Acute lung injury (ALI) is an inflammatory disease with a high mortality rate. Although typically seen in individuals with sepsis, ALI is also a major complication in severe acute pancreatitis (SAP). The pathophysiology of SAP-associated ALI is poorly understood, but elevated serum levels of IL-6 is a reliable marker for disease severity. Here, we used a mouse model of acute pancreatitis-associated (AP-associated) ALI to determine the role of IL-6 in ALI lethality. Il6-deficient mice had a lower death rate compared with wild-type mice with AP, while mice injected with IL-6 were more likely to develop lethal ALI. We found that inflammation-associated NF-κB induced myeloid cell secretion of IL-6, and the effects of secreted IL-6 were mediated by complexation with soluble IL-6 receptor, a process known as trans-signaling. IL-6 trans-signaling stimulated phosphorylation of STAT3 and production of the neutrophil attractant CXCL1 in pancreatic acinar cells. Examination of human samples revealed expression of IL-6 in combination with soluble IL-6 receptor was a reliable predictor of ALI in SAP. These results demonstrate that IL-6 trans-signaling is an essential mediator of ALI in SAP across species and suggest that therapeutic inhibition of IL-6 may prevent SAP-associated ALI. IntroductionAcute pancreatitis (AP) accounts for more than 220,000 hospital admissions in the United States each year. Risk factors for AP include gallstones and excessive alcohol use. Interestingly, 70%-80% of AP patients develop mild and uncomplicated AP, while 20%-30% will develop more severe symptoms with concomitant multiple organ failure (MOF) (1). MOF is a consequence of the systemic activation of the immune system, known as systemic inflammatory response syndrome (SIRS). The clinical and pathological features of SIRS mimic those of sepsis; however, efforts to identify any infecting organisms in many patients with SIRS have failed (2-4). Although this syndrome is typically seen in individuals with sepsis, SIRS also occurs in patients with severe AP (SAP), blunt trauma, aseptic burns, and widespread surgical manipulations (5, 6). A major complication during SAP is acute lung injury (ALI). Nevertheless, the clinical course of ALI in SAP is still unpredictable and has a mortality rate of up to 50%. Current therapeutic approaches in SAP and associated ALI are symptomatically based (1, 7).The pathophysiology of SAP with ALI is poorly understood. Researchers have long hypothesized that SAP results from activation of digestive enzymes within the pancreas, a process called autodigestion (8). Indeed, inherited mutations in genes encoding for digestive enzymes have been found in patients with a hereditary form of pancreatitis. However, all these patients develop chronic pancreatitis, rather than SAP with ALI (9, 10). Therefore,

NETs form in the pancreata of mice during the development of AP, and NET levels are increased in plasma from patients with AP, compared with controls. NETs regulate organ inflammation and injury in mice with AP, and might be targeted to reduce pancreatic tissue damage and inflammation in patients.

Smoking contributed to more hepatocellular carcinomas in this Europe-wide cohort than chronic HBV and HCV infections. Heavy alcohol consumption and obesity also contributed to sizeable fractions of this disease burden. These contributions may be underestimates because EPIC volunteers are likely to be more health conscious than the general population.