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Gadolinium blocks rat kupffer cell calcium channels: Relevance to calcium‐dependent prostaglandin E 2 synthesis and septic mortality
Author(s) -
Roland Claude R.,
Naziruddin Bashoo,
Mohanakumar T.,
Flye M. Wayne
Publication year - 1999
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.510290345
Subject(s) - calcium , ionomycin , medicine , endocrinology , prostaglandin e2 , thapsigargin , tumor necrosis factor alpha , chemistry , phorbol , protein kinase c , biochemistry , kinase
Hepatic Kupffer cells (KC), the major tissue macrophage population, produce the septic response mediators, tumor necrosis factor α (TNF‐α) and prostaglandin E 2 (PGE 2 ), and have been shown to internalize gadolinium chloride (GD), a rare earth metal of the lanthanide series. Because GD pretreatment of rats has been shown to inhibit the mortality of sepsis, we studied the secretory response to lipopolysaccharide (LPS) by KC isolated from rats injected with either saline or GD (7 mg/kg, intravenously) on the 2 days before KC isolation. Using culture conditions modified to reflect the intrasinusoidal milieu of arginine (RPMI‐1640 media with 10 or 100 μmol/L arginine), KC from GD‐treated rats responded to LPS (0.0025 μg/mL) with significantly ( P < .01) reduced PGE 2 release. In contrast, TNF‐α release by treated KC was significantly ( P < .05) enhanced, consistent with the loss of PGE 2 autocoid inhibition of TNF‐α. Calcium flux is an early signaling event in eicosanoid synthesis, and GD is known to block calcium channels. Therefore, KC were loaded with fura‐2‐AM to study the effect of GD on KC calcium flux. GD prevented ionomycin and platelet‐activating factor (PAF)‐mediated [Ca ++ ] i increase and calcium‐dependent PGE 2 synthesis, while GD did not affect PGE 2 synthesis when protein kinase C (PKC) was directly activated with tetradecanoylphorbolacetate (TPA). The inhibition of calcium flux and calcium‐dependent PGE 2 synthesis in the major cell of the monocytic phagocytic system by GD may explain the previously reported ability of this lanthanide to prevent the mortality of endotoxemia.