Study of Plasma mitDNA in Predicting Pancreatic Necrosis in Acute Pancreatitis

Acute pancreatitis (AP) is inflammation of the pancreas that can become a fatal disease or lead to severe complications . It is characterized clinically by abdominal pain and by increased pancreatic enzyme levels in the blood or urine. Gallstone migration and alcohol abuse are the two major risk factors for AP in humans . According to the updated Atlanta classification, AP is generally divided into mild, moderate or severe pancreatitis according to the presence or absence of multiple organ failure (MOF) or local or systemic complications . Mild pancreatitis has a good prognosis with rapid recovery. The late consequences of AP include impaired pancreatic exocrine function and glucose tolerance, diabetes and development of chronic pancreatitis . Moderately severe AP is characterized by the presence of transient organ failure, local complications or exacerbation of comorbid disease . About one-third of patients with AP develop severe necrotizing pancreatitis with persistent MOF and a high mortality rate. The main goals in the clinical management of AP are adequate fluid resuscitation and the prevention of MOF . Both genetic and environmental factors affect the development and severity of pancreatitis .

Although the pathogenic mechanisms remain largely unknown, increasing evidence suggests that damage-associated molecular pattern molecules (DAMPs) play a central role in the pathogenesis of AP. DAMPs link local tissue damage to systemic inflammation response syndrome (SIRS), which, if severe or sustained, can lead to subsequent MOF and even death . Most DAMPs are recognized by membrane-bound and cytosolic pattern recognition receptors (PRRs) expressed by both immune and nonimmune cell types. This triggers downstream signaling and manifests as sterile inflammation .

The development of AP involves a complex cascade of events , which start with injury or disruption of the pancreatic acini, which then permits the leakage of active pancreatic enzymes including amylolytic, lipolytic and proteolytic enzymes that destroy local tissues. This results in edema, vascular damage, hemorrhage and cell death . In addition to oxidative stress and calcium overload , hypotension and low acinar pH contribute to these initiation processes. After initial production of active pancreatic enzymes, local cell death and systemic inflammation ensue.

Mitochondria, the energy factories of cells, regulate pancreatic cell death through control of the production of adenosine triphosphate (ATP) and reactive oxygen species (ROS), as well as calcium . Dysfunction of mitochondrial calcium uptake and efflux, including elevation of cytosolic calcium from the endoplasmic reticulum, can cause mitochondrial calcium overload, which leads to enhanced generation of mitochondrial ROS and mitochondrial membrane permeabilization. Mitochondria dysfunction-mediated oxidative injury results in endoplasmic reticulum stress, lysosomal damage and the release of proteases (for example, cathepsin and trypsin) to degrade cytosolic proteins that cause pancreatic acinar cell death . Dead, dying and injured pancreatic acinar cells release intra-cellular contents, including DAMPs (for example, high mobility group box 1 [HMGB1], DNA, histones and ATP), which in turn promote infiltration of various immune cells (for example, neutrophils, monocytes and macrophages) and activation of inflammatory signaling pathways.

The severity of experimental AP correlates with the extent and type of cell injury and death. Although multiple forms of cell death exist in physiological and pathological conditions , necrosis and apoptosis are the most widely studied types in both clinical and experimental AP . Necrotic cells are capable of activating proinflammatory and immunostimulatory responses by releasing DAMPs and other molecules, whereas apoptosis is usually considered immunologically silent because the cytoplasmic content is packaged in apoptotic bodies and these membrane-bound cell fragments are rapidly taken up and degraded by phagocytes or autophagy .