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 Table of Contents  
Year : 2018  |  Volume : 9  |  Issue : 1  |  Page : 4-12

Prophylactic strategies to minimize the effect of whole body irradiation on hematopoietic, gastrointestinal and respiratory system leading to morbidity/mortality in animals

Division of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organisation, New Delhi, India

Date of Web Publication22-Jan-2018

Correspondence Address:
Dr. Manju Lata Gupta
Division of Radioprotective Drug Development Research, Institute of Nuclear Medicine and Allied Sciences, Defence Research and Development Organisation, New Delhi
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jrcr.jrcr_2_18

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Increase in radionuclide application has gone far and wide in the last many decades; though its usage has benefited the society at large, however occasional unplanned exposure to radiation (terrorist/accidental) has also troubled human life. Exposure of humankind to nuclear disaster, accidental and natural background radiation exposure, has created the need to develop complete understanding of the subject and preparedness for having safe countermeasures. In whole-body radiation exposure scenario, all the three organs are responsible for leading the animal to its death; however, hematopoietic (HP) organ is the first to collapse followed by gastrointestinal (GI) and respiratory systems. Radiation-induced basic damage in these organs follows more or less similar pattern. Derangement starts with radiation-induced reactive oxygen species causing damage to DNA, lipids, and proteins and disturbing their regulatory pathways. However, damage in HP and GI is more rapid and severe due to the presence of highly radiosensitive multipotent stem cells essential to meet the need of high cell turnover rate in these organs. To overcome radiation-induced damage to these vital organs, serious efforts are continued globally to find safe remedial measure.

Keywords: Gastrointestine, hematopoietic, radiation, radioprotection, respiratory

How to cite this article:
Gupta ML, Verma S. Prophylactic strategies to minimize the effect of whole body irradiation on hematopoietic, gastrointestinal and respiratory system leading to morbidity/mortality in animals. J Radiat Cancer Res 2018;9:4-12

How to cite this URL:
Gupta ML, Verma S. Prophylactic strategies to minimize the effect of whole body irradiation on hematopoietic, gastrointestinal and respiratory system leading to morbidity/mortality in animals. J Radiat Cancer Res [serial online] 2018 [cited 2020 Jul 3];9:4-12. Available from: http://www.journalrcr.org/text.asp?2018/9/1/4/223743

  Introduction Top

Ionizing radiation has been known to cause multiorgan dysfunction syndrome which may majorly include hematopoietic (HP), gastrointestinal (GI), and respiratory systems. All the three organ systems are more or less equally sensitive to radiation; however, the onset of symptoms depends on radiation type, dose, and rate. On radiation exposure, GI and HP systems lead to acute radiation syndrome (ARS) including HP and GI subsyndromes. Single dose of whole-body irradiation of animals to >1 Gy is known to affect the HP system, while a dose of 7 Gy and above develops GI and respiratory syndromes and subsyndromes.

  Radiosensitivity of Hematopoietic System Top

HP system has been amply documented for its radiosensitive nature. Even low doses of radiation (1 Gy) are known to cause marked fall in circulating blood cell count.[1],[2] This occurs predominantly due to direct damage to the differentiated peripheral blood cells and compromised functionality of bone marrow progenitor cells, leading to thrombocytopenia, lymphopenia, and neutropenia.[3] High doses of radiation inflict severe damage to the HP system which is invariably irreparable. The entire lympho-HP system including lymph nodes, thymus, and spleen gets severely affected by radiation exposure. Differentiated blood cells present in the peripheral blood originate from HP stem cells (HSCs), which are otherwise inoperative under normal conditions and serve as a reservoir during various stressful conditions due to its self-renewal and differentiation property. These HSCs generate multipotential lineage-committed myeloid and lymphoid progenitor cells.[4] Nonavailability of a sufficient number of functional HSCs in the bone marrow and differentiated peripheral blood cells after radiation exposure leads to HP crisis. Several reports revealed that altered myeloid/erythroid ratio in the bone marrow of radiation-exposed animals [Figure 1] extends additional information about radiosensitivity of different cell lineages.[5],[6] High-radiation dose inflicts reduction not only in HSCs [Figure 1] but also in lymphocytes of spleen, thymus, and peripheral blood, which lead to lymphopenia-induced immunosuppression.[7]
Figure 1: An overall representation showing the effect of whole-body irradiation on bone marrow histology, cell counts and myeloid/erythroid ratio of mice exposed to 9 Gy whole-body irradiation. Data collated from an earlier published study (Verma et al., 2015)

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Regulation of radiation-induced HP injury involves multiple pathways such as oxidative stress, apoptotic, inflammatory, and antioxidant. Reactive oxygen species (ROS) function as signaling molecules in the induction of these pathways by reacting with cellular macromolecules such as DNA, proteins, and lipids. Ionizing radiation predominantly damages HSCs and progenitors (HSPCs) by a well-understood process of apoptosis.[8] Studies have demonstrated coordinated regulation of radiation-induced apoptotic signaling mediated by p53 and Bcl-2 family proteins.[9] Increased p53 upregulates pro-apoptotic proteins (Bax, Bak, and puma) and downregulates anti-apoptotic Bcl-2 family proteins (Bcl-2 and Bcl-xl). Radiation-influenced overexpression of pro-apoptotic proteins (p53, Bax, Bak, puma, caspase-3, and caspase-7) in the mouse bone marrow and spleen cells has been reported in a time-dependent manner.[10],[11]

Besides, retaining HSPCs functionality includes participation of many cell lineages, genes, cytokines, enzymes, and proteins working through various signaling pathways. The presence of CD34-, CD117-, and SCA1-positive cells in sufficient quantity is also an important indicator for the evaluation of functional status of HSPCs.[12],[13] Besides their viability and colony-forming ability, regulation capability of various growth factors by these cells is also inevitable. Among others, granulocyte-colony stimulating factor (G-CSF) and granulocyte-macrophage CSF (GM-CSF) are the important stimulants for granulocyte and macrophage colony-forming cells. These growth factors facilitate the functionality and survivability of erythroid progenitors, megakaryocytes, multipotential stem cell, mature neutrophils, etc., The presence of FMS-like tyrosine kinase (Flt-3) ligand has also been explored extensively to evaluate ionizing radiation-induced HP aplasia.[14],[15] This cytokine stimulates proliferation and differentiation of the bone marrow stem/progenitor cells of lymphoid and myeloid lineages. Radiation-induced damage does not only affect the precursor cells but also derange their microenvironment which is essential for proliferation and differentiation of these cells.[16] Postexposure-mediated severe drops in the peripheral blood cells invite various infections, leading to septicemia predominantly due to immunosuppression.[17] Histological findings of the femur bone [Figure 1], confirmed by many authors, have reported radiation-induced aplasia and vascular distortion demonstrated by the presence of large number of red blood cells.[6],[18],[19] HP damage deranges the whole system by halting immune machinery and distressing other organs by reducing their supply of required blood cells.

  Radiosensitivity of Gastrointestine Top

GI, one of the major governing organs for survival, is highly radiation susceptible.[20] Radiosensitivity of GI tract has been directly related to the presence of large number of stem cells residing in the crypt of Lieberkuhn located at the base of villus.[21] These stem cells untiringly populate the villus cells, being constantly vanishing from its tip.[22] High sensitivity of these cells toward radiation has been primarily because of their large proliferation rate and then finally opting for suicide rather than undergoing repair due to less probability of their error-free DNA repair.[21] Stem cells though located at different sites in both HP and GI, yet their function has intense similarity in proliferation. Single surviving clonogenic stem cell in the crypt is known to be capable of regenerating the entire crypt, which later supports repopulation of intestinal epithelium.[23]

Exposure to radiation results in fall in crypt cellularity which can be correlated with high apoptotic rate and suspended/reduced mitosis.[24] Decline in viable crypts and mitotic yield leads to gradual decrease in villous cell count. To temporarily compensate the deficit by dividing cells, the remaining surviving cells hyperproliferate leading to increase in crypt size.[23] After radiation exposure, crypt epithelial cells undergo p53-dependent apoptosis within short time of irradiation resulting in crypt shrinkage.[25] Inhibition of cell proliferation and differentiation by radiation causes shortening and rupturing of villi leading to the formation of lesions, promoting loss of fluids and electrolytes, inflammation, and septic shock. Denudation and abrasion of the mucosal lining invite infective microorganisms [Figure 2]. Intestinal mucositis symptoms occur after break down of epithelial barrier, making fluid loss, and inviting bacterial entry. Inflammation and electrolyte imbalance further intensifies the pathology leading to organ dysfunction.
Figure 2: Histological representation shows shortening and shortening and rupturing of villi, lacteal shrinking, mucosal denudation in the jejunum of irradiated mice exposed to10 Gy whole-body irradiation. The second panel indicates differential expression of protein spots at early time points in mice exposed to lethal (9 Gy) whole-body irradiation. Data collated from earlier published study (Sankhwar et al., 2012, Bajaj et al., 2014)

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Pathogenic mechanism of radiation-induced GI damage has been discussed by explaining radiation attack on clonogenic cells resting at the crypt of GI resulting into inadequate proximity of cells required by intestinal mucosal lining to maintain its daily wear and tear. Molecular mechanism responsible for radiation-induced damage in GI is a multifactorial phenomenon primarily based on ROS-induced activation of nuclear factor-κB (NF-κB) that further prompts inflammatory response.[26] Studies in GI epithelial cells in mice have shown increase in prostaglandin E2 levels post-γ-ray irradiation by enhanced cyclooxygenase (COX-2) expression.[27] Reports have shown inducible nitric oxide synthase (iNOS) with nitric oxide (NO) affecting the functionality of irradiated intestine.[28],[29] These studies demonstrate a collective role of iNOS, NF-κB, and COX-2 in inflammatory response regulation in GI upon irradiation.[29],[30] A study on irradiated mouse GI proteome has revealed upregulation of growth arrest and DNA damage-inducible 45 gamma (GADD 45ү), A disintegrin and metalloproteinase domain-containing protein 28 (ADAM 28), and heat shock protein beta-9 (HSP-9) proteins at early time points (24 and 72 h).[31] These proteins play a crucial role in regulating cellular stress responses and apoptosis (GADD 45ү); cell adhesions and enzymatic cleavage of membrane proteins (ADAM 28); and degradation of misfolded proteins by proteasome pathway formed due to radiation stress (HSP-9) [Figure 2].

Death due to GI syndrome is much faster due to strategic limitations in its rescue. HP injuries can be repaired by administration of cytokines and bone marrow transplantation; however, against GI damage so far, there is no reported modus operandi in place.

Clinically, radiation is of prime importance for cancer therapy and in diagnosis of other diseases. Irrespective of its medicinal importance and known effect on biochemical changes such as lipid, protein, and nucleic acid, profile of GI radiosensitive tissues cannot be ignored.[32] Though cancer treatment via radiotherapy has advanced by each passing year, still there are limitations in safe dose delivery.[33] While radiotherapy procedure in treating cancer in pelvic, bladder, and prostate region, the exposure to various areas in GI tract resulting in radiation-induced GI toxicity has been inevitable. Along with epithelial cells, GI tract also contains microvascular nerve networks, a variety of stromal and immune cells, which make its radiation-induced pathophysiology more complex.[34] Persistence of mucosal ulceration, atrophy, and fibrosis indicate late toxic effects of radiation exposure. These symptoms can lead to poor absorption and intestinal obstruction/perforation promoting gut microbiome by increasing bacterial growth resulting in almost nonfunctioning of the gut.[35] Cascading effect of whole body irradiation on other related organs (HP) leads to non-functionality of GI, resulting in difficult survivability of exposed animal/individual.

  Radiosensitivity of the Lungs Top

Radiosensitivity of respiratory system and its crucial role in survival has developed late understanding due to comparatively less proliferative and more differentiated cells present in this organ. Radiation-induced lung injuries are manifested in the form of pneumonitis and finally development of fibrosis in the tissue which is usually recognized as life-threatening.[36],[37] Besides reduction in carbon monoxide defusing capacity, radiation has also been associated with pneumonitis. However, in humans, this phenomenon includes many other factors such as smoking habits, age, gender, and genetic predisposition. The presence of tumor, if it is there, its size, site, and treatment regimen (radiotherapy and chemotherapy), also affects this. There are reports documenting increase in pneumonitis with radiation dose.[38],[39] Radiosensitivity of the lung is often considered as the major limiting factor in chest radiotherapy.[39] As reported in various studies [Figure 3], the chances of formation of radiation-induced ROS/reactive nitrogen species (RNS) are more in lungs due to high oxygen content in this organ.[40],[41],[42] Evidence has also documented the major role of NO in causing lung injuries. Reports have also revealed increase in NOS during enhanced oxidative index induced by radiation.[43],[44] Oxidative stress leads to nitrosative stress involving chain of reaction between RNS, NO, and peroxynitrite. Inhibition of iNOS isoforms is known to decrease NO production and therefore reducing lung damage.[45] Like many other organs, lungs have less compartmentalized defense mechanism against ROS and RNS species, formed postradiation exposure. Both the reactive species agitate alveolar epithelium and vascular endothelium cells, leading to recruitment of certain inflammatory cells such as neutrophils, macrophages, lymphocytes, and eosinophils which can be measured by bronchoalveolar lavage fluid (BALF) [Figure 3] and by histological studies.[46],[47] These inflammatory cells induce the release of cytokines like interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), IL-6, platelet-derived growth factor, transforming growth factor β1 (TGF β1), fibroblast growth factor (FGF). The presence of these cytokines consequentially compromises the functional status of lungs.[48] The appearance of fibrosis in irradiated lungs majorly gets regulated by overexpression of TGF-β1 which converts fibroblasts and other cell types into myofibroblasts and leads to deposition of collagen.[36],[48] Fibrosis can be detected by histological studies as well as by estimation of hydroxyproline content in the lung tissues [Figure 3].
Figure 3: An overall representation showing generation of reactive oxygen species/nitric oxide in bronchoalveolar lavage fluid, infiltration of inflammatory cells, and development of fibrosis in the lungs of mice exposed to 13 Gy local (thoracic) irradiation. Data are from earlier published study (Verma et al., 2017)

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In a study, mice exposed to lethal radiation have demonstrated the presence of several up- and down-regulated proteins at 24 and 48 h of postirradiation by performing proteomic profile of mice lung tissues.[49] Radiation-induced damage to DNA and upregulation of pro-apoptotic pathways lead to clonogenic death in lung epithelial cells. Consequences of DNA damage results in clonogenic death of epithelial cells and upregulation of pro-apoptotic pathways causing nonfunctionality of irradiated lungs. Pulmonary fibrosis occurring in irradiated lungs has been explained in many studies by excessive release of pro-inflammatory and proliferative molecules by the affected cells resulting in fibrosis. Clinically progressive fibrosis can be observed by the accumulation of interstitial fluid resulting in reduction in lung function. Reports on proteomics and pathway analysis carried out in lung cancer cell lines to identify the critical insights for lung carcinoma have reported these cells to be less tolerant to large doses of radiation.[50]

  Radioprotective Strategies Top

Efforts to explore safe strategies against radiation-induced biological tissue damage have been on since last many decades. Synthetic as well as natural remedies to reduce or prevent radiation inflicted damage have been proposed as translational strategies. Despite important findings in the relevant field, it has been difficult to translate the outcome of studies on radiation countermeasures for bedside usage. Search in this field initially started with synthetic compounds of thiol and sulfhydryl groups (AET, 5-hydroxytryptophan, mercaptoethylamine, cysteine, amifostine, etc.).[51],[52] However, efforts were discontinued without getting the desired product due to various limitations including their toxic behavior. Amifostine has been approved by the US-Food and Drug Administration to minimize radiation-induced adverse effects of radiotherapy during cancer treatment.[53] Mechanistically, amifostine, a thiol group compound, scavenges radiation-mediated free radicals which otherwise would attack on major cellular molecules such as DNA, lipids, and proteins and make the cell biologically inactive.[54] Vitamins such as A, E, and C, enzymes, i.e., glutathione (GSH), superoxide dismutase (SOD), catalase, and minerals such as manganese, calcium, and selenium have also been part of test items as radioprotector but could not be converted into final products due to various limitations. Owing to safe nature, immense antioxidant potential and many other pharmacological properties, various natural preparations are under extensive study as radiation countermeasures in last more than a decade.[7],[55],[56],[57] Various preparations of bioactive molecules such as podophyllotoxin, podophyllotoxin glycoside, and rutin in different combinations have shown protection to mouse bone marrow, HP, GI, and pulmonary systems.[29],[58],[59],[60],[61] The protective action of these formulations has been due to their multitasking potential such as free radical scavenging, arresting the dividing cells at the most radiosensitive phase of cell division, i.e. G2-M, upregulation of apoptotic and inflammatory pathways.[29],[59],[62] Whole-body survival in mouse exposed to lethal dose of ionizing radiation has also been repeatedly shown by these authors using reported bioactive molecules in combination.

Radiation-induced reactive oxygen and nitrogen species activates various signaling pathways through redox-sensitive transcription factors and pro-inflammatory cytokines moving the cells into apoptosis and subsequent death.[63] These species are detoxified by a variety of antioxidants present endogenously in biological system. GSH reductase (GR) regenerates reduced form of GSH from its oxidized form and is essential for cell to combat oxidative stress.[64] SOD helps in metabolism of hydrogen peroxide (H2O2) by reducing superoxide radical to H2O2. Reports have revealed depletion of cellular antioxidants such as SOD, GSH, and GR in the serum of whole-body-irradiated mice and their upregulation by exogenous agents.[6],[65] Manganese SOD has also been shown as one of the radioprotector strategies at cellular level.[66]

HP system being most radiosensitive even to small doses of radiation in rodents has been shown recovered with exogenous intervention of cytokines and HP growth factors such as GM-CSF, G-CSF on tocopherol succinate has revealed enhanced G-CSF leading to 30 days whole-body survival in irradiated mice against HP syndrome.[67] The report has demonstrated significantly enhanced survival in those mice which had received transfused blood from tocopherol succinate-treated mice. The results further revealed that infusion of HSCs enrich peripheral blood monolayer cells from tocopherol succinate-treated mice improved survival of lethally irradiated mice.[67] Our very recent studies (unpublished data) have also demonstrated significant increase in serum G-CSF in lethally irradiated mice. Although 83% mice from lethally irradiated group survived during the observation period (60 days), their blood cell count also increased after 15 days of experimentation. However, it is too early to comment if survival was directly dependent on upregulated G-CSF until we do more experiment by inhibiting G-CSF increase. We also observed enhanced NF-κB in these mice. Gamma-tocotrienol has also been shown effectively working against ARS.[68]

GI radioprotection has been reported by transforming FGF2 and cytokines and stem cell factor (CSF);[69] however, their poor cost-effectiveness and short shelf life besides other limitations have affected their usage. Gamma-tocotrienol has been reported to alleviate intestinal radiation injury and reduce vascular oxidative stress mediated by whole-body exposure to 8 Gy.[70] Initial studies on combination of gamma-tocotrienol and amifostine have also been shown for optimal radioprotection along with reduced toxicity.[71] IL-11, amifostine, prostaglandins, and nutraceuticals (Vitamin A and E) are also shown as radioprotector to GI.[72] A very recent study has demonstrated radioprotective potential of G-003M, a combination of podophyllotoxin and rutin, for its effective protection to GI in whole-body lethally irradiated mice by reducing inflammation and apoptosis by negative regulation of NF-κB and p53 signaling pathways.[29]

Lung injuries by radiation have been found significantly reduced due to exogenous intervention of antioxidant molecules/enzymes by inhibiting radiation-induced ROS/RNS reactive species.[73] Radiation-mediated inflammatory cells in lung parenchyma lead to production of inflammatory cytokines, TNF-α in specific is an important cytokine known to trigger the production of other pro-inflammatory cytokines.[74] TGF-β1, an important mediator in development of pulmonary fibrosis, also activates a variety of pro-inflammatory and fibrogenic cytokines such as TNF-α, IL-1 β, and IL-13 which further perpetuates the fibrotic cascade.[75],[76] Prophylactic administration of a formulations, prepared by combining podophyllotoxin and rutin (G-003M), has been reported to reduce ROS/NO in BALF cells of irradiated mice lungs.[41],[42] The study has also reported inhibition of inflammatory cytokines in BALF besides reduction of fibrosis by inhibiting TGF-β1 in irradiated mice by preadministration G-003M.[42] The intraperitoneal administration of recombinant transforming factor-b3 after irradiation has been shown for a key regulatory role in pulmonary fibrosis developed by single localized exposure of 20 Gy.[77] Suppressed Th1 and enhanced Th2 in b3-treated mice has demonstrated increase in ILs suggesting that TGF-β3 might be involved in the regulatory mechanism for attenuation of radiation-induced pulmonary fibrosis.

  Conclusion and Perspectives Top

Conclusively, morbidity/mortality in whole-body-irradiated animals depends more on cumulative effects of radiosensitive organ systems (HP, GI, pulmonary system) rather than any individual organ. It is a well-demonstrated fact that vitality of any biological systems depends on its neighboring organ's functionality. Radiation-induced damage, irrespective to the organ, occurs by free radicals formation and their cascading effects. These reactive species deforms DNA, lipids, and proteins, the most vital entities of all the living cells.

Stem cells, existing in proliferative region of the body and responsible to form differentiated cells, are highly sensitive to radiation. To retain their viability and functionality, microenvironment of these cells, majorly formed by cytokines and ILs, is essential to be maintained. Therefore, the agents which can successfully protect stem cells regulate DNA damage and repair; antioxidant, anti-inflammatory, and immune-modulatory pathways can be the ultimate answer against radiation [Figure 4].
Figure 4: Damage interaction between hematopoietic, gastrointestinal, and respiratory systems on whole-body irradiation

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We acknowledge all the authors whose work has been cited in the manuscript.

Financial support and sponsorship

MLG supported by DRDO programme TD15-INM313 (Rakshak).

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]

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