Daniel Muthas1, Anna Reznichenko2, Clare A Balendran3, Gerhard Böttcher4, Ib Groth Clausen1, Carina Kärrman Mårdh1, Tomas Ottosson1, Mohib Uddin3, Thomas T MacDonald5, Silvio Danese6, Mark Berner Hansen1,7. 1. a Department of Respiratory , Inflammation and Autoimmunity, AstraZeneca R&D Gothenburg , Mölndal , Sweden. 2. b Department of Cardiovascular and Metabolic Diseases , AstraZeneca R&D Gothenburg , Mölndal , Sweden. 3. c Department of Personalised HealthCare & Biomarkers , AstraZeneca R&D Gothenburg , Mölndal , Sweden. 4. d Department of Drug Safety and Metabolism , AstraZeneca R&D Gothenburg , Mölndal , Sweden. 5. e Blizard Institute, Barts and the London School of Medicine and Dentistry, QMUL , London , UK. 6. f Department of Gastroenterology , IBD Center, Humanitas Research Hospital , Milan , Italy. 7. g Digestive Disease Center K, Bispebjerg Hospital, University of Copenhagen , Copenhagen , Denmark.
Abstract
OBJECTIVES: This review article describes the role of neutrophils in mucosal injury and the resulting crypt abscesses characteristic of ulcerative colitis. We also review selected biomarkers for monitoring neutrophil presence and activity in the mucosa as well as their potential as therapeutic targets. MATERIAL: We have collated and selectively reviewed data on the most prominent well-established and emerging neutrophil-related biomarkers and potential therapeutic targets (calprotectin, lactoferrin, CXCR1, CXCR2, MMP-9, NGAL, elafin, HNE, pANCAs, MPO, CD16, CD177, CD64, HNPs, SLPI and PTX3) in ulcerative colitis. RESULTS: Systemic and intestinal neutrophil activity increases substantially in active ulcerative colitis, driving tissue damage and extra-intestinal manifestations. Calprotectin is a robust neutrophil and disease biomarker, and a few neutrophil-related targets are being clinically explored as therapeutic targets. CONCLUSION: We propose that targeting neutrophils and their inflammatory mediators per se is an opportunity that should be explored to identify new effective medical therapies. The overall clinical goal for neutrophil-targeted therapy will be to modulate, but not completely silence, neutrophil activity, thereby abolishing the destructive inflammation with associated acute and chronic tissue damage without compromising host-defense.
OBJECTIVES: This review article describes the role of neutrophils in mucosal injury and the resulting crypt abscesses characteristic of ulcerative colitis. We also review selected biomarkers for monitoring neutrophil presence and activity in the mucosa as well as their potential as therapeutic targets. MATERIAL: We have collated and selectively reviewed data on the most prominent well-established and emerging neutrophil-related biomarkers and potential therapeutic targets (calprotectin, lactoferrin, CXCR1, CXCR2, MMP-9, NGAL, elafin, HNE, pANCAs, MPO, CD16, CD177, CD64, HNPs, SLPI and PTX3) in ulcerative colitis. RESULTS: Systemic and intestinal neutrophil activity increases substantially in active ulcerative colitis, driving tissue damage and extra-intestinal manifestations. Calprotectin is a robust neutrophil and disease biomarker, and a few neutrophil-related targets are being clinically explored as therapeutic targets. CONCLUSION: We propose that targeting neutrophils and their inflammatory mediators per se is an opportunity that should be explored to identify new effective medical therapies. The overall clinical goal for neutrophil-targeted therapy will be to modulate, but not completely silence, neutrophil activity, thereby abolishing the destructive inflammation with associated acute and chronic tissue damage without compromising host-defense.
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