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2015 ; 43
(7
): 1375-85
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Monocyte Tumor Necrosis Factor-?-Converting Enzyme Catalytic Activity and
Substrate Shedding in Sepsis and Noninfectious Systemic Inflammation
#MMPMID25867908
O'Callaghan DJ
; O'Dea KP
; Scott AJ
; Takata M
; Gordon AC
Crit Care Med
2015[Jul]; 43
(7
): 1375-85
PMID25867908
show ga
OBJECTIVES: To determine the effect of severe sepsis on monocyte tumor necrosis
factor-?-converting enzyme baseline and inducible activity profiles. DESIGN:
Observational clinical study. SETTING: Mixed surgical/medical teaching hospital
ICU. PATIENTS: Sixteen patients with severe sepsis, 15 healthy volunteers, and
eight critically ill patients with noninfectious systemic inflammatory response
syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Monocyte expression
of human leukocyte antigen-D-related peptide, sol-tumor necrosis factor
production, tumor necrosis factor-?-converting enzyme expression and catalytic
activity, tumor necrosis factor receptor 1 and 2 expression, and shedding at
48-hour intervals from day 0 to day 4, as well as p38-mitogen activated protein
kinase expression. Compared with healthy volunteers, both sepsis and systemic
inflammatory response syndrome patients' monocytes expressed reduced levels of
human leukocyte antigen-D-related peptide and released less sol-tumor necrosis
factor on in vitro lipopolysaccharide stimulation, consistent with the term
monocyte deactivation. However, patients with sepsis had substantially elevated
levels of basal tumor necrosis factor-?-converting enzyme activity that were
refractory to lipopolysaccharide stimulation and this was accompanied by similar
changes in p38-mitogen activated protein kinase signaling. In patients with
systemic inflammatory response syndrome, monocyte basal tumor necrosis
factor-?-converting enzyme, and its induction by lipopolysaccharide, appeared
similar to healthy controls. Changes in basal tumor necrosis factor-?-converting
enzyme activity at day 0 for sepsis patients correlated with Acute Physiology and
Chronic Health Evaluation II score and the attenuated tumor necrosis
factor-?-converting enzyme response to lipopolysaccharide was associated with
increased mortality. Similar changes in monocyte tumor necrosis
factor-?-converting enzyme activity could be induced in healthy volunteer
monocytes using an in vitro two-hit inflammation model. Patients with sepsis also
displayed reduced shedding of monocyte tumor necrosis factor receptors upon
stimulation with lipopolysaccharide. CONCLUSIONS: Monocyte tumor necrosis
factor-?-converting enzyme catalytic activity appeared altered by sepsis and may
result in reduced shedding of tumor necrosis factor receptors. Changes seemed
specific to sepsis and correlated with illness severity. A better understanding
of how tumor necrosis factor-?-converting enzyme function is altered during
sepsis will enhance our understanding of sepsis pathophysiology, which will help
in the assessment of patient inflammatory status and ultimately may provide new
strategies to treat sepsis.