Organ Failure due to Systemic Injury in Acute Pancreatitis

Inflammasome:
The inflammasome
109
is expressed in myeloid cells and has been implicated in systemic 
inflammation during pancreatitis 
103, 110
Inflammasome activation results in production of 
IL-1
β
111
, IL-18
112-114
and HMGB-1
104, 115
, all of which are associated with systemic injury 
during pancreatitis. Activation of the inflammasome is thought to be downstream of various 
receptors, some of which may be relevant to pancreatitis. These include nucleosomes (i.e. 
DNA-histone complexes), dsDNA and RAGE activating the AIM2 (absent in melanoma 2) 
inflammasome
110, 116
and extracellular ATP or NAD released from injured acinar cells 
activating the P2X7 receptor
103
. Additionally, cell surface pattern recognition receptors 
including TLR 4 and TLR9 may be activated by these DAMPs
103
. Interfering with 
nucleosomes activating the inflammasome or inhibiting RAGE signaling has been shown to 
reduce the severity of L-arginine and caerulein pancreatitis
104, 116
including lung 
inflammation. Interestingly, antagonism of TLR9 reduced lung inflammation, but not 
edema
103
. Similarly while IL-1
β increased lung inflammation, it did not induce lung 
injury
47
. Additionally while IL-18 (in combination with IL-12) induces pancreatitis
117
, the 
Garg and Singh
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systemic severity of pancreatitis these agents induce and the associated mortality are largely 
dependent on an increase in visceral fat
118
and its lipolysis to fatty acids
53
. In the absence of 
known genetic polymorphisms that govern inflammasome activation in pancreatitis, it is 
unclear how inflammasome activation variably affects the severity of pancreatitis in different 
individuals. This is further highlighted by early OF in pancreatitis occurring in the absence 
of extensive pancreatic necrosis and thus having a smaller source of inflammasome 
activators such as dsDNA or nucleosomes than later in AP, when necrosis is progressing. 
Future studies are needed to clarify the role of the inflammasome in systemic injury during 
pancreatitis.