Molecular Action Of Ionizing Radiation Pdf Download
The main target of radiation therapy is the DNA. Ionizing radiation causes direct damage by destroying chemical bonds and knocking out electrons. Ionizing radiation also causes indirect damage through generation of reactive oxygen species (ROS) . When ROS outweigh antioxidants, oxidative stress arises. ROS injure cellular macromolecules e.g. lipids, proteins or DNA [17, 18]. DNA double-strand breaks (DSB) are the most severe event of RT . Cells sense DSB by a system called DNA damage response (DDR). The DDR is initiated within minutes after irradiation and activates cell cycle checkpoints and DNA repair in order to achieve survival. When reparation processes are unsuccessful, DSB finally cause genomic instability, cell death, or cellular senescence . The reaction to DSB depends on the affected tissue and the integration of DDR in the affected cells. In rapidly reproducing tissues (such as the targeted tumour cells, but also hematopoietic cells and mucosal epithelium) unrepaired DSB and subsequent rounds of aberrant mitosis culminate in a morphotype of mitotic catastrophe and cell death . This reflects the therapeutic benefit with killing of tumour cells, but also the acute clinical toxicity of radiotherapy as a consequence of normal tissue cell death. This usually takes place within the first two weeks. Slowly reproducing tissues (such as fibroblasts) rather react with prolonged cell cycle arrest instead of cell death induction . While acute radiation toxicity is marked by acute cell death, the processes in chronic toxicity are generally characterized by fibrogenesis and extracellular matrix deposition. Those processes are most likely secondary through chronic inflammation and cellular senescence . Inflammation is present for example in gastrointestinal  and lung  radiation injuries. Fibrotic reorganisation leads to degeneration and decline of the specific organ function .
Molecular Action Of Ionizing Radiation Pdf Download
In RN, the initial renal cell injury, which may start the cascade towards CKD, are DSB of the DNA through ionizing radiation, either by direct ionization events in the DNA or indirectly via mediation of water ionization products and/or reactive oxygen species  (Fig. 1). This acute DNA damage can cause immediate cell death in the kidney [62,63,64]. In cancer patients undergoing RT, transcriptome profiling studies show nephrotoxicity with upregulation of genes for renal necrosis and apoptosis . In cells surviving the acute phase, DNA repair mechanisms are highly activated . Even when cells do not die from acute damage, misrepaired DSB can still induce cell death or cellular senescence in the long term . Cytokines released upon cell death , cellular senescence , and ionizing radiation itself  trigger chronic inflammation. Finally, chronic inflammation and cellular senescence may lead to renal fibrosis .
However, it is important to understand the difference between OS generated promptly after the irradiation and OS in the latent period of RN. In order to prove, that OS plays a role in the aetiology of chronic radiation nephropathy, OS needs to be present in the latent period. Such data are rare and still conflicting. Zhao et al. hypothesised that chronic OS is responsible for RN. The authors showed upregulated DNA oxidation in viable glomeruli and tubuli in rats 4 to 24 weeks after single dose irradiation with 20 Gy . By contrast, Lenarczyk et al. found no evidence for chronic OS in the latent period in rats that underwent TBI with either 18.8 Gy in 6 fractions or 10 Gy in a single dose. There was no evidence for lipid peroxidation or protein oxidation in the urine in the first 42 days. After 89 days renal tissue did not show evidence of DNA or protein oxidation . Likewise gene expression analysis revealed no relevant increase in genes related to OS in the first 49 days after single-dose TBI with 10 Gy . Rats became symptomatic with proteinuria approximately 6 weeks after irradiation and uremic morbidity occurred after 26 weeks. Hence, the investigated time points were in the latent phase of experimental RN, showing no evidence for OS in the latent period.
RAAS-inhibition is also beneficial in radiation injuries in lungs  and brain . These findings urgently raise the question, whether RAAS plays a mechanistic role in RN after RT. So far, no solid evidence for RAAS-induction in RN exists. Cohen et al. showed no RAAS-activation at all with normal renin activity, normal renin protein levels, and normal values for serum and intrarenal AT II after 17 Gy TBI in 6 fractions . Renal cell membrane AT II receptor binding was equally seen in rats after TBI with 18.8 Gy or 20.5 Gy given in six fractions over 3 days and the control group . Aldosterone is a peripheral component of the RAAS-system involved in various types of renal injuries . In one study no elevation in aldosterone was shown after 10 Gy single-dose TBI in rats and the aldosterone-antagonist spironolactone did not mitigate RN . However, another group found spironolactone to mitigate RN after internal alpha-particle irradiation in mice . It seems, that just like AT II-blockade, aldosterone-antagonists may mitigate RN, although aldosterone itself is not upregulated.
The clearly beneficial effect of RAAS-inhibition with no measurable increased RAAS-activity suggests that either normal RAAS-activity is harmful in irradiated subjects or RAAS-opposing systems such as nitric oxide (NO) decrease after irradiation . There is evidence of NO-reduction in RN in rats after 17 Gy TBI in 6 fractions over 3 days, and RN could be mitigated by captopril . In general, RAAS-inhibition stabilizes progress of numerous kidney diseases of different aetiologies. Its nephroprotective effect is mediated by the reduction of intraglomerular pressure and hence reduced proteinuria with consecutively less tubulointerstitial damage . In conclusion, RAAS-inhibition might have a protective effect by reducing intraglomerular pressure, renal fibrosis, and balancing the NO-reduction in RN. RAAS blockade is therefore a very promising strategy for RN therapy.
Cellular senescence (CS) is the combination of cell cycle arrest, suppression of apoptotic pathways, a high metabolic activity and a senescence-associated secretory phenotype (SASP). SASP includes an increased secretion of IL-1, IL-6, IL-8, connective tissue growth factor, transforming growth factor, vascular endothelial growth factor and TNF-α [104, 105]. While it is part of the normal chronological aging process, characterized by the attrition of telomeres, premature senescence is induced by stress factors, such as ionizing radiation directly or indirectly by OS [106, 107]. In the brain , heart  and lungs  CS contributes to radiation-induced organ damage. In CKD of other aetiologies than CRN, CS is also a suggested pathomechanism . In experimental RN with single-dose 18 Gy in rats, CS has been shown in glomerular endothelial cells and in podocytes of rats, underlining the impact of CS in RN. Glomerular endothelial injury was dominant, resulting in an increase in thrombotic microangiopathy, collapsing glomeruli, and a decreased number of endothelial cells in experimental RN. The renal cells demonstrated upregulated markers of cellular senescence (p53, p21, p16), cell cycle arrest, and had a SASP with increased IL-6 secretion. TNF-α, IL-8, and VEGF-A secretion were not significantly increased. Glomerular damage and impairment of kidney function were found in this experimental model of RN . Thus, cellular senescence seems to be activated in RN.
Inflammation has been proposed as a mechanism for RN because it is present in other radiation injuries such as gastrointestinal radiation injury  and radiation pneumonitis . Furthermore, mechanistically inflammation links renal cell injury and CKD. Necrotic tubular cells release damage-associated molecular patterns (DAMPs) and trigger secretion of pro-inflammatory cytokines and chemokines in tissue-resident cells and recruited leukocytes . Macrophages for example produce cytokines such as TNF-α and IL-6. These inflammatory responses lead to even more cell death and fuel a viscous cycle of cell death and inflammation , followed by a decline in kidney function and the initiation of renal fibrosis . However, there is only little data on active inflammation in RN. Pro-inflammatory cytokines, such as TNF-α, IL-1β and interferon-γ were found to be the primary upstream regulators of the upregulated transcripts in mice after 177Lu-Octreotate-admission . TNF-α expression levels increased and correlated with the metabolic activity detected in [18F]-FDG-PET-CT in tibet mini pigs after 2, 5, 8, 11 and 14 Gy single-dose TBI . Further evidence for the involvement of inflammation in RN derives from the observation that montelukast was able to mitigate RN in mice after 3 Gy single-dose TBI in a dose-dependent way . Montelukast has anti-inflammatory effects via inhibition of nuclear factor-κB activation and reduction of anti-inflammatory cytokines, such as TNF-α and IL-6 .
Although data on the molecular and cellular pathomechanisms in radiation-induced kidney toxicity exist, they are rare. To date, the precise signalling and pathomechanisms are not fully understood. There is some patient data, but most of it comes from experimental models (mostly rats and non-human primates). Ionizing radiation application schemes and doses vary, which further complicate comparability. In many aspects, RN has common features with acute kidney injury transforming into chronic kidney disease. The acute stimulus in RN is ionizing radiation, and the common final stage is renal fibrosis with organ atrophy and decline of kidney function. Oxidative stress and inflammation were proposed to be relevant pathomechanisms in the latent phase, but no solid evidence is present for either of them.
The international unit of measure for absorbed radiation (radiation dose) is the gray (Gy), defined as J/kg of mass. Since equal doses of IR elicit differential effects depending on source and properties of the biological target, the unit of sievert (Sv) is used to express the equivalent dose. Individuals receive an average of 2.4 mSv per year of IR from natural sources, though this figure is increased in more developed nations (173). While natural sources of gamma rays (K-40) exist, gamma rays most widely used in research and therapies are from manmade sources such as Co-60 and Cs-137. The focus of this review will be primarily on the interactions of gamma rays with biological macromolecules, though references to other types of radiation are included where relevant.