Biology Reference
In-Depth Information
also can be released by cells at sites remote from the infection.
Inactivated monocyte cells are known to continuously secrete low levels
of TNFα, and LPS stimulation leads to increased levels within minutes.
Circulating TNFα levels peak at 1.5 h when the host is challenged with
LPS and usually return to normal within 4 h of response (Taveira da
Silva
et al.
, 1993). Direct administration of recombinant TNFα to
animals has led to symptoms similar to those seen in human septic shock
(Maury and Teppo, 1987, Muto
et al.
, 1988).
Use of TNFα antibodies
prevented the same reaction when mice and primates were exposed to
otherwise lethal levels of LPS (Beutler
et al.
, 1985, Tracey
et al.
, 1987).
Interestingly, the levels of other cytokines such as IL-1β and IL-6, which
are normally associated with sepsis, also were attenuated, an observation
that suggests an early role for TNFα in the development of septic shock
progression (Fong
et al.
, 1989). In addition to the release of cytokines,
activated macrophages also increase their own intracellular stores of
antimicrobial agents such as lysozyme, cationic proteins, acid
hydrolases, lactoferrin, and oxygen free radical precursors.
Following LPS exposure, several other cytokines have been detected
in circulation: interleukin-2, interleukin-8, interleukin-11, interleukin-12,
interleukin-15, interleukin-18, interferon-γ (INF-γ), leukemia inhibitory
factor, ciliary neurotrophic factor, and colony-stimulating factor (CSF),
among others (Cavaillon, 2003). Furthermore, activation of the
complement system occurs (release of anaphylatoxins C3a and C5a) and
the discharge of other inflammatory mediators, including phospholipase
A2, cyclooxygenase (COX), adhesion molecules (selectins E, P, and L),
platelet-activating factor (PAF) follows. Release of coagulants such as
thrombin, coagulation factors (IXa, Xa, XIa, and XIIa), and tissue factor,
also occurs (Sharma and Dellinger, 2003, Demchenko
et al.
, 2003).
These inflammatory and adhesion molecules recruit phagocytic
polymorphonuclear (PMN) leukocytes and other mononuclear
phagocytes. Activated phagocytes then take up and destroy both LPS and
whole bacteria via their lysosomal antimicrobial mediators. In addition,
active B and T lymphocytes are also attracted to the site of infection and
in turn release mediators such as IL-2, INF-γ, and granulocyte-
macrophage (GM)-CSF (Akagawa and Tokunaga, 1985, Bone, 1991,
Heinzel
et al.
, 1994, Jaeschke, 1996, Yong and Linch, 1993). These
