Gadolinium Blocks Rat Kupffer Cell Calcium Channels: Relevance to Calcium–Dependent Prostaglandin E2 Synthesis and Septic Mortality

Abstract

Hepatic Kupffer cells (KC), the major tissue macrophage population, produce the septic response mediators, tumor necrosis factor ␣ (TNF-␣) 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 mol/L arginine), KC from GD-treated rats responded to LPS (0.0025 g/mL) with significantly (P F .01) reduced PGE 2 release. In contrast, TNF-␣ release by treated KC was significantly (P F .05) enhanced, consistent with the loss of PGE 2 autocoid inhibition of TNF-␣. 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 calciumdependent 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. (HEPATOLOGY 1999;29:756-765.)

Distribution and clearance of retained gadolinium in the brain: differences between linear and macrocyclic gadolinium based contrast agents in a mouse model

“…We suspected that the Gd dissociated from Gd-DTPA-BMA forms a specific complex, facilitating its transport across BBB or BCSFB and into the brain. Because Gd 31 is a potent calcium antagonist owing to its ionic radius being similar to that of calcium (Ca 21 ) 23,24 and its ability to bind with macromolecules (e.g. transferrin) 25,26 or endogenous molecules (e.g.…”

Allograft tolerance induced by donor apoptotic lymphocytes requires phagocytosis in the recipient

“…34,35 In order to further elucidate the role of phagocytosis, we employed annexin V to block phagocytosis of apoptotic cells specifically. Annexin V is well known for its high binding affinity for PS, a phospholipid normally situated on the inner leaflet of the cytoplasmic membrane.…”

Role of Kupffer Cells in Lung Injury in Rats Administered Endotoxin11

“…Upon activation, however, Kupffer cells release several active substances such as eicosanoids, inflammatory cytokines, and free radicals, which are all involved in deterioration due to septic shock [12][13][14]. It was previously reported in other studies using GdCl 3 [15][16][17] that the Kupffer cell plays a key role in endotoxemia. In our previous reports, inhibition of Kupffer cells by gadolinium chloride (GdCl 3 ) almost completely prevented respiratory disturbances as well as liver injury and improved mortality in both normal [12] and hepatectomized rats after infusion of a lethal dose of endotoxin [18] by inhibition of expression of tumor necrosis factor-alpha (TNF-␣) and interleukin-6 (IL-6) in the liver [19].…”