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.