Organ Failure due to Systemic Injury in Acute Pancreatitis

Figure 1: 
A conceptual model of early sterile injury and inflammation due to damage associated 
molecular patterns (DAMPs)/ Unsaturated fatty acids (UFAs), and late secondary septic 
inflammation due to pathogen associated molecular patterns (PAMPs) that may lead to organ 
failure in acute pancreatitis.
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Figure 2: Pathophysiology of systemic injury in AP:
The upper part of the figure describes the initiation of acinar injury by an AP etiology like 
high dose CCK (
↑CCK) during caerulein pancreatitis. The intra-acinar signaling events 
include the increase in cytosolic calcium (Ca
2+
), which has a role in mitochondrial 
depolarization (Memb. Depol.) and cytochrome C leakage, along with activating NF-kB via 
dissociation and proteasomal degradation of IkB, nuclear translocation of p65. This 
upregulates inflammatory mediator synthesis, which include cytokines and chemokines, and 
thus leads to neutrophil infiltration into the pancreas. The trypsin generated due to impaired 
autophagy involving lysosomes (L) and zymogen granules (ZG) and increased oxidized 
glutathione (GSSG) [from its reduced form (GSH), due to reactive oxygen species (ROS)], 
along with concurrent deleterious mechanisms, cause acinar injury. These other mechanisms 
include the loss of apical microvilli, inhibition of apical secretion, the reorganization of F-
actin, basolateral blebbing, release of DAMPs that can activate the inflammasome, and 
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leakage of exocrine enzymes such as lipase, trypsin. The DAMPS can worsen local injury, 
and may also contribute to systemic injury. Similarly, cytokines can cause the leukocytosis 
associated with SIRS, which can enter the systemic circulation and are a part of systemic 
injury. The lower part of the figure describes the types of systemic injury that may occur due 
to these, along with the underlying mechanisms. The mechanisms include unregulated 
hydrolysis of adipocyte triglyceride (Adipo. TG) by pancreatic lipase, resulting in fat 
necrosis, which generates UFAs, that inhibit mitochondrial complex I and V, which decrease 
ATP and worsen local injury. The effects of UFAs, trypsin, cytokine entry into the systemic 
circulation, and leukocytosis (from left to right) on end points of systemic injury are 
mentioned in the table below, with a + indicating 2 or more reports citing the agent in 
causing the end point. Unclear or weaker evidence is shown as ± or a – respectively.
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