Sepsis
Sepsis following trauma or major surgery results in prolonged
and expensive intensive care unit hospitalization and remains
a major cause of mortality. It is estimated that approximately
500,000 patients develop sepsis, or which 175,000 die. Surgical
sepsis is most often caused by bacterial infection, and even more
specifically by Gram-negative bacterial infections, though Gram-positive
bacterial sepsis is also a serious clinical problem with distinct
features. The host recognizes the presence of bacterial infections
through multiple mechanisms, involving both elements of the adaptive
immune response (e.g. antibodies and complement; T-cell responses
to bacterial superantigens) as well as elements of the innate
immune response. The innate immune response has evolved to recognized
so-called "molecular patterns" on microbes, rather than
the antigenically distinct structural distinct structural elements
recognized by antibodies or by T-cell receptors in the context
of major histocompatibility molecules. On Gram-negative bacteria,
the main stimulant of the innate immune response is endotoxin
(lipopolysaccharide: LPS), whereas mammalian hosts recognize a
diverse group of Gram-positive bacterial macromolecules including
lipoarabinomannan (LAM), peptodoglycan (PGN), lapidated outer
surface protein of Borrelia burgdorferi (OspA), and lipoteichoic
acid (LTA). Other bacterial "molecular patterns" include
N-formyl methionylated peptides and CpG DNA. This bacterial recognition
system relies on cell surface receptors that are highly conserved
throughout evolution, members of the Toll-like receptor (TLR)
family. This extremely sensitive system appears designed to detect
elevated levels of local or circulating microbial products and
rapidly initiate an antimicrobial response. Upon detection of
microbial products by the CD14/TLR system, the host elaborates
numerous pro-inflammatory cytokines leading to the upregulation
of adhesion molecules, the accumulation of leukocytes, and the
production of powerful effector mechanisms, including the free
radicals superoxide and nitric oxide (NO).
