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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

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

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ACUTE WOUND

ACUTE

• Heal completely• Minimal

scarring• Usually 8–12

weeks

SOURCE :- http://woundeducators.com/phases-wound-healing-part-2/

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CHRONIC WOUND

CHRONIC• Heal slowly• More than 12

weeks• Regularly

reoccur

SOURCE :- http://woundeducators.com/phases-wound-healing-part-2/

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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.

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PHASES OF WOUND HEALING

Stages of wound healing:

Hemostasis: immediate response

Inflammation: 0-4 days

Proliferation: 4-21 days

Granulation () :4-21 days Epithelialization

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NORMAL WOUND HEALING MECHANISM

SOURCE:- Fromm et al., (2015)

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Hemostasis

9Adapted by Karima et al., 2005

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NORMAL VERSUS CHRONIC WOUND HEALING

SOURCE: (Fromm et al., 2015)

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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

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DIABETES MELLITUS

It is a metabolic disorder

It is characterized by the presence of hyperglycaemia

Defective insulin secretion, defective insulin action or both. 

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

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Mechanism model to integrate NETosis and apoptosis into a paradigm of β-cell death and type 1 diabetes.

Source : (Richard et al., 2014)

Neutrophil Extracellular TRAPS (Spiderman)

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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.

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Mechanism of NETosis

SOURCE : (Kaplan et al., 2012)

Components of NETs

• Extracellar trap components• DNA• Neutrophil Elastase• Histones• Myeloperoxidase• Lactoferrin• MMP9/Gelatinase B• Cathepsin G

Components of NETs

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NEUTROPHIL KILLING MECHANISMS

Reactive oxygen species (ROS)

Neutrophil extracellular traps (NETs)

Reactive oxygen species

NETs

SOURCE : Kaplan et al., 2012 19

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

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EFFECT OF GLUCOSE ON NETs

Adapted from (Wang, Y., 2009). 21

EFFECT OF H3Cit & PAD4 ON NETs

22Adapted from (Wang, Y., 2009).

EFFECT OF DNase 1 ENZYME

FIGURE :- ACTION OF DNase 1 on diabetic mice. Source:-Wang et al., 2009

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CONCLUSION

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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.

Future Prospective

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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.

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 as sessment 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

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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.

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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.

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Thank You