ONE HEALTH ASPECTS OF ENDOTOXEMIA
Michelle Henry Barton DVM, PhD, DACVIM
Department of Large Animal Medicine, College of Veterinary Medicine,
University of Georgia, Athens, GA
INTRODUCTION
Richard Pfeifer first characterized endotoxin in the 1890s as a toxin that was an integral part of gramnegative bacteria that was distinctly different from actively secreted heat labile exotoxins .1 Endotoxin comprises
approximately 75% of the outer cell membrane of gram-negative bacteria and serves as a structural permeability
barrier. Pfeifer’s original observations were correct: bacteria do not actively secrete endotoxin. Rather, when
gram-negative bacteria multiply or lyse upon bacterial cell death, endotoxin is released from the outer cell
membrane. Endotoxin consists of three structural domains: a highly variable outer polysaccharide “O-antigenic”
region, a core region consisting mostly of monosaccharides, and the highly conserved toxic moiety, lipid A.
Variation in the number, length, saturation, and position of fatty acids on the glucosamine disaccharide backbone of
lipid A confers its degree of toxicity. Endotoxin has been evolutionarily conserved as a pathogen associated
molecular pattern that is immediately recognized by the innate immune system that subsequently initiates a series of
inflammatory signals that serve to warn of and control the bacterial invasion. However, mammalian species vary
considerably in their ability to recognize the presence of endotoxin. The main purpose of this discussion is to
review what is known about endotoxemia among species, with particular emphasis on comparative aspects between
human beings, laboratory animals used in research, and two common domestic companion-animals representing a
large animal (horse) a small animal (dog) model.
PATHOLOGY OF ENDOTOXEMIA
Endotoxin is not directly toxic to epithelial barriers rather it must translocate through the epithelium to fully
manifest its toxic effects. Once in the blood, endotoxin’s amphipathic properties cause it to form aggregates that
resemble micelles. Lipopolysaccharide binding protein (LBP), a 65 kDa plasma constituent that belongs to a family
of lipid transfer proteins, efficiently extracts molecules of endotoxin from aggregated micelles in the blood and
serves as a transporter, shuttling molecules of endotoxin to various locations .2 Once at the cell surface, endotoxin is
transferred to cluster differentiation antigen 14 (CD14), a well-conserved receptor attached by a
glycosylphosphatidylinositol anchor. Mononuclear phagocytes (monocytes and macrophages) express abundant
CD14, though other inflammatory cells also express minute amounts. CD14 is a 53 kDa glycoprotein that exists as
both a cell membrane receptor (mCD14) and as a soluble form (sCD14) in the circulation .3 CD14 does not
structurally transverse the cell membrane. Thus it must associate with a secondary protein, Toll-like receptor
(TLR4)4 that contains a transmembrane portion that is capable of communication with the intracellular domain.
Both CD14 and TLR4 are classified as bacterial recognition receptors, indicating that they are evolutionarily
conserved receptors that are a part of the innate immune system.
Once the CD14-TLR4-endotoxin complex is assembled at the cell surface, TLR4 requires the help of a 160
amino acid helper molecule, MD2, to transmit a signal to the cytosol.5 Numerous intracellular signaling pathways
have been reported to link the endotoxin-occupied cell surface receptor to a response from the cell; however, the
nuclear factor kB (NFkB) pathway is well characterized.4 Ultimately, the deleterious effects of endotoxin are the
result of overzealous endogenous synthesis of pro-inflammatory mediators triggered by this cell receptor mediated
pathway. The most widely studied of these mediators are the metabolites of arachidonic acid (the prostaglandins,
thromboxane, and the leukotrienes), platelet activating factor, cytokines (tumor necrosis factor and interleukins 1
and 6), vasoactive and chemotactic peptides (histamine, serotonin, bradykinin, complement components), tissue
factor, proteolytic enzymes, and reactive oxygen species.
MODELS OF ENDOTOXEMIA
It is well recognized that the response to endotoxin varies tremendously among mammalian species. It is
often argued that human beings and horses are more sensitive to endotoxin than rodents, common laboratory models
of endotoxemia. It is difficult to directly compare the response of endotoxin among species, as rarely are multiple
species investigated under the exact same conditions. Variation in the source of endotoxin, doses, in vitro or cell
culture systems, and species-specific methodologies to quantitate the response to endotoxin further hinder direct
comparisons. The LA50 for endotoxin in dogs and mice is reported to be 1 mg/kg and between 1 to 25 mg/kg,
respectively.6,7 High dose endotoxin infusion models are not performed in people for obvious reasons and to the
author’s knowledge, the actual LD50 of endotoxin in horses is not known. However, it is known that doses in the
µg/kg range can be lethal or near lethal in horses and people.8,9 In low dose infusion models, people and horses
demonstrate a significant response to nanograms of endotoxin per kilogram of body weight, whereas to evoke a
similar response in rodents and dogs, micrograms of endotoxin per kilogram of body weight are required. 10,11
Accounting for Species Differences in the Response to Endotoxin
There are numerous explanations for the differential response to endotoxin, many of which reside at the
cellular and molecular level. When endotoxin gains access to the circulation, differential concentrations and binding
affinities of natural ligands of endotoxin, such as LBP, sCD14, high-density lipoproteins, and antibodies to
endotoxin can influence the toxicity, transport, and final destination of endotoxin. Next, differential expression of
and subtle differences in the molecular structure of the cellular receptors for endotoxin can have profound effects on
the responsiveness to endotoxin. Gene knockout and transfection experiments have demonstrated that the type and
degree of responsiveness to endotoxin is conferred by the species of origin of the receptors. Much of this discovery
was afforded by the results of treatment trials with lipopolysaccharides. For example, Rhodobacter sphaeroides and
a synthetic derivative of its lipid A moiety (E5531) are endotoxin antagonists in humans and mice. 12 That is, R.
sphaeroides endotoxin is a nontoxic molecule that does not evoke an inflammatory response in humans and mice
and in fact, will competitively inhibit the response to native toxic enteric endotoxin. However this same molecule is
a potent agonist in hamsters and horses.12 Through a series of transfection experiments of a cell culture line with
vectors encoding CD14, TLR4, and MD2 of either human or equine origin, it was determined that both TLR4 and
MD2 must be of human origin to be recognized by R. sphaeroides lipopolysaccharide as an antagonist. Similarly,
both TLR4 and MD2 must be of equine origin to be recognized by R. sphaeroides as an agonist. Interestingly,
within this same study, comparison of the cellular response to E. coli endotoxin in the cells transfected with human
receptors versus the same cells transfected with an equivalent amount of the equine receptors showed that the equine
response was more sensitive than the human response.
In addition to the importance of species-specific recognition of different sources of endotoxin, molecular
differences in the endotoxin receptors themselves are important. For example, for decades, it was known that
C3H/HeJ mice were incapable for responding to endotoxin. Only recently was it discovered that the inability of
C3H/HeJ mice to respond to endotoxin was caused by a mutation in the gene encoding for TLR4. 4 Furthermore,
polymorphism in TLR4 is associated with differences in the degree of response to endotoxin in people and offers
explanation to the well-recognized clinical phenomenon that some individuals react violently to endotoxin, while
others have little to no response.25 Polymorphisms in CD14 and TLR4 have been described in horses; however, it is
yet to be seen if these molecular changes explain a differential response to endotoxin.13 Lastly, differences in the
intracellular signaling cascades that transfer the signal of endotoxin-receptor complex to the nucleus for
transrepression or transactivation of proinflammatory and anti-inflammatory genes may account for variable species
sensitivity to endotoxin.14
Naturally Acquired Endotoxemia: Looking Back at the Big Picture
The keystone of studying clinically important diseases is to secure a model that is most relevant to the
naturally occurring scenario. Considering that endotoxin is released during gram-negative bacterial replication, the
two most common sources of endotoxin in mammalian species are the gastrointestinal tract flora and acquired gramnegative bacterial invasion. Bacteria comprise 40% of the human fecal mass15 (which is even greater in horses) and
thus clearly the resident population of gram negative bacteria in the intestinal tract is a virtual septic tank of
endotoxin. For example, the cecum of the horse contains approximately 80 g of endotoxin per ml and thus only
one ml of cecal liquor could be lethal to a horse.16 However, this source of endotoxin is normally confined to the
lumen of the healthy intestine by protective mucosal barriers. If the intestinal wall is damaged, such as occurs in
acute gastrointestinal diseases that cause inflammation or ischemia, the otherwise contained endotoxin gains access
to the peritoneal cavity as well as the circulation. Interestingly, the natural flora, and therefore the source and
amount of endogenous endotoxin, varies among species and this fundamental difference can account for some
degree of the diverse response to endotoxin. For example, germ free animals have a dampened clinical response and
lower mortality rate in intestinal strangulation and hemorrhagic shock models than do their nongerm free cohorts. 15
Differences in the anatomy and permeability of the mucosal barrier to endotoxin also determine the degree of
translocation of both bacteria and endotoxin further contributing to diversity in the response to endotoxin.
In the scenario of gram-negative bacterial invasion, endotoxin is released into the immediate environment
as bacteria replicate. In the case of local sepsis, the endotoxin can eventually be absorbed into nearby lymphatics or
blood vessels to gain access to the general circulation. In the situation of bacteremia, the bacteria and endotoxin are
concurrently present in the circulation.
For rodents, it is difficult to know how often endotoxemia occurs naturally and if it does, what is its
epidemiology. In people, endotoxin has been detected in the plasma under many different scenarios including
patients with severe burns, liver disease, gastrointestinal disease, hemorrhagic shock, and trauma and in patients
undergoing dialysis, invasive procedures, cardiopulmonary by-pass surgery, organ transplantation and
chemotherapy.17 Endotoxin is even detectable in exhausted marathon runners.17 However, it is sepsis in both
neonates and adults that carries the greatest prevalence of endotoxemia. 17 Septic shock is the most common cause of
death in noncardiac patients in the ICU and is currently among the top ten causes of death in the United States.18 In
a 2003 report on the epidemiology of sepsis, gram negative infections predominated before 1987. 18 In infants,
septicemia occurs in approximately 20 out of very 1000 live births with E. coli reported as the most commonly
isolated pathogen in early onset sepsis.19 In one large study in human beings with sepsis, endotoxin was detected in
the circulation of 33% of the patients (mean of approximately 100 pg/ml, range 40 to 1,100 pg/ml). 20 There are only
a few studies that have investigated the incidence of endotoxemia in infants. Although it appears that the detection
rate is lower in septic infants than in adults, large endotoxin concentrations are detectable in infants with necrotizing
entercolitis.21,22
In horses, endotoxemia has been most intensively studied in the adult patient with acute gastrointestinal
disease and the neonatal foal with septicemia.23-28 In mature horses referred to tertiary care centers with any
etiology of acute gastrointestinal disease causing colic, endotoxin has been detected in the plasma of approximately
25% of the horses.23,24 In horses with surgical colic, endotoxin was detected in the plasma of 41% of referred cases
(mean of 36 pg/ml, range 7-197 pg/ml).25 In the largest published study on detection of endotoxin in horses with
acute gastrointestinal disease (n=155), endotoxin was detected in the plasma of 10% (mean 218 pg/ml) and
peritoneal fluid of 30% (mean of 509 pg/ml) of all referred cases. 26 Although endotoxemia is also implicated in
pleuropneumonia, peritonitis, and metritis in mature horses, there are no comprehensive clinical studies
documenting its occurrence in these scenarios.
Accurate data on the incidence of septicemia in foals is lacking, though it is generally agreed that
septicemia is a major cause of morbidity and mortality in the first week of life. Like human infants, gram-negative
septicemia with E. coli predominates. The incidence of endotoxemia in foals suspected to have septicemia ranges
from 28 to 50% (mean plasma concentrations of roughly 240 to 400 pg/ml). 27,28 When gram negative sepsis was
detected by blood culture in foals, up to 269,600 pg of endotoxin was concurrently detected per ml of plasma! 27
In dogs, endotoxemia is reported to occur most commonly with primary septic diseases, such as peritonitis
and pyometria, or secondary to gastrointestinal diseases that culminate in translocation of luminal endotoxin, such as
occurs in puppies with parvovirus enteritis and adult dogs with gastric dilatation and volvulus.29,30 There are only a
few clinical studies that document naturally-occurring endotoxemia in dogs. In puppies with parvovirus, the mean
concentration of endotoxin was 46 pg/ml,31 which is similar to that reported in bitches with pyometria. 32
Whether released from endogenous sources from the intestinal lumen or from overwhelming gram-negative
sepsis, the systemic features of endotoxemia are very similar in people and horses. Within an hour of intravenous
injection of low doses of endotoxin (2 to 4 ng/kg body weight), human subjects experience symptoms ranging from
chills, headache, back pain, myalgias, fever, nausea, and photophobia. Tachycardia, mild hypertension, and
leukocytosis ensue.33 Within the first hour of intravenous challenge with endotoxin (10 to 30 ng/kg), horses yawn
frequently, have mucous membrane pallor, become depressed, anorectic, tachypneic, tachycardic, and restless,
develop fasciculations and mild to moderate signs of abdominal pain, and pass loose feces. 34,35 This period is the
early hyperdynamic phase of endotoxemia that is characterized by pulmonary hypertension and ileus. Mucous
membranes are often hyperemic and capillary refill time is prolonged. By 1 to 2 hours after challenge, depression
and anorexia continue and are affiliated with the onset of fever and hypotension. With reduced tissue perfusion, the
classic “toxic line” develops as a red to blue-purple line at the periphery of the gums. If hypotension advances,
mucous membranes become diffusely congested, progressing to cyanosis and then a grayish-purple pallor. One
notable difference between people and horses/dogs is the hemogram changes that occur during endotoxemia. In
people, lymphopenia and neutrophilia are reported with low dose infusion of endotoxin,33 whereas in horses (both
neonates and adults) and dogs, profound neutropenia with toxic neutrophil morphology is a cardinal sign of
endotoxemia and/or acute overwhelming bacterial infection.34
With the similarities in the systemic features of sepsis and endotoxemia, it should not be surprising that
documentation of pro-inflammatory mediator release in human patients and horses is abundant and, in general,
similar profiles are described in both experimental infusion models and naturally-occurring endotoxemia.10,33,34 The
cytokines tumor necrosis factor (TNF) and interleukin 6 (IL6) have probably received the most attention as early and
late markers, respectively, of endotoxemia, Specifically, in horses, TNF and IL6 were detected in the serum of 10%
and 67% of equine patients with acute surgical abdomens.25 TNF and IL6 in serum or peritoneal fluid are greater in
horses with strangulating or inflammatory lesions and are significantly correlated with the concurrent detection of
endotoxin and a poor prognosis for survival to discharge. 25,26 In foals with presumed septicemia, endotoxemia
correlated with a positive sepsis score, a positive blood culture, increased cytokine concentrations, and poor
outcome.27,28 Likewise, cytokine profiles in dogs and rodents experimentally infused with endotoxin is similar to that
reported for people and horses36 and in endotoxemic dogs with parvovirus, TNF levels correlated with mortalitiy.29
Recent work comparing the cytokine gene profiles between people and mice demonstrated very poor correlation,
again questioning the use of the mouse as a human model.37 Although it generally takes a much larger dose of
endotoxin to elicit similar cytokine profiles in rodents, their role in understanding the pathophysiology of
endotoxemia cannot be undermined for it was mice and rat models that first led to the discovery of TNF and the role
of eicosanoids in endotoxemia.10
Advanced Sepsis and Endotoxemia
When the systemic pro-inflammatory response to infection or endotoxemia is uncontrolled and malignant,
the clinical state of Systemic Inflammatory Response Syndrome (SIRS) ensues. Based on a consensus statement
issued by the American College of Chest Physicians and Society of Critical Care Medicine, a patient should be
considered to have SIRS if at least two of the following signs are present: fever/hypothermia, tachycardia, tachypnea
and/or altered white blood cell count.38 Though specific criteria for SIRS have not been developed for equine or
canine patients, the syndrome of SIRS is applicable. And in fact, the sepsis scoring system proposed in the 1980's
for foals contains several of the human SIRS criteria.39 However, SIRS criteria have been proposed for horses and
dogs and are patterned after the human criteria, taking into account species differences on variation from normal
(see Table 1 below).
As endothelial damage, the release of vasoactive and unregulated inflammatory mediators, and
microthrombi formation progress, Multiple Organ Dysfunction Syndrome (MODS) develops.38 In people, the
syndrome is defined by criteria for identification of individual organ dysfunction with the respiratory, renal,
hemostatic, cardiovascular, gastrointestinal, hepatic, nervous, musculoskeletal, and adrenal systems most commonly
affected and has been reviewed early in this series.40 Multiple organ dysfunction is a syndrome that is definition
dependent and unfortunately, a consensus of definition has not yet been accepted for horses or dogs, though there
have been some proposed criteria suggested for the dog (see Table 2 below).41 In general terms, many of the
diagnostic criteria that have been proposed in people could also be applied to the horse, with some exceptions. For
example, bilirubin concentration, the criteria used for liver dysfunction in people, may not be specific in the horse
owing to physiologic hyperbilirubinemia that occurs with anurexia. One body system affected by endotoxemia and
sepsis that has been extensively studied in horses with SIRS is coagulation. In mature horses with colic, an
abnormally prolonged prothrombin time (PT) was reported in 25-80% of all colic cases at admission and 58% of
cases diagnosed with disseminated intravascular coagulopathy (DIC). 42 Similarly, prolonged activated partial
thromboplastin time (APTT) was reported in 43-100% of all colic admissions, and 60% of horses with colic in
DIC.42 Both PT and APTT were prolonged in septic foals and both were correlated with detection of endotoxin in
the blood.28 Thus PT or APTT may be better criterion for coagulopathy in horses than a citrated platelet count.
Finally, laminitis is a recognized manifestation of endotoxemia and systemic illness in the horse and thus could be
proposed as a unique musculoskeletal manifestation of MODS in this species.
Concluding Remarks
Collectively considering species-specific pathophysiologic responses, it would appear that the horse more
closely approximates the human clinical response to endotoxin, than does the mouse or dog. Advantages of the
horse as a model of endotoxemia and sepsis are that horses and foals have a high rate of naturally-acquired disease
that allows study of endotoxemia in a clinical setting and their size allows collection of large amounts of blood and
body cavity fluids or tissue samples in either a clinical or experimental setting. The largest disadvantage is the cost
of maintenance of horses with the per diem approaching 30 times that of a mouse in an exclusive research setting.
The ability to use horses in teaching herds at veterinary colleges for nonlethal, ex vivo, and in vitro studies
significantly offsets the per diem, making them an attractive animal model for the study of endotoxemia.
Table 1. Systemic Inflammatory Response Syndrome Criteria in Humans and Proposed Criteria for Horses
and Dogs.
HUMAN38
HORSE43
DOG44
Temperature
< 96.8F or > 100.4F
(98.6F)*
<98 or >101.5
(99-100.9)*
< 99 or > 103
(100-102.5)*
Heart Rate
> 90 bpm
(60 to 100)
> 50
(24-48)
>150
(60-140)
Respiratory
Rate
>20 or PaCO2 < 32
(12 to 18)
> 25
(8-20)
>40
(18-24)
WBC
< 4,000 or > 12,000/µL or
> 10% bands
(4,500 to 10,000)
< 5,000 or > 14,500/µL or
> 10% bands
(4,500-12,000)
< 5,000 or >19,000/µL
(5,000-14,000)
*numbers in parentheses represent normal reference range.
Table 2. Proposed Canine Criteria for Multiple Organ Dysfunction41
Organ
System
Criteria
Respiratory
Renal
SpO2 < 95%
Need for supplemental O2
A-a O2 gradient > 10 mmHg*
Serum creatinine > 0.5 mg/dl
Hepatic
Bilirubin > 0.5 mg/dl
Cardiovascular
If pressors needed
Hematologic
PT or APTT > 25% above upper range or platelet
count < 100,000/µL
None proposed
Neurologic
*on room air, A-a gradient = [150-5/4(PaCO2)] – PaO2
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