Acute pancreatitis is an inflammatory condition. It is associated with a
systemic inflammatory response, the degree of which appears to correlate with the
severity of the illness. The role of circulating leucocytes and their production of
cytokines in the development of severe acute pancreatitis is unknown. Monocytes
are believed to be a major source of pro-inflammatory cytokines, but lymphocytes
and endothelial cells also produce such cytokines. These cell types, in particular
lymphocytes, also produce a variety of down-regulatory signals so that monocytes,
lymphocytes and endothelial cells interact to produce a net systemic inflammatory
signal, influenced further by the varying degree of lymphocyte sub-populations to
undergo blastogenesis in response to inflammation. The focus of this thesis is on
pro-inflammatory cytokines and their release in vitro from peripheral blood
mononuclear cells (PBMCs) isolated from patients with acute pancreatitis.On admission to hospital, patients with acute pancreatitis demonstrated
increased interleukin-6 and interleukin-8 release but not tumour necrosis factor-a
release from isolated PBMCs compared with healthy volunteers. The severity of the
disease was not related to the level of cytokine release from a standard cell number.
However, when allowance was made for the variation in PBMC numbers in the
blood, the estimated IL-6 and IL-8 release per unit of blood was greater in those
patients with severe disease compared with those with mild disease. Severe disease
is also characterised by a more prolonged duration of increased pro-inflammatory
cytokine release compared with patients with mild disease. Products of the cyclooxygenase
pathway play a down-regulatory role in PBMCs in patients with acute
pancreatitis as indomethacin (a cyclo-oxygenase inhibitor) had no significant effect on pro-inflammatory cytokine release by PBMCs isolated from healthy volunteers,
but increased IL-6 and IL-8 release by PBMCs isolated from patients with both mild
and severe disease. PBMC pro-inflammatory cytokine release remains sensitive to
the down-regulatory action of the T-cell regulatory cytokines, interleukin-4 and
interleukin-10. Lymphocyte proliferation (as measured by thymidine incorporation)
is impaired in acute pancreatitis and correlates with the severity of the disease.
Following the successful isolation and culture of human umbilical vein endothelial
cells, IL-4 and IL-10 (in contrast to their inhibitory action on PBMCs), produce a
dose dependent increase in endothelial cell IL-6 and IL-8 release. TNFa is often
undetectable in patients with acute pancreatitis on admission, even in severe disease.
However, elevation in the serum concentration of soluble TNFa receptors would
suggest significant TNFa-induced inflammation early in the course of the disease.
Glutamine is a conditionally essential amino acid in patients with severe acute
pancreatitis and is important for immune function. A double blind, randomised
controlled trial of glutamine supplemented versus conventional total parenteral
nutrition in patients with severe acute pancreatitis demonstrated a trend towards
improved lymphocyte proliferation in the glutamine supplemented group.
Furthermore, PBMC IL-8 release but not TNFa and IL-6 release was significantly
reduced over the study period.Severe acute pancreatitis is associated with prolonged PBMC pro¬
inflammatory cytokine release and impaired lymphocyte proliferation. However,
these cells remain sensitive to the down-regulatory action of T-cell cytokines in
vitro, but the exogenous administration of these cytokines may have an
unpredictable clinical effect because of their different actions on various cell types.
More general methods of immuno-modulation, such as the exogenous
administration of glutamine may have therapeutic benefit in patients with severe
acute pancreatitis