Endotoxin Alters Serum-Free Choline and Phospholipid-Bound Choline Concentrations, and Choline Administration Attenuates Endotoxin-Induced Organ Injury in Dogs

Abstract

This study in dogs was performed to assess circulating choline status during endotoxemia and to determine whether choline administration can protect dogs from endotoxin-induced tissue injuries. Baseline serum-free and phospholipid-bound choline concentrations were 19.2 +/- 0.6 micromol/L and 3700 +/- 70 micromol/L, respectively. After intravenous endotoxin infusion, serum-free choline concentrations decreased by 14% to 49% (P < 0.05-0.001) at 2 to 6 h after 0.02 mg/kg endotoxin, and increased by 23% to 98% (P < 0.05-0.001) at 1 to 48 h after 1 mg/kg endotoxin. Serum phospholipid-bound choline concentrations increased by 19% to 27% (P < 0.05) at 12 to 24 h or by 18% to 53% (P < 0.05-0.001) at 1 to 48 h after 0.02 or 1 mg/kg endotoxin, respectively. The changes in serum-free and -bound choline levels in response to endotoxin were accompanied by dose- and time-related elevations in serum cortisol and biochemical markers for tissue injury and/or organ dysfunction. Intravenous administration of choline (20 mg/kg) 5 min before, and 4 and 8 h after endotoxin (1 mg/kg) attenuated endotoxin-induced elevations in serum alanine aminotransferase (P < 0.05-0.001), aspartate aminotransferase (P < 0.05-0.001), gamma-glutamyl transferase (P < 0.05-0.001), alkaline phosphatase (P < 0.05-0.001), lactate dehydrogenase (P < 0.05-0.001), myocardial creatine kinase (P < 0.001), urea (P < 0.05-0.01), creatinine (P < 0.05), uric acid (P < 0.01-0.001), and tissue necrosis factor-alpha (P < 0.001). Choline also attenuated alanine aminotransferase (P < 0.05-0.01), alkaline phosphatase (P < 0.05-0.01), lactate dehydrogenase (P < 0.05-0.01), creatine kinase (P < 0.05-0.001), myocardial creatine kinase (P < 0.05-0.001), and uric acid (P < 0.05-0.01), but failed to alter the serum urea, creatinine, aspartate aminotransferase, and gamma-glutamyl transferase responses to 0.02 mg/kg endotoxin. These data show that choline status is altered during endotoxemia and that choline administration diminishes endotoxin-induced tissue injury.

Cytidine 5′-diphosphocholine ameliorates hyperoxic lung injury in a neonatal rat model

“…Choline may have anti-inflammatory effects by activating α-7 nicotinic ACh receptors (18). In agreement, choline administration was shown to reduce the elevation of circulating TNF-α levels and attenuate endotoxin-induced multiple organ injury (19), whereas choline deficiency results in increased levels of proinflammatory cytokines such as TNF-α (20). Because exogenously administered CDP-choline is a source of choline (16), our observation that CDP-choline reduces tissue levels of proinflammatory cytokines might have resulted from the anti-inflammatory action of choline (through stimulation of α-7 nicotinic ACh receptors) that derived from CDP-choline metabolism.…”

Modulation of TNF Release by Choline Requires α7 Subunit Nicotinic Acetylcholine Receptor-Mediated Signaling

“…In contrast, choline (20 mg/kg, intravenous [i.v.]) administration suppresses TNF release and attenuates inflammation during endotoxemia in dogs (19,20). Moreover, choline (60 mg/kg, i.v.)…”

“…Choline also has other important physiological functions; this essential nutrient is a major donor of methyl groups, a cell membrane constituent, and a precursor in the biosynthesis of the neurotransmitter acetylcholine (15)(16)(17). Although previous studies have shown protective effects of choline against endotoxin-induced shock and organ damage (18)(19)(20), the mechanism of the anti-inflammatory action of…”

Pathophysiologic and Immunologic Changes in a Canine Endotoxemia over a Period of 24 Hours

“…Generally, bolus injection of LPS has been used to induce endotoxemia in dogs [2,16], but it has been problematic in that it does not simulate the conditions of clinical sepsis [8]. Thus, Sakaue et al established a canine endotoxemia model using a CRI-LL for an 8-hr of experimental period [25,26].…”