![]() Neutrophil granulocytes may trespass epithelial layers, phagocytise and serve as a first line of defense. Flares often feature rectal bleeding and the presence of large numbers of polymorphonuclear granulocytes. 6 Failure to clear instigating factors or repeated challenges in a structurally vulnerable microenvironment 7 favour sustained chronic inflammation in UC and the development of flares of acute inflammation. Additionally, non-infectious causes of mucosal damage exist, ranging from drug-induced to diet-induced mucosal stress. 5 Colitis can be caused by various infectious microorganisms. 4 Emergency barriers need to provide provisional control of microbial invasion, avoid loss of blood and mucosal tissue fluids and support a timely restitution of mucosal epithelial integrity. 2 3 In UC, the epithelial lining is breached and emergency barriers are immediately required before epithelial restitution can be achieved. Increased rectal bleeding may require hospitalisation and rarely emergency surgical interventions. Thus, NET-associated immunothrombi are protective in acute colitis, while insufficient immunothrombosis is associated with rectal bleeding.Įver since the initial therapeutic studies of Truelove and Witts, 1 rectal bleeding has been considered as an important component of the clinical features of patients suffering from severe ulcerative colitis (UC). PAD4-deficient mice failed to remodel blood clots on mucosal wounds eliciting impaired healing. PAD4-deficient mice experienced an exacerbated course of dextrane sodium sulfate-induced colitis with markedly increased rectal bleeding (96 % vs 10 %) as compared with controls. In experimentally inflicted wounds, we found that neutrophils underwent NET formation in a PAD4-dependent manner hours after formation of primary blood clots, and remodelled clots to immunothrombi containing citrullinated histones, even in the absence of microbiota. ![]() Transcriptome analyses showed significantly elevated PAD4 expression in active UC. Fibrin layers contained ample amounts of neutrophils coaggregated with neutrophil extracellular traps (NETs) with detectable activity of PAD. Fibrin layers rather than fresh blood or haematin on erosions were inversely correlated with rectal bleeding in UC. Results Erosions and ulcerations in UC were covered by fresh blood, haematin or fibrin visible by endoscopy. Correspondence to Dr Moritz Leppkes, Department of Medicine 1, University Clinic, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.7 Institute for Laboratory Animal Science, Hannover Medical School, Hannover, Germany.6 Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.5 Friedrich Alexander University, Institute of Pathology, Klinikum Bayreuth, Erlangen, Germany.4 Institute of Pathology, University Medical Center, Mainz, Germany.3 Medical Clinic 3, University Clinic, Friedrich Alexander University, Erlangen, Germany.2 Deutsches Zentrum Immuntherapie, Erlangen, Germany.1 Medical Clinic 1, University Clinic, Friedrich Alexander University, Erlangen, Germany.
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