D M I T R I P O P O V . P H D , R A D I O B I O L O G Y . M D ( R U S S I A )

A D V A N C E D M E D I C A L T E C H N O L O G Y A N D S Y S T E M S I N C . C A N A D A .

I N T E R V A C C I N E @ G M A I L . C O M

Radiation Toxicity: Post-Radiation Inflammation.

Radiation Toxicity: Post-Radiation Inflammation.

Inflammation is a protective response involving host cells, blood vessels, and proteins and other mediators that is intended to eliminate the initial cause of cell injury, as well as the necrotic cells and tissues resulting from the original insult, and to initiate the process of repair.

Acute inflammation is the initial response of the body to harmful stimuli and is achieved by the increased movement ofplasma and leukocytes (especially granulocytes) from the blood into the injured tissues. A cascade of biochemical events propagates and matures the inflammatory response, involving the local vascular system, the immune system, and various cells within the injured tissue. http://en.wikipedia.org/wiki/Inflammation

Radiation Toxicity: Post-Radiation Inflammation.

The process of acute inflammation is initiated by cells already present in all tissues, mainly resident macrophages, dendriticcells,histiocytes, Kupffer cells and mastocytes. These cells present on their surfaces certain receptors named pattern recognition receptors (PRRs), which recognize molecules that are broadly shared by pathogens but distinguishable from host molecules, collectively referred to as pathogen-associated molecular patterns (PAMPs).

http://en.wikipedia.org/wiki/Inflammation

Radiation Toxicity: Post-Radiation Inflammation.

At the onset of an infection, burn, RADIATION, UV Radiation or other injuries, these cells undergo activation (one of their PRRs recognize a PAMP) and release inflammatory mediators responsible for the clinical signs of inflammation. Vasodilation and its resulting increased blood flow causes the redness (rubor) and increased heat (calor). Increased permeability of the blood vessels results in an exudation (leakage) of plasma proteins and fluid into the tissue (edema), which manifests itself as swelling (tumor).

http://en.wikipedia.org/wiki/Inflammation

Radiation Toxicity: Post-Radiation Inflammation.

Some of the released mediators such as bradykinin increase the sensitivity to pain (hyperalgesia, dolor). The mediator molecules also alter the blood vessels to permit the migration of leukocytes, mainly neutrophils and macrophages, outside of the blood vessels (extravasation) into the tissue.

http://en.wikipedia.org/wiki/Inflammation

Radiation Toxicity: Post-Radiation Inflammation.

In addition to cell-derived mediators, several acellular biochemical cascade systems consisting of preformed plasma proteins act in parallel to initiate and propagate the inflammatory response. These include the complement system activated by bacteria and thecoagulation and fibrinolysissystems activated by necrosis, e.g. a burn or a trauma.

http://en.wikipedia.org/wiki/Inflammation

Radiation Toxicity: Post-Radiation Inflammation.

The exudative component involves the movement of plasma fluid, containing important proteins such as fibrin and immunoglobulins(antibodies), into inflamed tissue. This movement is achieved via the chemically induced dilation and increased permeability of blood vessels, which results in a net loss of blood plasma.

Radiation Toxicity: Post-Radiation Inflammation.

Acute inflammation is characterized by marked vascular changes, including vasodilation, increased permeability and increased blood flow, which are induced by the actions of various inflammatory mediators. Vasodilation occurs first at the arteriole level, progressing to the capillary level, and brings about a net increase in the amount of blood present, causing the redness and heat of inflammation.

http://en.wikipedia.org/wiki/Inflammation

Radiation Toxicity: Post-Radiation Inflammation.

Increased permeability of the vessels results in the movement of plasma into the tissues, with resultant stasis due to the increase in the concentration of the cells within blood - a condition characterized by enlarged vessels packed with cells. Stasis allows leukocytes to marginate (move) along theendothelium, a process critical to their recruitment into the tissues.

http://en.wikipedia.org/wiki/Inflammation

Radiation Toxicity: Post-Radiation Inflammation.

Plasma cascade systems

The complement system, when activated, creates a cascade of chemical reactions that promotes opsonization, chemotaxis, and agglutination, and produces the MAC.

The kinin system generates proteins capable of sustaining vasodilation and other physical inflammatory effects.

The coagulation system or clotting cascade, which forms a protective protein mesh over sites of injury.

The fibrinolysis system, which acts in opposition to the coagulation system, to counterbalance clotting and generate several other inflammatory mediators.

http://en.wikipedia.org/wiki/Inflammation

Radiation Toxicity: Post-Radiation Inflammation.

Various leukocytes are critically involved in the initiation and maintenance of inflammation. These cells must be able to get to the site of injury from their usual location in the blood, therefore mechanisms exist to recruit and direct leukocytes to the appropriate place. The process of leukocyte movement from the blood to the tissues through the blood vessels is known as extravasationю

Radiation Toxicity: Post-Radiation Inflammation.

Leukocyte localisation and recruitment to the endothelium local to the site of inflammation –involving margination and adhesion to the endothelial cells: Recruitment of leukocytes is receptor-mediated. The products of inflammation, such ashistamine, promote the immediate expression of P-selectin on endothelial cell surfaces. This receptor binds weakly to carbohydrate ligands on leukocyte surfaces and causes them to "roll" along the endothelial surface as bonds are made and broken.

http://en.wikipedia.org/wiki/Inflammation#Process_of_acute_inflammation

Radiation Toxicity: Post-Radiation Inflammation.

Cytokines from injured cells induce the expression of E-selectin on endothelial cells, which functions similarly to P-selectin. Cytokines also induce the expression of immunoglobulin ligands such as ICAM-1 and VCAM-1 on endothelial cells, which further slow leukocytes down. These weakly bound leukocytes are free to detach if not activated by chemokines produced in injured tissue. Activation increases the affinity of bound integrinreceptors for immunoglobulin ligands on the endothelial cell surface, firmly binding the leukocytes to the endothelium.http://en.wikipedia.org/wiki/Inflammation#Process_of_acute_inflammation

Radiation Toxicity: Post-Radiation Inflammation.

Migration across the endothelium, known as transmigration, via the process of diapedesis: Chemokine gradients stimulate the adhered leukocytes to move between endothelial cells and pass the basement membrane into the tissues.

http://en.wikipedia.org/wiki/Inflammation#Process_of_acute_inflammation

Radiation Toxicity: Post-Radiation Inflammation.

Movement of leukocytes within the tissue via chemotaxis: Leukocytes reaching the tissue interstitium bind to extracellular matrixproteins via expressed integrins and CD44 to prevent their loss from the site. Chemoattractants cause the leukocytes to move along a chemotactic gradient towards the source of inflammation.

http://en.wikipedia.org/wiki/Inflammation#Process_of_acute_inflammation

Radiation Toxicity: Post-Radiation Inflammation.

Cell-derived mediators.

Lysosome granules. Granulocytes contain a large variety of enzymes that perform a number of functions. Granules can be classified as either specific or azurophilic depending upon the contents, and are able to break down a number of substances, some of which may be plasma-derived proteins that allow these enzymes to act as inflammatory mediators.

Histamine. Stored in preformed granules, histamine is released in response to a number of stimuli. It causes arteriole dilation and increased venous permeability.

IL-8. http://en.wikipedia.org/wiki/Inflammation#Process_of_acute_inflammation

Radiation Toxicity: Post-Radiation Inflammation.

Acute Radiation Disease (ARD) or Acute Radiation Syndromes (ARS) are defined as the

collective toxic clinical states observed from the acute pathological processes in various

doses of irradiated mammals; to include: systemic inflammatory response syndrome (SIRS),

toxic multiple organ injury (TMOI), toxic multiple organ dysfunction syndromes (TMODS),

and finally, toxic multiple organ failure (TMOF). http://www.intechopen.com/books/current-topics-in-

ionizing-radiation-research/radiation-toxins-molecular-mechanisms-of-toxicity-and-radiomimetic-properties-

Radiation Toxicity: Post-Radiation Inflammation.

Necrosis especially, initiates inflammation and formation of specific Radiation Toxins (RTs).

Specific Radiation Toxins are playing an important role as the trigger mechanism for inflammation, cell lysis, and damage to vital cellular structures such as mitochondria, DNA, ion channels and cell membranes.

http://www.intechopen.com/books/current-topics-in-ionizing-radiation-research/radiation-toxins-molecular-mechanisms-of-toxicity-and-radiomimetic-properties-

Radiation Toxicity: Post-Radiation Inflammation.

The mechanism and action of Radiation Toxins could be compared to actions of different microbial toxins, snake and scorpion venoms, enteric bacterial toxins, natural and plant-borne toxins.

http://www.intechopen.com/books/current-topics-in-ionizing-radiation-research/radiation-toxins-molecular-mechanisms-of-toxicity-and-radiomimetic-properties-

Radiation Toxicity: Post-Radiation Inflammation.

Acute Radiation Disease (ARD) or Acute Radiation

Syndromes (ARS) were defined as a toxic, poisonous exposure with development of the acute pathological processes in irradiated animals: systemic inflammatory response syndrome (SIRS), toxic multiple organ injury (TMOI), toxic multiple organ dysfunction syndromes (TMOD), toxic multiple organ failure (TMOF)ю

http://www.intechopen.com/books/current-topics-in-ionizing-radiation-research/radiation-toxins-molecular-mechanisms-of-toxicity-and-radiomimetic-properties-

Radiation Toxicity: Post-Radiation Inflammation.

References :

Azizova T.V. et al. Multi-organ Involvement and failure in selected accident cases with acute radiation syndrome observed at the Mayak Nuclear Facility. The British Institute of Radiology.

Fliedner T. et al. Multi-organ involvement as a pathogenic principle of the radiation syndromes: a study involving 110 cases histories documented in SEARCH and classified as the bases of hematopoietic indicators of effect. The British Institute of Radiology, 2005, p.1-6.

Radiation Toxicity: Post-Radiation Inflammation.

Kalm M. Inflammation and behavior following irradiation-induced injury in the developing brain. Center for Brain Repair and Rehabilitation, Institute of Neuroscience and Physiology, SahlgrenskaAcademy, University of Gothenburg, Sweden, 2009.

Konchalovsky M. et al. Multiple Organ Involvement and failure: selected Russian radiation accident cases re-visited. The British Institute of radiology. 2005,pp.26-29.

Radiation Toxicity: Post-Radiation Inflammation.

Trot K. Radiation Risks from Imaging of Intestinal and Abdominal Inflammation.

Scandinavian Journal of Gastroenterology. 1994, vol. 29, No 203, pp. 43-47.

Van Der Kogel, A. Radiation-induced damage in the central nervous system: An interpretation of target cell responses. Br. J. Cancer Suppl. 7, 207–217 (1986).

Radiation Toxicity: Post-Radiation Inflammation.

Molla M, Panes J. Radiation-induced intestinal inflammation. World Journal of Gastroenterology, 2007, No 13, pp. 3043-3046.

Wasalenko J, McVittie T et al. Medical Management of the Acute Radiation Syndrome: Recommendations of the Strategic National Stockpile Radiation Working Group. 2004. Ann Int Med. No. 140, pp.1037-1051.

Radiation Toxicity: Post-Radiation Inflammation.

Molla M. et al. Influence of dose-rate on inflammatory damage and adhesion molecule

expression after abdominal radiation in the rat. International Journal of Radiation

Oncology and Biological Physics. 1999.45. pp.1011-1018.

[66] Linard C., et al. Acute induction of inflammatory cytokine expression after gammairradiation

in the rat: effect of an NF-kappa B inhibitor. International Journal of

Radiation Oncology and Biological Physics. 2004.58. pp.427-434.

Radiation Toxicity: Post-Radiation Inflammation.

Maliev V., Kirchin V., Popov D. Antiradiationvaccine. Herald of VSC of Russian

Academy of Science. 2003. № 3. P. 12–28.

Maliev V., Popov D., Casey R, Jones J. Mechanisms of Action for an Anti-Radiation

Vaccine in reducing the biological impact of high dose and dose-rate, low-linear energy transfer Radiation Exposure. J. Radiation Biology, v.47.N3. pp. 286-291.

Radiation Toxicity: Post-Radiation Inflammation.

Popov D., Maliev S. Antiradiation Vaccine: Immunological neutralization of Radiation Toxins at Acute Radiation Syndromes. 38th COSPAR Scientific Assembly. Held 18-15 July 2010, in Bremen, Germany, p.3.

Popov D., Maliev S. Radiation Toxins: Molecular mechanisms and radiomimetic properties. 38th COSPAR Scientific Assembly. Held 18-15 July 2010, in Bremen, Germany, p.3.

Popov D., Maliev S. Countermeasure development : Specific Immunoprophylaxis and

Immunotherapy of Combined Acute Radiation Syndromes. 38th COSPAR Scientific Assembly. Held 18-15 July 2010, in Bremen, Germany, p.3.