Pathogenic mechanisms of acute pancreatitis

Abstract

Purpose of review: In this article, recent advances in the pathogenesis of acute pancreatitis have been reviewed.

Recent findings: Pathologic intra-acinar trypsinogen activation had been hypothesized to be the central mechanism of pancreatitis for over a century. This hypothesis could be explored for the first time with the development of a novel mouse model lacking pathologic intra-acinar trypsinogen activation. It became clear that intra-acinar trypsinogen activation contributes to early acinar injury, but local and systemic inflammation progress independently during pancreatitis. Early intra-acinar nuclear factor kappa B (NFκB) activation, which occurs parallel to but independent of trypsinogen activation, may be crucial in pancreatitis. Although the mechanism of NFκB and trypsinogen activation is not entirely clear, further insights have been made into key pathogenic cellular events such as calcium signaling, mitochondrial dysfunction, endoplasmic reticulum (ER) stress, autophagy and impaired trafficking, and lysosomal and secretory responses. Cellular intrinsic damage-sensing mechanisms that lead to activation of the inflammatory response aimed at repair, but lead to disease when overwhelmed, are beginning to be understood.

Summary: New findings necessitate a paradigm shift in our understanding of acute pancreatitis. Intra-acinar trypsinogen activation leads to early pancreatic injury, but the inflammatory response of acute pancreatitis develops independently, driven by early activation of inflammatory pathways.

Figure 1. Two key parallel and independent events occurring early during pancreatitis

Both these events are capable of causing pancreatic damage leading to acute pancreatitis. The relative contribution of these events in acute pancreatitis is one of the central questions in the pathogenesis of pancreatic injury at present.

Figure 2. Sources and clearance routes of pathologic cytoplasmic calcium response [Ca²⁺_i]

Ryanodine Receptors (RyR) (34) and store operated calcium channels (SOCs) (35, 36) are major sources of Ca²⁺_i. RyRs are calcium sensitive channels, and open in response to mild rise in Ca²⁺_i although cADPR and NADDP are also possible RyR ligands (–29, 33). The identity of SOCs and the mechanism of their regulation by ER calcium signals has been a field of active research. Recently TRPC3 and ORAI channels have been identified as important SOCs (35, 36) and it is postulated that STIMs that sit on ER membrane sense calcium depletion within the ER (as would occur after opening of RyRs) and migrate to plasma membrane where they open the SOCs (35, 36). Acidic pools are thought to be important in alcohol induced injury (30) and include organelles with low pH such as lysosomes, endososomes and zymogens. Recently recognized Two Pore Channels (TPCs) release calcium from acid pools (–33). Mitochondria have been recognized as another source of calcium (not shown in the figure). Note that clearance of Ca²⁺_i is an ATP requiring process, and ATP depletion or direct inhibition of SERCA prolongs Ca²⁺_i, a mechanism thought to be important in pancreatic injury due to bile acids and ethanol metabolites.

Figure 3. Signal transduction events resulting in pathologic trypsinogen activation and NFkB activation

Cholecystokinin analog Caerulein induced pancreatitis has been used as a model in this schematic. CCK_A: Cholecystokinin receptor subtype A, G_q: G-protein q subtype; PLC: phospholipase C, PIP2: Phosphoinositol 4-phosphate, IP3: Inositol-3 Phosphate, DAG: Diacylglycerol; PKC: protein kinase C, PKD: protein kinase D. Caerulein (CCK analog) binds to its receptor as shown and leads to generation of IP3 and DAG. IP3 opens ER membrane IP3 receptors which are implicated in physiologic calcium signaling. Calcium released through IP3R leads to opening of RyRs as described in figure 2. The grey lines in the figure depict either unknown steps or proposed mechanisms awaiting verification in future studies.

Figure 4. Effect of low extracellular pH, role of bioenergetics in determining cell fate and dual role of oxidative stress

Low pH in the lumen leads to enhanced activity of vATPase, enhanced pathologic calcium response and disruption of intercellular junctions leading to zymogen activation and spread of activated zymogens causing further damage (–50). High ATP states favor apoptosis and this mode of death avoids inflammatory response leading to relatively less severe injury compared to necrosis which elicits intense inflammation (39). Necrosis is the mode of death during low ATP states and causes severe pancreatic injury. ROS depletion in the acinar cells leads to low ATP state and favors necrosis while ROS induction favors apoptosis avoiding severe pancreatic damage, and therefore seems to be protective to the acinar cell (72). At the same time, ROS in the neutrophils leading to inflammation may contribute to pancreatic injury. Thus oxidative stress spears to have dual role in pancreatitis.