The Immunopathology of Sepsis: Pathogen Recognition, Systemic Inflammation, the Compensatory Anti‐Inflammatory Response, and Regulatory T Cells

Abstract

Sepsis, the systemic inflammatory response to infection, represents the major cause of death in critically ill veterinary patients. Whereas important advances in our understanding of the pathophysiology of this syndrome have been made, much remains to be elucidated. There is general agreement on the key interaction between pathogen‐associated molecular patterns and cells of the innate immune system, and the amplification of the host response generated by pro‐inflammatory cytokines. More recently, the concept of immunoparalysis in sepsis has also been advanced, together with an increasing recognition of the interplay between regulatory T cells and the innate immune response. However, the heterogeneous nature of this syndrome and the difficulty of modeling it in vitro or in vivo has both frustrated the advancement of new therapies and emphasized the continuing importance of patient‐based clinical research in this area of human and veterinary medicine.

Clinical utility of currently available biomarkers in inflammatory enteropathies of dogs

“…C‐reactive protein is a positive type II acute phase protein expressed in the liver69 in response to infection, inflammation, or cancer,70 and the serum CRP concentration is a nonspecific marker of inflammation 71, 72, 73, 74, 75, 76, 77, 78, 79, 80. Quantification of canine CRP in serum can be done using several assay formats,81, 82, 83, 84, 85, 86, 87, 88 all of which have a reference interval of approximately 0–8 mg/L.…”

Clinical, haematological, cytokine and acute phase protein changes during experimental Babesia gibsoni infection of beagle puppies

“…However, these increases were delayed by more than two weeks following infection and did not develop until after a peripheral parasitaemia was detected. Cytokines are fundamentally involved in the pathophysiology of the systemic inflammatory response to infection (Borghetti et al, 2009;Lewis et al, 2012). The interval between experimental B. gibsoni infection and the cytokine alterations detected in this study indicates that the systemic inflammatory response induced by experimental B. gibsoni infection, like the acute phase response, may be delayed by more than two weeks following infection.…”

“…Cytokines play a critical role in the initiation and M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 5 development of systemic inflammation and are responsible for mediating and regulating all aspects of the immune response to infection (Borghetti et al, 2009;Lewis et al, 2012).…”

“…However, while important for host defence, excessive production and release of these immunoregulatory mediators can prove deleterious to the host, initiating widespread tissue injury and organ damage (Borghetti et al, 2009;Lewis et al, 2012). Longitudinal kinetic profiling of a broad range of cytokine alterations that occur during an infection can be useful to expand our understanding of the immunopathogenesis of infectious diseases and hostadaptive humoral and cell-mediated immune responses to infection, as well as potentially allowing the identification of future diagnostic markers and therapeutic interventions.…”

Looped Host Defense Peptide CLP-19 Binds to Microtubules and Inhibits Surface Expression of TLR4 on Mouse Macrophages

“…The combined LPS/LBP interacts with CD4 and TLR4/MD-2 at the cell membrane surface, which leads to activation of the MyD88-dependent and -independent signaling pathways (29,30). Therefore, abundant exposure to LPS may induce an exaggerated stimulation of these immunerelated signaling pathways and upregulate expression and release of inflammatory cytokines; such an unmitigated inflammation process is the hallmark of severe sepsis and underlies sepsisrelated death (31,32). Recent therapeutic approaches for treating sepsis have included targeted inhibition of TNF-a and other inflammatory mediators (33); however, these approaches have not yet produced a significant increase in the survival rate of sepsis patients (34).…”