Organ Failure due to Systemic Injury in Acute Pancreatitis

Neutrophil extracellular traps (NETs):
NETs are web like structures containing neutrophil granule proteins (e.g. myeloperoxidase, 
elastase) and chromatin. These are released by neutrophils and are increased in the sera of 
patients with severe pancreatitis
93
. In addition, they occlude pancreatic ducts in human AP 
and may perpetuate pancreatitis
94
. NET formation in pancreatitis is catalyzed by the enzyme 
Protein Arginine Deiminase 4 (PAD4)
95
, which causes histone modification of arginine 
residues to citrulline
96
. This modification weakens DNA- histone interactions and allows the 
neutrophils to expel the de-condensed chromatin. PAD4 inhibition reduces NET formation 
in humans
97
and rodents. Whether inhibition of NET formation will prove to be beneficial in 
reducing systemic injury in pancreatitis remains to be seen, more so since recent studies also 
show NET formation to wall off pancreatic necrosis from viable tissue in humans, and thus 
may play a role as a protective barrier to the progression of pancreatitis
98
.
Damage associated Molecular patterns (DAMPs):
DAMPs, which are released from dying cells during necrosis correlate with human AP 
severity 
99-102
, and are potential mediators of severity based on animal studies
103104
DAMPs 
include small molecules such ATP, proteins- including S100 proteins, the soluble receptor 
for advanced glycation end products (sRAGE), and high-mobility group box 1 (HMGB1), 
nuclear components (e.g. histones, DNA, nucleosomes), and molecules released from the 
extracellular matrix such as hyaluronic acid. Serum HMGB1 significantly correlated with 
AP severity in humans in a meta-analysis
105
. DAMPs can worsen inflammation by causing 
activation of the inflammasome
103, 106
, as shown for sRAGE and HMGB1, and also directly 
via inducing a sterile inflammatory response
107
by disrupting the plasmalemma
108
, and 
further increasing DAMP release (e.g. HMGB1
104
). However, it remains to be confirmed if 
DAMPs alone can induce the clinically relevant end points of OF or their inhibition during 
pancreatitis models, which induce OF, averts these end points