Radiation, Radiation Toxins, Lipid, Oxidation, Reactive Oxigen Species, Radiation Toxicity, Acute Radiation Syndromes,

1. Dmitri Popov. PhD, Radiobiology. MD (Russia)
Advanced Medical Technology and Systems Inc.
Canada.

2. Radiation Toxicity: Lipid’s Radiation
Toxins.
 Exposure to radiation induces generation of
reactive oxygen species (ROS) especially hydroxyl
radical
 (·OH) and peroxyl radical (ROO·), which are
capable of inducing lipid peroxidation.
B. Lakshmi et al. CURRENT SCIENCE, VOL. 88, NO.
3, 10 FEBRUARY 2005

3. Radiation Toxicity: Lipid’s Radiation
Toxins.
 Exposure of a cell to radiation can both directly and indirectly
alter molecules within the cell to affect cell viability. Radiation
energy absorbed by tissues and fluids is dissipated by the
radiolysis of water molecules and biomolecules. These reactions
result in redox-reactive products such as hydroxyl radical (HO*),
hydrogen peroxide (H2O2), hydrated electron (e-aq), and an
array of biomolecule-derived carbon-, oxygen-, sulfur-, and
nitrogen-centered radicals (i.e., RC*, RO*, RS*, and RN*) that
can in turn lead to the formation of organic peroxides and
superoxide anion radicals ( O2*- ) in the presence of molecular
oxygen. Jay A, LaVerne JA. OH Radicals and Oxidizing Products
in the Gamma Radiolysis of Water. Radiation Research. 2000;
153:196-200.

4. Radiation Toxicity: Lipid’s Radiation
Toxins.
 While the strongly electrophilic HO* has the capacity
to damage molecules like polypeptides, amino acids,
and polyunsaturated fatty acids (PUFAs) directly, the
alterations caused by peroxide and superoxide radicals
are usually produced indirectly via Fenton-type
reactions. Juliann G. Kiang, Risaku Fukumoto and
Nikolai V. Gorbunov. http://dx.doi.org/10.5772/48189

5. Radiation Toxicity: Lipid’s Radiation Toxins.
 Lipid A is a lipid component of an endotoxin held
responsible for toxicity of Gram-negative bacteria. It is
the innermost of the three regions of
the lipopolysaccharide(LPS, also called endotoxin)
molecule, and its hydrophobic nature allows it to
anchor the LPS to the outer membrane. While its toxic
effects can be damaging, the sensing of lipid A by the
human immune system may also be critical for the
onset of immune responses to Gram-negative
infection, and for the subsequent successful fight
against the infection.
http://en.wikipedia.org/wiki/Lipid_A.

6. Radiation Toxicity: Lipid’s Radiation
Toxins.

7. Radiation Toxicity: Lipid’s Radiation
Toxins.

8. Radiation Toxicity: Lipid’s Radiation Toxins. Infections and Radiation share
similar mechanisms of protease activation, transcription of pro-inflammatory
proteins, development of apoptosis or necrosis.

9. Radiation Toxicity: Lipid’s Radiation
Toxins.
 http://www.scielo.br/scielo.php?pid=S1806-
37132009001200011&script=sci_arttext&tlng=en
 http://www.jlr.org/content/39/8/1529/F6.expansion
 http://www.nature.com/cdd/journal/v19/n11/fig_tab/c
dd201274f8.html
 http://www.cosmobio.co.jp/export_e/products/detail/
products_nns_20060421_1.asp?entry_id=5540

10. Lipid A.

11. Lipid A. Synthetic form.

12. Radiation Toxicity: Lipid’s Radiotoxins.
 Many of the immune activating abilities of LPS can be
attributed to the lipid A unit. It is a very potent
stimulant of the immune system, activating cells (for
example, monocytes or macrophages) at picogram per
milliliter quantities.
 When present in the body at high concentrations
during a Gram-negative bacterial infection, it may
cause shock and death by an "out of control" excessive
immune reaction.
http://en.wikipedia.org/wiki/Lipid_A.

13. Radiation Toxicity: Lipid’s Radiation Toxins.
 Lipid A consists of two glucosamine (carbohydrate/sugar)
units with attached acyl chains ("fatty acids”), and
normally containing one phosphate group on each .
carbohydrate
 The optimal immune activating lipid A structure is
believed to contain 6 acyl chains. Four acyl chains
attached directly to the glucosamine sugars are beta
hydroxy acyl chains usually between 10 and 16 carbons in
length. Two additional acyl chains are often attached to the
beta hydroxy group. E. coli lipid A, as an example, typically
has four C14 hydroxy acyl chains attached to the sugars and
one C14 and one C12 attached to the beta hydroxy groups.

14. Radiation Toxicity: Lipid’s Radiation Toxins.
 Lipid A with a reduced number of acyl chains (for
example; four) can serve as an inhibitor of immune
activation induced by Gram-negative bacteria, and
synthetic versions of these inhibitors are in clinical
trials for the prevention of harmful effects caused
by Gram-negative bacterial infections.
 On the other hand, modified versions of lipid A can be
used as components of vaccines (adjuvants) to
improve their effect

15. Radiation Toxicity: Lipid’s Radiation Toxins.
 Lipid A (and LPS) has been demonstrated to activate
cells via Toll-like receptor 4 (TLR4), MD2 and CD14on
the cell surface (Poltorak, Beutler et al., Blood Cells
Mol Dis 1998)(Beutler, Poltorak, J Endotoxin Res
2000)(Park et al., Nature 2009). Consequently, lipid
A analogs like eritoran can act as TLR4 antagonists.
They are being developed as drugs for the treatment of
excessive inflammatory responses to infections with
Gram-negative bacteria.

16. Radiation Toxicity: Lipid’s Radiation
Toxins.
 Clinical symptoms induced by Bacterial
Superantigene:
 Central Nervous System involvement
 Peripheral nervous system
 Confusion, Irritability, Lethargy
 Cardio-Vascular System involvement
 Systolic Blood Pressure :< 90 mmHg
 Tachycardia >100 beats/min,
 Hypotension, Hyperventilation, Loss of
 Sympathetic responsiveness .

17. Radiation Toxicity: Lipid’s Radiation
Toxins.
 Clinical symptoms induced by Bacterial
Superantigene:
Gastro-Intestinal System Involvement
 Vomiting, diarrhea, hematochezia and
 stool mucous (depending on which
 enteric toxin).
 Bacterial Superantigen hematotoxicity
 Thrombocytopenia, Platelet count <
 100,000/mm3.- Thrombocytopenia.,
 leukopenia, pancytopenia. Disseminated
 Intravascular Coagulation (DIC)
Syndrome.

18. Radiation Toxicity: Lipid’s Radiation
Toxins.
 Clinical symptoms induced by Bacterial
Superantigene:
 Cutaneous involvement: diffuse
 maculopapular, petechial or ecchymotic
 rash, intense erythroderma,
 desquamation (e.g. meningococcemia or
 toxic shock syndrome).

19. Radiation Toxicity: Lipid’s Radiation
Toxins.
 Clinical symptoms induced by Bacterial
Superantigene:
 Multiple Organ Failure and Multiple Organ
Involvement.
 Renal failure, Renal hypo-perfusion;
 Oliguria, Acute tubular necrosis.
 Hepatic failure and inflammation.

20. Radiation Toxicity: Lipid’s Radiation
Toxins.
 Clinical symptoms induced by Bacterial
Superantigene:
 Pulmonary System:
 Hyperventilation with
 Respiratory alkalosis, pulmonary
 hypertension and edema,
 hypoxemia, ARDS

21. Radiation Toxicity: Lipid’s Radiation
Toxins.
 CNS involvement: Cerebro-Vascular Acute
 Radiation Syndrome. Radiation Induced
 Neurotoxin. Neurological and Cognitive
 Deficit, Vomiting. Severe form of brain
 microcirculation disorder. Clinical futures of
 hemorrhagic stroke.

22. Radiation Toxicity: Lipid’s Radiation
Toxins.
 Cardio-Vascular System involvement:
 Cardio-vascular Radiotoxin-induced Acute
 Radiation Syndrome.- Tachycardia,
 Bradicardia, Arrythmias, Hypertension
 followed by severe hypotension
 (Systolic Blood Pressure:< 80 mmHg),
 hyperventilation.

23. Radiation Toxicity: Lipid’s
Radiation Toxins.
 Gastro-intestinal System Involvement:
 Gastro-Intestinal Acute Radiation Disease.
 Radiotoxin. Vomiting, diarrhea. Melena and
 hematochezia. Abdominal pain- moderate to
 severe.

24. Radiation Toxicity: Lipid’s
Radiation Toxins.
 Hematopoietic Toxicity:
 Acute Radiation Hematopoetic Syndrome.
 Hematopoietic Radiation Toxin-
 Thrombocytopenia, Lymphocytopenia,
 Granulocytopenia. Pancytopenia.

25. Radiation Toxicity: Lipid’s
Radiation Toxins.
 Cutaneous System Involvement:
 Possibleaction of any type of Radiation
 Toxins. Swelling, edema, blustering,
 desquamation, hair loss, ulceration
 and skin necrosis

26. Radiation Toxicity: Lipid’s
Radiation Toxins.
 Multiple Organ Failure and Multiple Organ
 Involvement.
 Renal failure, renal hypo-perfusion,
 Acute tubular necrosis.
 Hepatic failure
 Pulmonary System:
 Hyperventilation.
 Radiation induced pneumonitis and
 subsequent pneumonia, ARDS.

27. Radiation Toxicity: Lipid’s
Radiation Toxins.
 Comparative analysis of clinical symptoms induced by
radiation and/or Radiation
 Toxins – (SRD group 1-4)- induced ARS and those
produced by Toxic Shock Syndrome
 induced by Bacterial Superantigene

28. Radiation Toxicity: Lipid’s Radiation
Toxins.
 Biochim Biophys Acta. 1987 Oct 16;903(3):519-24.
 Radioprotective effects of lipid A, liposomes, and
liposomes containing lipid A in mice.
 Richardson EC1, Alving CR.

29. Radiation Toxicity: Lipid’s Radiation
Toxins.
“Lipid A from Gram-negative bacterial
lipopolysaccharide (endotoxin) was incorporated into
liposomal membranes and examined as a prophylactic
radioprotectant compound in lethally irradiated mice.
Splenic hematopoietic activity, resulting in increased
numbers of spleen cell colonies, was induced both by
lipid A alone or more strongly by liposomal lipid A.
Increased survival of lethally irradiated animals was
induced to a slight extent by liposomes alone, to a
greater extent by lipid A, and at the highest level by
liposomes containing lipid A.”

30. Radiation Toxicity: Lipid’s Radiation
Toxins.
 “Under conditions where 100% of untreated or saline-
treated animals died of acute radiation syndrome after
20 days, more than 90% of the animals pretreated with
liposomal lipid A were still alive 30 days after
irradiation. We conclude that lipid A had substantial
radioprotectant activity by itself, and the activity was
enhanced by incorporation into liposomes. Liposomes
alone also exhibited mild radioprotectant effects.”