Sepsis and the Immune System
Sepsis, also known as septicemia, is defined as a dysregulated host
systemic inflammatory response to infection (Sheats 2019). In neonatal
foals, the most common causes of septicemia are Gram negative organisms
such as Escherichia coli (E.coli), Klebsiella pneumoniae,
Pseudomonas aeruginosa, Salmonella species, Enterobacterspecies, and Actinobacillus species, or Gram-positive organisms
such as Streptococcus species, Enterococcus species, orStaphylococcus species (Frederick et al 2009; Taylor 2015).
Limited studies are available evaluating sepsis in post-neonatal foals.
When a horse is infected, key protective mechanisms include a physical
barrier composed of epithelial cells, normal gastrointestinal flora,
gastrointestinal mucus, phagocytic cells, and molecular defenses. These
molecular defenses are soluble molecules such as cytokines, chemokines,
and immunoglobulins which also may exist on cell surfaces such as
antigen receptors (Barton 2006). The gastrointestinal tract has
additional protection due to Mucosal Associated Lymphoid Tissues (MALT).
The MALT are present close to epithelial surfaces for more rapid
response. Microfold cells rapidly phagocytose and antigen present
foreign organisms to B cells, leading to their more rapid
differentiation. When the gastrointestinal mucosal barrier is breached
pro-inflammatory chemokines, such as tumor necrosis factor 𝝰, are
produced. These chemokines attract neutrophils, monocytes, and mast
cells. Neutrophils that have been activated after extravasation from the
bloodstream release an oxidative burst of molecules that stimulate
bacterial killing and attract more inflammatory mediators (Mealey and
Long 2018). Mast cells increase vascular permeability, cause
vasodilation, enhance epithelial secretion, and are phagocytic.
Monocytes play a cell role as antigen presenting cells to cellular
receptors (Figueiredo et al 2009).
If the inflammatory response is uncontrolled it can lead to Severe
Inflammatory
Response Syndrome (SIRS) and there is a risk of multiple organ failure
due to the accumulation of neutrophils in organs causing secondary
injury (Sheats 2019). As such, one of the main goals in the treatment of
sepsis is the control of the inflammatory response (Werners 2016). The
normal inflammatory response, as described above, has vasoactive and
phagocytic components, mediated by inflammatory mediators. If these
responses become uncontrolled, the activation of the inflammatory
pathway exceeds the host’s ability to regulate and contain that
inflammation. Normal neutrophil response is to migrate to a site of
infection/inflammation, then release inflammatory mediators and ROS. In
sepsis, neutrophils lose their molecular compass and as such may attack
host cells, have delayed apoptosis, and accumulate in organs (Sheats
2019). This leads to inappropriate activation of the innate immune
system through pathogen associated molecular patterns or damage
associated molecular patterns as well as activation of the complement
and coagulation cascades. These released molecules also damage
endothelial cells, leading to vasodilation and an increase in capillary
permeability, causing fluid leakage (edema) and poor maintenance of
intravascular pressure. The cytokines and other molecules released by
the neutrophils change vascular perfusion due to endothelial cell
damage, activation of protease cascades, and disrupt the coagulation
system equilibrium (Wong and Wilkins 2015). The ROS become cytotoxic to
host cells if uncontrolled (Mealey and Long 2018). Neuroendocrine
responses stimulate central nervous system activity which in turn
affects the function of organs distant to the site of inflammation as
well as releasing neurotransmitters (Wong and Wilkins 2015). The number
of organs affected have been correlated with the odds of six-month
survival; with animals having three or more organs affected having a
poorer survival rate (Sheats 2019). In horses the most common organs
affected are the lungs, heart, kidney, and laminae of the hoof.