Nets (NEUTROPHILL EXTEACELLULAR TRAPS) in wound healing mohit
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Nets - NEUTROPHIL EXTRACELLULAR TRAPS
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Nets (NEUTROPHILL EXTEACELLULAR TRAPS) in wound healing mohit
- 1. 1 Presented By: MOHIT Reg. No.: 15mslsmm01 Centre for Human Genetics and Molecular Medicine School of Health Sciences Central University of Punjab ROLE OF NEUTROPHIL EXTRACELLULAR TRAPS IN WOUND HEALING
- 2. WOUND • It is a constrained injury which is caused by an external force and it can involve any tissue or organ. It can be mild, severe, or even lethal. It has two types:- • Acute • Chronic 2
- 3. ACUTE WOUND ACUTE • Heal completely • Minimal scarring • Usually 8–12 weeks SOURCE :- http://woundeducators.com/phases-wound- healing-part-2/ 3
- 4. CHRONIC WOUND CHRONIC • Heal slowly • More than 12 weeks • Regularly reoccur SOURCE :- http://woundeducators.com/phases- wound-healing-part-2/ 4
- 5. WOUND HEALING It is a specific biological process related to the general phenomenon of growth and tissue regeneration. It progresses through a series of interdependent and overlapping stages in which a variety of cellular and matrix components act together to re-establish the integrity of damaged tissue and replacement of lost tissue. 5
- 6. Stages of wound healing: Hemostasis: immediate response Inflammation: 0-4 days Proliferation: 4-21 days Granulation () :4-21 days Epithelialization 6
- 7. 7 NORMAL WOUND HEALING MECHANISM SOURCE:- Fromm et al., (2015)
- 8. 8 Hemostasis
- 9. 9Adapted by Karima et al., 2005
- 10. 10 NORMAL VERSUS CHRONIC WOUND HEALING SOURCE: (Fromm et al., 2015)
- 11. 11 Although wound healing and infection are often overlapping processes, whether the wound healing response modulates the immune response is not well understood. Diabetes is a condition in which the body does not effectively use sugar. Wound healing can be slowed when the patient is diabetic. WOUND HEALIND AND DIABETES
- 12. 12 DIABETES MELLITUS It is a metabolic disorder It is characterized by the presence of hyperglycaemia Defective insulin secretion, defective insulin action or both.
- 13. Type of Diabetes Melitus Type 1 Develops when there is a severe lack of insulin in the body because most or all insulin producing beta cells in the pancreas have been destroyed. This is treated by insulin injections and diet Type 2 Develops when pancreas still produces insulin but there is cellular resistance and insulin cannot be used properly by the body. This is treated by diet alone or diet and tablets, or diet and insulin injections 13
- 14. 14 Mechanism model to integrate NETosis and apoptosis into a paradigm of β-cell death and type 1 diabetes. Source : (Richard et al., 2014)
- 15. Neutrophil Extracellular TRAPS (Spiderman) 15
- 16. 16 Ilya Ilyich Mechnikov (1845-1916), Nobel prize in 1908. Arturo Zychlinsky Discovered NETs in 2004, The study of neutrophils: sensation after more the 100 years of investigation.
- 17. 17 Mechanism of NETosis SOURCE : (Kaplan et al., 2012)
- 18. Components of NETs • Extracellar trap components • DNA • Neutrophil Elastase • Histones • Myeloperoxidase • Lactoferrin • MMP9/Gelatinase B • Cathepsin G Components of NETs 18
- 19. NEUTROPHIL KILLING MECHANISMS Reactive oxygen species (ROS) Neutrophil extracellular traps (NETs) Reactive oxygen species NETs SOURCE : Kaplan et al., 2012 19
- 20. Neutrophils Impair Wound Healing in Diabetes. •Neutrophils are the main leukocytes involved in the early phase of wound healing, which is impaired in patients with diabetes. •Neutrophils form extracellular traps (NETs) that can also induce tissue damage. •These researchers isolated neutrophils from type 1 and type 2 diabetic humans and mice, and showed they were primed to produce NETs, a process termed NETosis. Neutrophills 20
- 21. EFFECT OF GLUCOSE ON NETs Adapted from (Wang, Y., 2009). 21
- 22. EFFECT OF H3Cit & PAD4 ON NETs 22Adapted from (Wang, Y., 2009).
- 23. EFFECT OF DNase 1 ENZYME FIGURE :- ACTION OF DNase 1 on diabetic mice. Source:-Wang et al., 2009 23
- 24. CONCLUSION 24 Neutrophils are key immune cells NETs like as an double edge sword NETs involve in wound healing. Diabetics mellitus are major problem in present time. NETs also slow wound healing process in diabetic patient. Use of DNase we can fast the healing process.
- 25. Future Prospective 25 Identifying the range of biological events activating NET. The mechanisms of the regulation of NET generation is still unknown. To understand the association of netosis with pathophysiological and immunological processes may potentially lead to discovery of new effective therapeutic agents. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice needs to be further studied.
- 26. REFRENCES • Lazarus, G.S., Cooper, D.M., Knighton, D.R., Margolis, D.J., Percoraro, E.R., Rodeheaver, G. and Robson, M.C. (1994). Definitions and guidelines for assessment of wounds and evaluation of healing. Archives of Dermatology 130: 489–493. • Percival, J.N. (2002). Classification of wounds and their management. Surgery 20: 114–117. • Harding, K.G., Morris, H.L. and Patel, G.K. (2002). Science ,medicine and the future: Healing chronic wounds. British Medical Journal 324: 160–163. • Cooper, D.M. (1999). Wound healing: New understandings. Nurse practitioner forum 10: 74–86. • Martin, P. (1997). Wound healing: Aiming for perfect skin regeneration. Science 276: 75–81. • Agarwal, A., Nayak, .B.P. and Rao, K. V. (1998). B cell responses to a peptide epitope. VII. Antigen- dependent modulation of the germinal center reaction. Journal of Immunology 161: 5832–5841. • Ahmed, R. and Gray, D. (1996). Immunological memory and protective immunity: understanding their relation. Science 272: 54–60. 26 Continue…………
- 27. REFRENCES • Diane, L., Chau, M.D. Steven, V. and Edelman, MD. (2002). Clinical Diabetes 20: 153-157. • Brinkmann, V. (2004). Neutrophil extracellular traps kill bacteria. Science 303: 1532–1535. • Wang, Y. (2004). Human PAD4 regulates histone arginine methylation levels via demethylimination. Science 306: 279–283. • Wang, Y. (2009). Histone hypercitrullination mediates chromatin decondensation and neutrophil extracellular trap formation. Journal of Cell Biology 184: 205–213. • Thomas, G.M. (2012). Extracellular DNA traps are associated with the pathogenesis of TRALI in humans and mice. Blood 119: 6335–6343. • Li, P. (2010). PAD4 is essential for antibacterial innate immunity mediated by neutrophil extracellular traps. Journal of Experimental Medicine 207: 1853–1862. 27Continue…………
- 28. REFRENCESS • Alexiewicz, J. M., Kumar, D., Smogorzewski, M., Klin, M. and Massry, S. G. (1995). Polymorphonuclear leukocytes in non-insulin-dependent diabetes mellitus: abnormalities in metabolism and function. Internal Medicine 123: 919–924. 28
- 29. 29 Thank You
Notas del editor
- PAD4-PLATELET DERIVED GROWTH FACTOR VEGF-Vascular endothelial growth factor (VEGF),( originally known as vascular permeability factor (VPF), is a signal protein produced by cells that stimulates vasculogenesis and angiogenesis.) TGF-B –TRANSFORMING GROWTH FACTOR FGF -Basic fibroblast growth factor IL 1 - INTERLEUKEN 1 Normal wound healing processes can be divided into 4 overlapping phases: inflammatory phase (A), proliferative phase/granulation tissue formation (B), and remodeling phase (C). During coagulation and inflammatory phases (A) of the healing,- blood-borne cells—neutrophils, macrophages, as well as platelets—play critical roles. These cells provide growth factors and provisional matrices that are necessary for recruitment of epidermal and dermal cells into the wound bed. The proliferative phase (B) starts at - approximately 3 days after injury and is characterized by increased levels of keratinocyte and fibroblast proliferation, migration, and ECM synthesis in response to autocrine, paracrine, and juxtacrine growth factors. Angiogenesis/neovascularization also occurs during this phase. Because of the presence of blood vessels, the tissue has a granular appearance (granulation tissue). Finally, at approximately 1 to 2 weeks after injury,differentiated fibroblastic cells (myofibroblasts) that present within the granulation tissue begin to remodel extracellular matrix (C) . Extracellular matrix remodeling followed by apoptosis of resident cells leads to the formation of an acellular scar.
- Hemostasis - formation of a blood clot and subsequent stopping of the bleed.
- TIMP – TISSUE INHIBHITOR OF METAL PROTEINS Microenvironment within a normal wound bed (left) is characterized by the presence of numerous growth factors, a well-organized ECM, and responsive cell populations. Matrix synthesis, here, exceeds its degradation, and MMP activity is regulated by the presence of MMP inhibitors (TIMPs). Angiogenesis and neovascularization of normal wounds proceed in a timely manner via well-regulated sprouting of existing blood vessels and recruitment of endothelial progenitor cells (EPC), respectively. Finally, unlike their chronic counterparts, acute wounds are generally characterized by low bacterial burden. Chronic wounds (right) often have high incidence of bacterial biofilms, leading to persistent inflammation, excessive proteolysis, and degradation of critical growth factors, receptors, and/or ECM. Cells residing within these wounds are unable to proliferate and/or migrate effectively perhaps because of the absence of functional receptors or appropriate promigratory matrix substrates. Impaired angiogenesis and neovascularization, both hallmarks of chronic wounds, result in insufficient oxygen and nutrient supply for the cells residing within the wound bed, which leads to further wound bed mutilation and impaired healing.
- Dendritic cells (DCs) are antigen-presenting cells (also known as accessory cells) Beta cells (β cells) are a type of cell found in the pancreatic islets of the pancreas. They make up 65-80% of the cells in the islets Shared mechanism model to integrate NETosis and apoptosis into a paradigm of β-cell death and type 1 diabetes. In this model, both apoptosis and NETosis are predicted to play a role during both disease initiation and propagation. The model requires that β-cells are the initiating source of autoantigens, there is impaired clearance of cell debris with activation of dendritic cells, there is increased production of cytokines/chemokines and subsequent presentation of autoantigens to T-helper cells. Modified with permission from Darrah and Andrade (20). B, B cell; DC, dendritic cell; T, T-helper cell.
- ROS PRDODUCTION-
- Neutrophil elastase -is a serine proteinase in the same family as chymotrypsin and has broad substrate specificity. Secreted by neutrophils and macrophages during inflammation, it destroys bacteria and host tissue Histones are highly alkaline proteins found in eukaryotic cell nuclei that package and order the DNA into structural units called nucleosomes. Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene on chromosome 17. MPO is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells), and produces hypohalous acids to carry out their antimicrobial activity Lactoferrin (LF), also known as lactotransferrin (LTF), is a multifunctional protein of the transferrin family. Lactoferrin is a globular glycoprotein with a molecular mass of about 80 kDa that is widely represented in various secretory fluids, such as milk, saliva, tears, and nasal secretions. ABSORPTION OF IRON. Due to its role in cleaving collagen in the extracellular matrix, gelatinase B has multiple functional roles in normal physiology. Cathepsin G is an enzymatic protein belonging to the peptidase or protease families Neutrophil elastase, proteinase 3, and cathepsin G are three hematopoietic serine proteases stored in large quantities in neutrophil cytoplasmic azurophilic granules. They act in combination with reactive oxygen species to help degrade engulfed microorganisms inside phagolysosomes. These proteases are also externalized in an active form during neutrophil activation at inflammatory sites, thus contributing to the regulation of inflammatory and immune responses. Gelatinase B/matrix metalloproteinase-9 cleaves interferon-beta and is a target for immunotherapy
- Neutrophils can kill bacteria and other pathogens by intracellular or extracellular means. First, the PMN recognizes the invading pathogen and engulf it into a membrane-bound compartment known as the phagosome. This phagosome is fused with specific and azurophilic granules cointaining antimicrobial proteins as well as ROS generated by the enzyme NADPH. Therefore the microbe is exposed to these antimicrobial molecules in the phagolisosome where the pathogen is destroyed. Also the activated PMN can release some of these ROS to the extracellular space or mix its own nuclear material mixed with antimicrobial molecules, released these structures known as nets to physically trap and destroy the pathogen in a process known as extracellular traps formation.
- phorbol 12-myristate 13-acetate (PMA) INDUCER FOR NETosis. NE is the first to be transported into the nucleus, where it catalyzes the cleavage of the linker histone H1 and modifies the core histones . Ionomycin is an ionophore produced by the bacterium Streptomyces conglobatus. It is used in research to raise the intracellular level of calcium (Ca2+) and as a ...
- H3CIT - HISTONE CITTRULATION PAD4 -Protein Arginine Deiminases posttranslationally converts peptidylarginine to citrulline, in a process known as citrullination STZ -Streptozotocin (Streptozocin, STZ, Zanosar®) is a naturally occurring chemical that is particularly toxic to the insulin-producing beta cells of the pancreas in