Systemic Inflammation with Multiorgan Dysfunction Is the Cause of Death in Murine Ligation-Induced Acute Pancreatitis

Abstract

Systemic inflammation with multiorgan dysfunction causes death in pancreatic duct ligation-induced acute pancreatitis in mice. This experimental model is a suitable experimental analogy of "early severe gallstone pancreatitis" to investigate disease pathogenesis and to evaluate novel therapeutic strategies.

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“…Beyond these local effects, mitochondrial function in the lungs and kidneys was also reduced early after induction of pancreatitis (27). A time-dependent onset of MODS (lung, kidney, heart, and liver) induced by experimental pancreatitis with associated acinar cell necrosis and systemic inflammatory response has been reported to involve neutrophil influx and extracellular regulated kinase (ERK) activation (28). Immune cell infiltration of lung tissue during experimental pancreatitis has been shown to be accompanied by enhanced expression of endothelial adhesion molecules, such as intercellular adhesion molecule-1 (ICAM-1) (29).…”

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“…The inflammatory cytokines play a crucial role in the pathogenesis of SAP [3, 8, 9]; furthermore, the damaged pancreatic acinar cells and the activated inflammatory cells produce a large amount of oxygen radicals in AP, and these ROS molecules can damage the lipid membranes of pancreatic acinar cells, they can also injure the capillary endothelium in the circulation to accelerate the progress of SAP [7]. Currently, therapeutic efforts are limited to supportive measures, because no effective specific treatment exists.…”

“…Gut mucosal injury and intestinal BT in SAP is particularly important because the intestine is the biggest reservoir of bacteria in the body and leakage of bacteria or microbial products, notably LPS, from the lumen of the gut into the systemic circulation, which drives the development of systemic inflammation and multiple organ dysfunction syndrome (MODS) in experimental models [26]. SAP frequently induces gut barrier dysfunction [6, 9, 27, 28]. The small intestine becomes damaged by intestinal ischemia-reperfusion during SAP [29, 30], and the failure of gut barrier is associated with BT [29], which is evident in SAP [6, 27, 28, 31].…”

“…BT and/or gut derived LPS play a critical role in the development of systemic inflammatory response syndrome (SIRS) and MODS during SAP [29, 33], because BT not only contributes to pancreatic infection [28, 33], but also induces/triggers SIRS/sepsis in critical illness [33, 34]. The profound SIRS/sepsis can lead to MODS and mortality in SAP [9, 29, 31, 33], this is one of the underlying mechanisms that AP frequently affects extrapancreatic organs [6, 25], and the incidence of MODS in SAP is not available but certainly higher than the 20–30% of mortality rate in SAP [3]. Systemic inflammation with multi-organ dysfunction is the cause of death in a murine ligation-induced SAP, and SIRS and MODS can lead to the preponderance of mortality (75%) in this lethal SAP model [9] while bile duct ligation does not have mortality, even though obstructive jaundice is prone to sepsis [9].…”

“…The profound SIRS/sepsis can lead to MODS and mortality in SAP [9, 29, 31, 33], this is one of the underlying mechanisms that AP frequently affects extrapancreatic organs [6, 25], and the incidence of MODS in SAP is not available but certainly higher than the 20–30% of mortality rate in SAP [3]. Systemic inflammation with multi-organ dysfunction is the cause of death in a murine ligation-induced SAP, and SIRS and MODS can lead to the preponderance of mortality (75%) in this lethal SAP model [9] while bile duct ligation does not have mortality, even though obstructive jaundice is prone to sepsis [9]. Therefore, the gut is thought to act as the starter of SIRS [29] and HMGB1 may be an important factor that links gut barrier dysfunction and MODS during SAP.…”