thromboplastin and Colitis

The interaction of coagulation factors with the perivascular environment affects the development of disease in ways that extend beyond their traditional roles in the acute hemostatic cascade. Key molecular players of the coagulation cascade like tissue factor, thrombin, and fibrinogen are epidemiologically and mechanistically linked with diseases with an inflammatory component. Moreover, the identification of novel molecular mechanisms linking coagulation and inflammation has highlighted factors of the coagulation cascade as new targets for therapeutic intervention in a wide range of inflammatory human diseases. In particular, a proinflammatory role for fibrinogen has been reported in vascular wall disease, stroke, spinal cord injury, brain trauma, multiple sclerosis, Alzheimer's disease, rheumatoid arthritis, bacterial infection, colitis, lung and kidney fibrosis, Duchenne muscular dystrophy, and several types of cancer. Genetic and pharmacologic studies have unraveled pivotal roles for fibrinogen in determining the extent of local or systemic inflammation. As cellular and molecular mechanisms for fibrinogen functions in tissues are identified, the role of fibrinogen is evolving from a marker of vascular rapture to a multi-faceted signaling molecule with a wide spectrum of functions that can tip the balance between hemostasis and thrombosis, coagulation and fibrosis, protection from infection and extensive inflammation, and eventually life and death. This review will discuss some of the main molecular links between coagulation and inflammation and will focus on the role of fibrinogen in inflammatory disease highlighting its unique structural properties, cellular targets, and signal transduction pathways that make it a potent proinflammatory mediator and a potential therapeutic target.

Topics: Alzheimer Disease; Animals; Arthritis, Rheumatoid; Bacterial Infections; Blood Coagulation; Brain Injuries; Colitis; Fibrinogen; Humans; Inflammation; Kidney Diseases; Multiple Sclerosis; Muscular Dystrophy, Duchenne; Neoplasms; Pulmonary Fibrosis; Spinal Cord Injuries; Stroke; Thrombin; Thromboplastin; Vascular Diseases

Intestinal mesenchymal cells play essential roles in epithelial homeostasis, matrix remodeling, immunity, and inflammation. But the extent of heterogeneity within the colonic mesenchyme in these processes remains unknown. Using unbiased single-cell profiling of over 16,500 colonic mesenchymal cells, we reveal four subsets of fibroblasts expressing divergent transcriptional regulators and functional pathways, in addition to pericytes and myofibroblasts. We identified a niche population located in proximity to epithelial crypts expressing SOX6, F3 (CD142), and WNT genes essential for colonic epithelial stem cell function. In colitis, we observed dysregulation of this niche and emergence of an activated mesenchymal population. This subset expressed TNF superfamily member 14 (TNFSF14), fibroblastic reticular cell-associated genes, IL-33, and Lysyl oxidases. Further, it induced factors that impaired epithelial proliferation and maturation and contributed to oxidative stress and disease severity in vivo. Our work defines how the colonic mesenchyme remodels to fuel inflammation and barrier dysfunction in IBD.

Topics: Animals; Cell Proliferation; Colitis; Colon; Epithelial Cells; Fibroblasts; Genetic Heterogeneity; Homeostasis; Humans; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Mesenchymal Stem Cells; Mesoderm; Mice; Mice, Inbred C57BL; Myofibroblasts; Pericytes; RAW 264.7 Cells; Single-Cell Analysis; SOXD Transcription Factors; Thromboplastin; Tumor Necrosis Factor Ligand Superfamily Member 14; Wnt Signaling Pathway

Topics: Animals; Chemokines; Colitis; Colon; Female; Humans; Male; Thromboplastin

There is growing evidence for an interplay between inflammatory and coagulation pathways in acute and chronic inflammatory diseases. However, it remains unclear whether components of the coagulation pathway, such as tissue factor (TF), contribute to intestinal inflammation, and whether targeting TF will blunt the inflammatory cell recruitment, tissue injury, and enhanced thrombus formation that occur in experimental colitis. Mice were fed 3% dextran sodium sulfate (DSS) to induce colonic inflammation, with some mice receiving a mouse TF-blocking antibody (muTF-Ab). The adhesion of leukocytes and platelets in colonic venules, light/dye-induced thrombus formation in cremaster muscle microvessels, as well as disease activity index, thrombin-antithrombin (TAT) complexes in plasma, and histopathologic changes in the colonic mucosa were monitored in untreated and muTF-Ab-treated colitic mice. In untreated mice, DSS elicited the recruitment of adherent leukocytes and platelets in colonic venules, caused gross and histologic injury, increased plasma TAT complexes, and enhanced thrombus formation in muscle arterioles. muTF-Ab prevented elevation in TAT complexes, reduced blood cell recruitment and tissue injury, and blunted thrombus formation in DSS colitic mice. These findings implicate TF in intestinal inflammation and support an interaction between inflammation and coagulation in experimental colitis.

Topics: Animals; Antithrombins; Blood Coagulation; Blood Platelets; Colitis; Colon; Disease Models, Animal; Inflammation; Leukocytes; Mice; Microcirculation; Thromboplastin; Thrombosis

Procoagulant membrane microparticles can be released from activated or apoptotic cells in response to various environmental stimuli. The aim of this study was to investigate the presence of microparticles in Crohn's disease and to assess their variations after infliximab therapy. We compared the levels of circulating microparticles in 38 patients with Crohn's disease, 16 patients with ulcerative colitis, 7 patients with infectious colitis, and 17 control subjects. The evolution of microparticle levels was assessed after infliximab therapy in 13 patients with Crohn's disease. Circulating microparticle levels were elevated in patients with Crohn's disease (9.31+/-0.66 nmol/L phosphatidylserine equivalent [PS Eq]) or infectious colitis (10.71+/-0.92 nmol/L PS Eq) compared to patients with ulcerative colitis (5.75+/-0.59 nmol/L PS Eq) and control subjects (4.06+/-0.37 nmol/L PS Eq) (P = 0.001). Infliximab induced a significant diminution of the amounts of circulating microparticles, from 10.33+/-1.20 to 6.45+/-0.90 nmol/L PS Eq (P = 0.002). Generation of circulating microparticles occurs in Crohn's disease; infliximab induces significant diminution. Release of microparticles could be linked to the type of inflammatory response underlying Crohn's disease.

Topics: Adolescent; Adult; Aged; Antibodies, Monoclonal; Apoptosis; Biomarkers; Case-Control Studies; Cohort Studies; Colitis; Colitis, Ulcerative; Crohn Disease; Female; Humans; Infliximab; Male; Middle Aged; Particle Size; Prognosis; Sensitivity and Specificity; Thromboplastin