Radiation Toxicity: Lipid’s Radiotoxins.

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

Inc. Canada.

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

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.

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

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.

Radiation Toxicity: Lipid’s Radiation Toxins.

Radiation Toxicity: Lipid’s Radiation Toxins.

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.

Radiation Toxicity: Lipid’s Radiation Toxins.http://www.scielo.br/scielo.php?pid=S1806-3

7132009001200011&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/cdd201274f8.html

http://www.cosmobio.co.jp/export_e/products/detail/products_nns_20060421_1.asp?entry_id=5540

Lipid A.

Lipid A. Synthetic form.

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.

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.

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

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.

Radiation Toxicity: Lipid’s Radiation Toxins.Clinical symptoms induced by Bacterial Superantigene: Central Nervous System involvementPeripheral nervous systemConfusion, Irritability, LethargyCardio-Vascular System involvementSystolic Blood Pressure :< 90 mmHgTachycardia >100 beats/min,Hypotension, Hyperventilation, Loss ofSympathetic responsiveness .

Radiation Toxicity: Lipid’s Radiation Toxins.Clinical symptoms induced by Bacterial Superantigene: Gastro-Intestinal System InvolvementVomiting, diarrhea, hematochezia andstool mucous (depending on whichenteric toxin).Bacterial Superantigen hematotoxicityThrombocytopenia, Platelet count <100,000/mm3.- Thrombocytopenia.,leukopenia, pancytopenia. DisseminatedIntravascular Coagulation (DIC) Syndrome.

Radiation Toxicity: Lipid’s Radiation Toxins.Clinical symptoms induced by Bacterial Superantigene: Cutaneous involvement: diffusemaculopapular, petechial or ecchymoticrash, intense erythroderma,desquamation (e.g. meningococcemia ortoxic shock syndrome).

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.

Radiation Toxicity: Lipid’s Radiation Toxins.Clinical symptoms induced by Bacterial Superantigene: Pulmonary System:Hyperventilation withRespiratory alkalosis, pulmonaryhypertension and edema,hypoxemia, ARDS

Radiation Toxicity: Lipid’s Radiation Toxins.CNS involvement: Cerebro-Vascular AcuteRadiation Syndrome. Radiation InducedNeurotoxin. Neurological and CognitiveDeficit, Vomiting. Severe form of brainmicrocirculation disorder. Clinical futures ofhemorrhagic stroke.

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

Radiation Toxicity: Lipid’s Radiation Toxins.Gastro-intestinal System Involvement:Gastro-Intestinal Acute Radiation Disease.Radiotoxin. Vomiting, diarrhea. Melena andhematochezia. Abdominal pain- moderate tosevere.

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

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

Radiation Toxicity: Lipid’s Radiation Toxins.Multiple Organ Failure and Multiple OrganInvolvement.Renal failure, renal hypo-perfusion,Acute tubular necrosis.Hepatic failurePulmonary System:Hyperventilation.Radiation induced pneumonitis andsubsequent pneumonia, ARDS.

Radiation Toxicity: Lipid’s Radiation Toxins.Comparative analysis of clinical symptoms

induced by radiation and/or RadiationToxins – (SRD group 1-4)- induced ARS and

those produced by Toxic Shock Syndromeinduced by Bacterial Superantigene

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.

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.”

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.”