title: CXCR2 inhibition suppresses acute and chronic pancreatic inflammation.
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.
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.|Department of Surgery, Glasgow Royal Infirmary, Glasgow, UK.
authors.forename: Colin W
authors.initials: CW
authors.lastname: Steele
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Saadia A
authors.initials: SA
authors.lastname: Karim
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Mona
authors.initials: M
authors.lastname: Foth
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Loveena
authors.initials: L
authors.lastname: Rishi
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Joshua D G
authors.initials: JD
authors.lastname: Leach
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Ross J
authors.initials: RJ
authors.lastname: Porter
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Colin
authors.initials: C
authors.lastname: Nixon
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: T R
authors.initials: TR
authors.lastname: Jeffry Evans
authors.affiliation: Department of Surgery, Glasgow Royal Infirmary, Glasgow, UK.
authors.forename: C Ross
authors.initials: CR
authors.lastname: Carter
authors.affiliation: Centre for Immunobiology, Institute of Infection, Immunity, and Inflammation, University of Glasgow, Glasgow, UK.
authors.forename: Robert J B
authors.initials: RJ
authors.lastname: Nibbs
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.|Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.affiliation: Cancer Research UK Beatson Institute, Glasgow, UK.
authors.forename: Jennifer P
authors.initials: JP
authors.lastname: Morton
mesh_terms: D000208:Acute Disease; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D002108:Ceruletide; D019610:Cytoprotection; D004195:Disease Models, Animal; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D010179:Pancreas / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D010195:Pancreatitis / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D050500:Pancreatitis, Chronic / Q000139:chemically induced / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D010455:Peptides / Q000494:pharmacology*; D023063:Receptors, Interleukin-8B / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D000893:Anti-Inflammatory Agents; D010455:Peptides; D023063:Receptors, Interleukin-8B; D002108:Ceruletide
keywords: CXCR2; chemokines; inflammation; pancreatitis