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Abstract
Pancreatitis is a significant clinical problem and the lack of effective therapeutic options means that treatment is often palliative rather than curative. A deeper understanding of the pathogenesis of both acute and chronic pancreatitis is necessary to develop new therapies. Pathological changes in pancreatitis are dependent on innate immune cell recruitment to the site of initial tissue damage, and on the coordination of downstream inflammatory pathways. The chemokine receptor CXCR2 drives neutrophil recruitment during inflammation, and to investigate its role in pancreatic inflammation, we induced acute and chronic pancreatitis in wild‐type and Cxcr2−/− mice. Strikingly, Cxcr2−/− mice were strongly protected from tissue damage in models of acute pancreatitis, and this could be recapitulated by neutrophil depletion or by the specific deletion of Cxcr2 from myeloid cells. The pancreata of Cxcr2−/− mice were also substantially protected from damage during chronic pancreatitis. Neutrophil depletion was less effective in this model, suggesting that CXCR2 on non‐neutrophils contributes to the development of chronic pancreatitis. Importantly, pharmacological inhibition of CXCR2 in wild‐type mice replicated the protection seen in Cxcr2−/− mice in acute and chronic models of pancreatitis. Moreover, acute pancreatic inflammation was reversible by inhibition of CXCR2. Thus, CXCR2 is critically involved in the development of acute and chronic pancreatitis in mice, and its inhibition or loss protects against pancreatic damage. CXCR2 may therefore be a viable therapeutic target in the treatment of pancreatitis. © 2015 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
Highlights
Pancreatitis is a source of significant morbidity and mortality
CXCR2 drives acute pancreatic inflammation and acinar damage To assess the role of CXCR2 in the pathogenesis of acute pancreatitis, we compared the responses of Cxcr2−/−
Many of the known molecular processes characterized in acute pancreatitis converge on CXCR2 signalling and stimulate CXC chemokine release
Summary
Pancreatitis is a source of significant morbidity and mortality. the lack of effective interventions means the emphasis in clinical practice is on supportive care or prevention, rather than cure, and an improved understanding of the pathogenesis of pancreatic inflammation is required to develop new strategies for therapeutic intervention [1].Acute pancreatitis arises as a result of damage to acinar cells. The transcription factors NF-κB [3], AP-1, and NFAT [5,6] are activated and induce the production of pro-inflammatory mediators including CXC chemokines (eg CXCL1 [7] and CXCL2 [8]), CC chemokines (including CCL2 [9]), and cytokines such as interleukin (IL)-6 [10], TNFα [11], and IL-1β. These mediators drive an acute inflammatory response characterized by the influx of innate immune cells, first neutrophils and monocytes, to the site of damage. Acute pancreatitis resolves with tissue repair and regeneration, but in severe cases a cycle of damage and inflammation is set in motion whereby pro-inflammatory cytokines act systemically and, unless reversed, result in systemic inflammatory response syndrome and potentially organ failure and death
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