Diagnosis and Treatment of Endotoxemia

ENDOTOXEMIA

Endotoxemia occurs when gram negative bacteria or their toxins gain access to the systemic circulation. Endotoxin is a structural component of the outer cell membrane of gram negative enteric bacteria. It is composed of three parts, each of which has important biologic characteristics. The inner most portion is termed the lipid A, which is unique because it is well conserved among different species of gram negative bacteria and it imparts the toxic qualities to the endotoxin molecule. The middle region of endotoxin is the core oligosaccharide which links the lipid A with the outer polysaccharide portion. The core region is well conserved in gram negative bacteria. The outermost portion is comprised of repeating polysaccharides, which is quite diverse and accounts for the serologic differentiation among bacterial species.

Because endotoxin is an integral component of the outer cell wall of gram negative bacteria it is liberated when the bacterium dies or undergoes periods of rapid proliferation. The gastrointestinal tract lumen harbors large quantities of gram negative bacteria and free endotoxin. To prevent the development of endotoxemia, the horse has evolved several efficient mechanisms to restrict transmural movement of endotoxin across the bowel wall and to remove endotoxin from the portal blood. The mucosal epithelial cells of the intestine function as a physical barrier against transmural movement. These mucosal epithelial cells also secrete substances such as lysozyme, enzymes, and antibodies which limit the ability of enteric bacteria to invade the mucosal lining. If a small quantity of endotoxin traverses the intestinal mucosal barrier and gains access into the portal circulation, Kupffer cells (hepatic macrophages) become effective scavengers of endotoxin. Additionally, many horses have small quantities of circulating anti-endotoxin antibodies directed against the core region which can bind endotoxin and permit its removal from the circulation.

If the integrity of the intestinal mucosal barrier is disrupted, the quantity of endotoxin traversing the barrier may exceed the ability of these protective mechanisms from removing endotoxin from the circulation. Additionally, endotoxin can also traverse full-thickness bowel, enter the peritoneal cavity, and reach the systemic circulation via the thoracic duct. Once endotoxin gains access to the systemic circulation, it may associate with high density lipoproteins or lipopolysaccharide-binding protein, which has a strong avidity for the lipid A region of endotoxin. This protein seems to play a crucial role in the binding of endotoxin to specific sites on the surface of mononuclear phagocytes and other cells. The endotoxin- lipopolysaccharide-binding protein complex recognizes the CD14 which is present as a surface antigen on inflammatory cells and present as a soluble for allowing for cells without the surface antigen to enhance their response to LPS. Since CD14 lacks a transmembrane and cytoplasmic domain has no intrinsic signaling capabilities; therefore, the CD14-LBP-LPS complex must interact with another receptor which is known to be toll-like receptor 4/MD-2 complex. Binding to the TLR4/MD-2 complex activates a signal transduction cascade that leads to the production of the transcription factors such as NF-•B. This results in inflammatory gene expression and subsequent synthesis of inflammatory mediators which result in the characteristic clinical signs and clinicopathologic findings characteristic of endotoxemia.

Approximately 25% of horses admitted to university teaching hospitals for acute gastrointestinal tract disease have detectable endotoxin in the plasma. Because the half-life of circulating endotoxin in plasma is less than 2 minutes, these results suggest that there is constant movement of endotoxin from the intestinal lumen into the circulation. Most horses with gastrointestinal tract disease with endotoxemia have an ischemic or inflammatory bowel disease. Therefore, the prevalence of endotoxemia is greatest for horses with intestinal strangulation obstruction (small intestinal or large colon volvulus, incarceration, etc), enteritis (colitis, proximal enteritis), and septic peritonitis.

The interaction of gram negative endotoxin and the horse’s inflammatory cells results in the synthesis and release of numerous inflammatory mediators, including tumor necrosis factor, interleukin-1 and -6, thromboxane A2, prostaglandin I2, platelet activating factor, and procoagulant activity. Entrance of endotoxin into the systemic circulation results in a complex pathophysiologic cascade of events that frequently leads to morbidity and mortality despite aggressive treatment. [...]