Organ Failure due to Systemic Injury in Acute Pancreatitis

Distinction between markers, mediators and end-points of systemic injury:
It is important to appreciate the difference between markers vs. mediators vs. end points of 
systemic injury. Markers of systemic injury such as SIRS, or serum cytokines are distinct 
from the endpoints that determine the severity of systemic injury during pancreatitis. The 
clinical or biochemical clues do not themselves depict end organ injury, but may be markers 
or mediators of it. A marker in contrast to a mediator, when administered to an organism or 
when inhibited would not affect the endpoint of systemic injury. However, a mediator when 
administered would elicit an endpoint of systemic injury or when it is neutralized or 
inhibited the systemic injury would be ameliorated. As discussed previously, the end points 
of systemic injury during AP are renal, respiratory and cardiovascular failure.
Animal models and systemic injury in AP:
Although there are several AP models, it is important to realize their limitations in 
measuring systemic injury. Most AP models have a strong emphasis on local pancreatic 
injury in the context of specific initiators or etiologies like caerulein. Recently, clinically 
relevant risk factors such as obesity have been shown to result in systemic injury by 
modifying the course of AP in animal models.
47-49
These studies have used clinically 
relevant end points such as renal failure. Thus, it is important to analyze whether the end 
points used in basic/ animal models equate to human disease. For example, a common end 
point of lung injury used in animal models is the accumulation of myeloid inflammatory 
cells in the lung, shown as increase in lung myeloperoxidase (MPO) activity. Since 
pulmonary inflammation can be protective (please see section on neutrophils), it is important 
to realize the limitations of lung MPO as a parameter of lung injury. More relevant end 
points may be pulmonary microvascular permeability studied as the leakage into the alveolar 
space of an intravenously administered fluorescently tagged macromolecule such as 
albumin
50-52
, the oxygen saturation as determined by pulse oximetry
47
, or dead cells in the 
alveolar space
47-49, 53
which are relevant to pulmonary edema or adult respiratory distress 
syndrome (ARDS) in humans.
54
Similarly, clinically relevant end points for renal failure in 
animal models include a sustained increase in serum blood urea nitrogen (BUN)
48
like in 
sustained renal failure in humans.
48, 55
While basic models typically cannot distinguish between primary and secondary organ 
failure due to their short course, we cover markers and potential mediators (Table 3) 
increased in early human AP independent of pancreatic necrosis, and where relevant 
distinguish these from those associated with infection in the following discussion.
Garg and Singh
Page 6
Gastroenterology. Author manuscript; available in PMC 2020 May 01.
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