Organ Failure due to Systemic Injury in Acute Pancreatitis



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Lipid mediators:
Platelet activating factor (PAF):
Apart from trypsin, PAF has been extensively targeted in pancreatitis. PAF is a phospholipid 
(acetyl-glyceryl-ether-phosphorylcholine) produced by myeloid cells, platelets and 
endothelial cells. Intra-arterial delivery of PAFs into the pancreas causes AP
142
. PAF 
production in inflammation is mediated by phospholipase A2, and it is degraded by PAF 
acetylhydrolase 
143
. Its receptor is a G-protein receptor
144
. PAF has a broad range of effects 
including increasing vascular permeability, worsening inflammation and initiating cell 
death
145
. Its levels are increased in severe biliary pancreatitis
146
in which it was thought to 
mediate shock and acute lung injury
147
, and the protective effect of antagonizing it was 
shown in multiple models including biliary, choline deficient ethionine supplemented diet 
(CDE diet)
148
, caerulein model in rats, and severe biliary pancreatitis in opossums
51
. While 
initial clinical trials using lexipafant, a PAF antagonist were promising
149
, the large 
definitive clinical trial did not show benefit in OF or mortality, even though local 
complications and sepsis were reduced
150
. Whether this was due to a limitation of targeting 
PAF or the high prevalence of early OF remains to be studied (please see below).
Unsaturated fatty acids (UFAs):
The pancreas by its location is proximal to visceral fat in humans. Several studies report an 
increased risk of severe pancreatitis to be associated with an increase in visceral fat 
151-154 
which ranges from 1-10% of body weight 
155
. This fat is composed of adipocytes, the mass 
of which is predominantly (>80%) triglyceride
156-158
. This triglyceride is predominantly 
composed of UFAs
159, 160
, covalently linked to a glycerol backbone, which when released 
by unregulated lipolysis affect severity of AP. Interestingly, adipocyte triglyceride has 
become enriched in UFAs like linoleic acid over the last few decades
161
, which mirrors the 
15-25% linoleic acid composition of necrosectomy samples from severe AP patients
47, 53

Previous studies have shown pancreatic lipases to be present in the adipocytes, damaged 
during AP
162
. This results in a morphology known as fat necrosis, which can worsen 
pancreatic parenchymal necrosis
49, 53
, but can also occur independently 
163, 164
. This 
lipolytic fatty acid generation can increase systemic injury during pancreatitis, in parallel 
with an increase in serum UFAs such as linoleic and arachidonic acid
165, 166
, which like 
visceral fat
15947, 48, 53, 160
are unsaturated. These UFAs when liberated in excess, inhibit 
mitochondrial complexes I and V
53
, and increase apoptotic cells in the lungs
17, 48, 49, 53 
(similar to patients with acute respiratory distress syndrome
54, 167, 168
), elevate serum 
BUN
47, 49, 53, 169
due to renal tubular injury , and result in mortality. Interestingly, elevated 
serum levels of TNF-
α, IL-1β, MCP-1 and IL-18 can all be induced during this fatty acid 
toxicity, perhaps due to the widespread release of DAMPs. Importantly, inhibition of this 
excessive lipolysis can result in prevention of systemic injury, hypercytokinemia and 
mortality
47-49, 53
. While it remains to be seen if lipase inhibition will reduce systemic injury 
during human AP, it is encouraging to note that the cyclooxygenase inhibitor indomethacin
which is known to affect the metabolism of UFA products, may reduce progression of 
moderate-severe AP.
170
.
Garg and Singh
Page 10
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
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