D(-/-) mice were treated with the NADPH oxidase inhibitors diphenylene iodonium chloride and apocynin. Inhibition of NADPH oxidase suppressed 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 peptide, decreased MMP production by AMs from SP-D(-/-) mice. Oxidant production and reactive oxygen species were increased in lungs of SP-D(-/-) mice, in turn activating NF-kappaB and MMP expression. SP-D plays an unexpected inhibitory role in the regulation of NF-kappaB in AMs.
Yoshida
M
M
Division of Pulmonary Biology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
Korfhagen
T R
TR
Whitsett
J A
JA
D000111:Acetylcysteine / Q000494:pharmacology; D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006023:Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D008168:Lung / Q000201:enzymology / Q000378:metabolism; D016676:Macrophages, Alveolar / Q000201:enzymology* / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000096:biosynthesis*; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000096:biosynthesis* / Q000378:metabolism; D016877:Oxidants / Q000502:physiology*; D010084:Oxidation-Reduction; D018384:Oxidative Stress / Q000502:physiology; D037663:Pulmonary Surfactant-Associated Protein D; D011663:Pulmonary Surfactants / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011759:Pyrrolidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013859:Thiocarbamates / Q000494:pharmacology
D000975:Antioxidants; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D061965:Matrix Metalloproteinase Inhibitors; D016328:NF-kappa B; D016877:Oxidants; D037663:Pulmonary Surfactant-Associated Protein D; D011663:Pulmonary Surfactants; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D013859:Thiocarbamates; C020972:pyrrolidine dithiocarbamic acid; D020782:Matrix Metalloproteinases; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D000111:Acetylcysteine