Kupffer Cell Function in Host Defense

In addition to its effect on surfactant lipids, surfactant protein (SP)-A promotes host defense. To define further the role of SP-A in regulating immune cell function, we evaluated the effect of SP-A on lipopolysaccharide (LPS)-activated alveolar macrophages in two settings. First, cocultured LPS-activated macrophages significantly inhibited lung fibroblast growth, but SP-A (added daily) attenuated this effect. Both LPS and SP-A acted via macrophages rather than directly on the fibroblasts, at least partially by affecting tumor necrosis factor (TNF)-alpha activity. TNF-alpha reproduced the growth suppression, anti-TNF-alpha antibodies attenuated the effect LPS-activated macrophages, and SP-A reduced TNF-alpha activity in conditioned medium. Second, SP-A reduced TNF-alpha activity in medium from isolated LPS-stimulated macrophages. The effects of SP-A were noted with or without serum, were dose-dependent and reversible, and were seen with two different serotypes of smooth LPS. Equimolar concentrations of immunoglobulin G and C1q had no effect. Thus SP-A both enhances host defense and modulates immune functions of alveolar macrophages.

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Mechanism of Hepatic Heme Oxygenase-1 Induction by Isoflurane

Anesthesiology ◽

10.1097/00000542-200601000-00016 ◽

2006 ◽

Vol 104 (1) ◽

pp. 101-109 ◽

Cited By ~ 24

Author(s):

Alexander Hoetzel ◽

Daniel Leitz ◽

Rene Schmidt ◽

Eva Tritschler ◽

Inge Bauer ◽

...

Keyword(s):

Nitric Oxide ◽

Protein Kinase C ◽

Protein Kinase ◽

Phospholipase A2 ◽

Heme Oxygenase ◽

Kupffer Cell ◽

Cell Function ◽

Heme Oxygenase 1 ◽

Gadolinium Chloride ◽

Kinase C

Background The heme oxygenase pathway represents a major cell and organ protective system in the liver. The authors recently showed that isoflurane and sevoflurane up-regulate the inducible isoform heme oxygenase 1 (HO-1). Because the activating cascade remained unclear, it was the aim of this study to identify the underlying mechanism of this effect. Methods Rats were anesthetized with pentobarbital intravenously or with isoflurane per inhalation (2.3 vol%). Kupffer cell function was inhibited by dexamethasone or gadolinium chloride. Nitric oxide synthases were inhibited by either N(omega)-nitro-L-arginine methyl ester or S-methyl thiourea. N-acetyl-cysteine served as an antioxidant, and diethyldithiocarbamate served as an inhibitor of cytochrome P450 2E1. Protein kinase C and phospholipase A2 were inhibited by chelerythrine or quinacrine, respectively. HO-1 was analyzed in liver tissue by Northern blot, Western blot, immunostaining, and enzymatic activity assay. Results In contrast to pentobarbital, isoflurane induced HO-1 after 4-6 h in hepatocytes in the pericentral region of the liver. The induction was prevented in the presence of dexamethasone (P < 0.05) and gadolinium chloride (P < 0.05). Inhibition of nitric oxide synthases or reactive oxygen intermediates did not affect isoflurane-mediated HO-1 up-regulation. In contrast, chelerythrine (P < 0.05) and quinacrine (P < 0.05) resulted in a blockade of HO-1 induction. Conclusion The up-regulation of HO-1 by isoflurane in the liver is restricted to parenchymal cells and depends on Kupffer cell function. The induction is independent of nitric oxide or reactive oxygen species but does involve protein kinase C and phospholipase A2.

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