Repeated dose toxicity studies of Trichostatin A in Swiss albino mice through oral and intravenous route of administration with special emphasis on genotoxicity.

Intravenous and oral 14 d repeated dose toxicity studies of Trichostatin A (TSA) were carried out in Swiss albino mice using low, intermediate, and high doses. Intravenous doses were 10, 25, and 50 µg/kg b.w while the oral doses were 20, 50, and 100 µg/kg b.w. Respective control groups of mice were administered phosphate buffered saline (vehicle only) for 14 consecutive days. All external morphological, hematological, biochemical, urine, histopathological, food intake in addition to body weight and vital organ weight were recorded. During the study no mortality in any animal was observed in either treatment routes. There were no significant changes in morphology, food intake, hematology, biochemical, urine analysis, organ weight. Animals treated high dose of TSA intravenously (50 µg/kg b.w) and orally (100 µg/kg b.w) had enlarged, congested, and discolored kidneys which were statistically significant. Histopathological studies had shown statistically significant degenerated glomerulus in high dose of intravenous and orally treated animals and degenerated tubule were found in orally treated animals. Genotoxicity was evaluated using micronucleus frequency at 14 and 21 d after treatment and chromosomal aberration at 21 d after treatment. Micronucleaus assay and chromosomal assay however did not show any significant changes at any doses and administration routes. Therefore, this study concludes that dose ∼25 µg/kg and ∼50 µg/kg b.w may be considered as No Observed Adverse Effect Level (NOAEL) for intravenous and oral administration of TSA respectively.

Sulforaphane inhibits histone deacetylase causing cell cycle arrest and apoptosis in oral squamous carcinoma cells.

Background: Biologic compounds have recently generated interest in cancer chemoprevention. Sulforaphane (SFN), an isothiocyanate from cruciferous vegetables, has profound epigenetic actions. Since epigenetic aetiology is crucial for oral cancer, this study evaluated the role of SFN in oral cancer prevention. Methods: Oral squamous cell carcinoma cells (UPCI-SCC-172) were treated with SFN in three concentrations: 10 µM, 20 µM and 30 µM for two time periods: 24 h and 48 h. MTT assay assessed cell proliferation. Histone deacetylase (HDAC) enzyme activity was colorimetrically estimated in the nuclear extracts. Flow cytometry determined cell cycle stages, reactive oxygen species (ROS) generation and mitochondrial membrane potential (MMP) changes. Extrinsic and intrinsic apoptotic pathways were evaluated from caspase enzyme assays. Results: Cell proliferation and HDAC activity (44% in 24 h and 40% in 48 h) were significantly inhibited (p < 0.01). For 10 µM concentration, G2/M cell cycle arrest was found with a reduction in G1 phase cell population at 24 h and 48 h. Concentrations of 20 µM and 30 µM SFN presented cells in apoptosis marked by increased sub G1 cells at 48 h. Concentrations of 10 µM and 20 µM SFN showed a 1.3 to 2.8-fold increase in ROS generation at 24 h and 48 h. The concentration of 30 µM SFN showed a drop in ROS production, denoting cells already in apoptosis. Fall in MMP was also dose- and time-dependent. Caspase enzyme assays (p < 0.001) demonstrated activation of both extrinsic and intrinsic apoptotic pathways. Conclusion: Inhibitory action of SFN on oral cancer cell proliferation and HDAC activity led to cell cycle arrest and apoptosis. These effects marked by increase in ROS, a decrease in MMP and activation of apoptotic pathways offer exciting therapeutic options.

COVID-19 lockdown and environmental pollution: an Indian multi-state investigation.

Originating from China, COVID-19 became the first-ever coronavirus pandemic, wreaking havoc in 218 nations. The lack of a potential treatment exacerbated by the inability of the healthcare infrastructure to contain the viral trajectory led to a worldwide lockdown. The anthropogenic halt presented an unprecedented background to quantify the effect of the anthroposphere on environmental pollution. Consequently, we analyzed the variations in the air (PM10, PM2.5, NO2, SO2) and water pollutants (BOD, COD, DO, coliform) using real-time monitoring data in the majorly hit Indian metropolitan states during the lockdown in contrast to 2019 levels. The overall AQI (air quality index) de-escalated by -31.35%, -34.35%, -32.63%, -29.25% in Delhi, Tamil Nadu, West Bengal, and Karnataka, respectively, from the 2019 levels. The daily concentrations of NO2, PM2.5, and PM10 plunged tremendously. The exact pre-disposing factors responsible for higher COVID-19 transmission in some geographical centers remain elusive. Investigations have corroborated putative links between air pollutants and COVID-19 mortalities. Therefore, we further mapped PM2.5, PM10, NO2, and SO2 to co-relate with COVID-19 infectivity and mortality across the study states. Significant (P < 0.001) positive correlation between COVID-19 transmission was established for all pollutants with maximum co-relation with AQI followed by NO2. River Ganga water in Uttarakhand was deemed "fit for drinking" for the first time in two decades. An aggregate of -71.94, -61.32, and -77.94 decrease in BOD, COD, total coliform levels, and an 11.75 rise in the average DO levels from 2019 data. This study will better assist the future framework of health and environment restoration policies.

Trichostatin A mitigates radiation-induced teratogenesis in C57Bl/6 mice.

Radiation exposure in utero is known to lead to serious concerns to both the mother and children, including developmental anomalies in the children. In the recent past, trichostatin A, an HDAC (histone deacetylase) inhibitor and epigenetic modifier, has been shown to mitigate radiation-induced anomalies in the male reproductive system of C57BL/6 mice. Therefore, the current study was undertaken to evaluate the mitigating effects of trichostatin A (TSA) against radiation-induced developmental anomalies in mice. Foetuses of in utero whole-body gamma-irradiated mice during the active organogenesis period were examined for developmental anomalies at 8.5 and 18.5 days of gestation. In utero radiation exposure caused developmental anomalies like microcephaly, microphthalmia, gastroschisis and kinky tail besides prenatal mortality. TSA administration post-irradiation was observed to reduce 50% of prenatal mortality at E18.5 by reducing congenital and developmental anomalies. Observation of such results could be corroborated with the HDAC inhibitory potential of TSA knowing that developmental anomalies may have epigenetic origin. TSA, therefore, can be considered as a potential radiomitigator.

Extracellular RNA facilitates hypoxia-induced leukocyte adhesion and infiltration in the lung through TLR3-IFN-γ-STAT1 signaling pathway.

Endogenous ligands released from dying cells, including extracellular RNA (eRNA), cause TLR activation, which is associated with inflammation and vascular diseases. However, the importance of this response in acute hypoxia (AH) remains unexplored. Here, we observed eRNA-mediated TLR3 activation during exposure of mice to AH in the absence of exogenous viral stimuli. RNaseA treatment diminished AH-induced expression of IFN and cell adhesion molecules (CAMs) and myeloid cell infiltration in the lung, and TLR3 gene silencing or neutralization with antibodies markedly attenuated AH- or poly I:C-induced IFN and CAM expression and leukocyte adhesion (LA) and myeloid cell infiltration in the lung. However, RNaseA treatment or TLR3 gene silencing failed to alter AH-induced cell death and proliferation in lung vasculature. Furthermore, IFN-γ--but not IFN-α--regulated AH-induced CAM expression and LA. Treatment with RNaseA, TLR3 siRNA, neutralizing antibodies, or a STAT1 inhibitor substantially decreased AH- and poly I:C-induced STAT1 phosphorylation, CAM expression, and myeloid cell infiltration, suggesting a central role for STAT1 phosphorylation in AH-induced LA and infiltration. We conclude that eRNA activates TLR3 and facilitates, through in vivo IFN-γ-STAT1 signaling, AH-induced leukocyte infiltration in the lung. Thus, RNaseA might provide a therapeutic alternative for patients with lung diseases.

Sulforaphane mitigates genotoxicity induced by radiation and anticancer drugs in human lymphocytes.

Sulforaphane, present in cruciferous vegetables such as broccoli, is a dietary anticancer agent. Sulforaphane, added 2 or 20 h following phytohemaglutinin stimulation to cultured peripheral blood lymphocytes of individuals accidentally exposed to mixed γ and ß-radiation, reduced the micronucleus frequency by up to 70%. Studies with whole blood cultures obtained from healthy volunteers confirmed the ability of sulforaphane to ameliorate γ-radiation-induced genotoxicity and to reduce micronucleus induction by other DNA-damaging anticancer agents, such as bleomycin and doxorubicin. This reduction in genotoxicity in lymphocytes treated at the G(0) or G(1) stage suggests a role for sulforaphane in modulating DNA repair. Sulforaphane also countered the radiation-induced increase in lymphocyte HDAC activity, to control levels, when cells were treated 2 h after exposure, and enhanced histone H4 acetylation status. Sulforaphane post-irradiation treatment enhanced the CD 34(+)Lin(-) cell population in culture. Sulforaphane has therapeutic potential for management of the late effects of radiation.

Mitigative and anti-inflammatory effects of Trichostatin A against radiation-induced gastrointestinal toxicity and gut microbiota alteration in mice.

PURPOSE: Radiation-induced gastrointestinal injury (RIGI) is a serious side effect of abdominal and pelvic radiotherapy, which often limits the treatment of gastrointestinal and gynaecological cancers. RIGI is also observed during accidental radiological or nuclear scenarios with no approved agents available till date to prevent or mitigate RIGI in humans. Trichostatin A (TSA), an epigenetic modulator, has been currently in clinical trials for cancer treatment and is also well known for its antibiotic and antifungal properties. METHODS: In this study, partial body (abdominal) irradiation mice model was used to investigate the mitigative effect of TSA against gastrointestinal toxicity caused by gamma radiation. Mice were checked for alterations in mean body weight, diarrheal incidence, disease activity index and survival against 15 Gy radiation. Structural abnormalities in intestine and changes in microbiota composition were studied by histopathology and 16S rRNA sequencing of fecal samples respectively. Immunoblotting and biochemical assays were performed to check protein nitrosylation, expression of inflammatory mediators, infiltration of inflammatory cells and changes in pro-inflammatory cytokine. RESULTS: TSA administration to C57Bl/6 mice improved radiation induced mean body weight loss, maintained better health score, reduced disease activity index and promoted survival. The 16S rRNA sequencing of fecal DNA demonstrated that TSA influenced the fecal microbiota dynamics with significant alterations in the Firmicutes/Bacteriodetes ratio. TSA effectively mitigated intestinal injury, down-regulated NF-κB, Cox-2, iNOS expression, inhibited PGE2 and protein nitrosylation levels in irradiated intestine. The upregulation of NLRP3-inflammasome complex and infiltrations of inflammatory cells in the inflamed intestine were also prevented by TSA. Subsequently, the myeloperoxidase activity in intestine alongwith serum IL-18 levels was found reduced. CONCLUSION: These findings provide evidence that TSA inhibits inflammatory mediators, alleviates gut dysbiosis, and promotes structural restoration of the irradiated intestine. TSA, therefore, can be considered as a potential agent for mitigation of RIGI in humans.

Biophysical studies of the binding of histone deacetylase inhibitor (Trichostatin-A) with bovine serum albumin.

Trichostatin A (TSA), a potential radiomitigator in pre-clinical models, inhibits the class I and II mammalian histone deacetylase (HDAC) enzyme family preferentially. In the current study, the ADME assessment of TSA was explored in terms of its binding affinity for serum protein via spectroscopic and molecular docking techniques. Fluorescence spectroscopy was used to examine changes in the protein microenvironment, and affinity was quantified in terms of binding constant and stoichiometry. Post binding conformational changes were observed using circular dichroism (CD) and UV-Visible spectroscopy. Specific binding was visualized using molecular docking to support experimental studies. UV-vis spectra demonstrated a blue shift in the interaction of TSA to BSA. The calculated binding constants ranged from 3.10 to 0.78 x 10 5(M-1) and quenching constants from 2.75 to 2.15 x 104 (l mol-1), indicating TSA has a strong binding affinity for BSA. Based on the FRET theory, the distance between BSA (donor) and TSA (acceptor) was calculated to be 2.83 nm. The Stern-Volmer plot revealed (Ksv) static quenching. Thermodynamic parameters were calculated, and a negative ΔG value showed that the interaction is spontaneous. The CD spectra analysis further revealed a change in the protein's secondary structure, indicating TSA-BSA interaction. The molecular docking studies also indicated strong binding affinity of TSA with BSA. The results indicate that good bio-availability of TSA is possible because of the spontaneous and strong binding affinity with BSA.Communicated by Ramaswamy H. Sarma.

Mitigation of radiation injury to reproductive system of male mice by Trichostatin A.

Trichostatin A (TSA), derived from the bacteria Streptomyces hygroscopicus, is a hydroxamic acid having various biological properties such as histone deacetylase inhibition, anticancer and radiomitigative action. However the mitigative activity of TSA against radiation-induced damages in the mouse reproductive system has not yet been elucidated. The present study unraveled the effects of 2 Gy whole body irradiation (60Co γ- radiation) on C57BL/6 mice male reproductive system including structural damages to testes, increase in apoptosis and reduction in germ cell viability, reduced fertility as well as increased genomic instability in the next generation. Moreover, hematological study and micronuclei assay were used to record chances of radiation-induced hematologic cancer and disruption of genomic integrity in F1 generation. Interestingly, TSA administration 1 and 24 h post-irradiation attenuated radiation-induced morphological damage and cellular apoptosis in testes. In male mice, TSA restored hematological parameters and micronuclei frequency to normal levels, restored sperm viability, and helped them overcome radiation-induced temporary sterility 5 weeks after the irradiation. Thus our results showed that TSA reduced the probability of radiation-induced hematologic cancers as well as genotoxicity and restored genomic integrity in the progenies of paternally exposed mice by reducing radiation-induced apoptosis in spermatogenic cells and restoring cell proliferation. This study suggested that TSA could be used as potential radiomitigator for male reproductive system.

Immune-modulation by 7, 8-diacetoxy-4-methylthiocoumarin in total body-irradiated mice: Implications for the mitigation of radiation-induced hematopoietic injury.

AIMS: Development of novel medical countermeasures (MCMs) against acute radiation syndrome (ARS) and the associated lethality involves protection from and/or mitigation of radiation-induced hematopoietic injury, a critical clinical component of ARS. We earlier identified the molecule 7,8-diacetoxy-4-methylthiocoumarin (DAMTC) as a potent mitigator of hematopoietic injury and mortality in C57BL/6 mice when administered 24 h following total body irradiation (TBI). In the present study, we investigated mechanisms and functional relevance of immune modulation by DAMTC during the mitigation of hematopoietic injury. MAIN METHODS: C57BL/6 mice were subjected to TBI doses of 3 and 7.6Gy; administered DAMTC intra-peritoneally 24 h post TBI. Isolation, characterization, intra-cellular cytokine analysis of myeloid cells from bone marrow and spleen accompanied by flow cytometric determination and characterization of B-lymphocytes, serum isolation from peripheral blood and cytokine analysis. KEY FINDINGS: Results showed that DAMTC induced stimulation of pro-inflammatory myeloid subsets in the bone marrow and spleen of TBI mice. Further, it promoted a favorable transition from Th2 to Th1 immunity, triggered humoral immunity, and activated an intricately balanced inflammatory response that appear to contribute to immune-modulation. SIGNIFICANCE: Thus, the present study shows that immune-modulation maybe one of the contributing factors for the mitigation of hematopoietic injury by DAMTC and underscores its efficacy as a potent mitigator of hematopoietic injury that merits to be developed further as a novel MCM to combat H-ARS.

Repurposing sodium diclofenac as a radiation countermeasure agent: A cytogenetic study in human peripheral blood lymphocytes.

We assessed the radioprotective and mitigative actions of sodium diclofenac, a non-steroidal anti-inflammatory drug using cultured human peripheral blood as a model. Both pre- and post-irradiation treatments with the drug reduced gamma radiation-induced formation of dicentric chromosome, cytochalasin-blocked micronuclei and γ-H2AX foci in human peripheral blood lymphocytes. This work supports the concept that sodium diclofenac may be a useful radiation countermeasure agent.

Design and in silico screening of aryl allyl mercaptan analogs as potential histone deacetylases (HDAC) inhibitors.

The Zn+2 HDACIs show promising anticancer activity. Allyl mercaptan (AM), a metastabilzed monomeric form of diallyl disulphide (DADS) shows better HDACI activity. The present work screens a dataset of aryl AM derivatives 1(a-g) for potential HDACI action via in silico models. DFT calculations predicted the geometrical parameters and frontier orbital calculations suggested better chemical reactivity. Negative chemical potential and NBO hyper conjugative interactions predicted their chemical stability. ADME study confirmed favourable drug likeliness. Molecular docked models suggested the formation of coordinate bond between sulphur of allylmercaptan and Zn2+ cofactor of HDAC8. Besides, models also predicted the dominance of hydrophobic interactions. The aryl AM analogs docked perfectly with HDAC3 as well. The glide score and S-Zn distance of compounds 1a, 1f and 1g were found to be better than allylmercaptan. Therefore, the designed aryl AM analogs filtered as better HDACIs. These could be further used for design and synthesis of new improved HDACIs.

Gut microbiota response to ionizing radiation and its modulation by HDAC inhibitor TSA.

AIM: Trichostatin A (TSA) has been shown to mitigate whole body γ-radiation-induced morbidity and mortality. The current study aimed at studying the effects of TSA post-irradiation treatment on gut-microbiota, especially the translocation of the microbes from the intestine to other organs in C57 Bl/6 mice model. MATERIALS AND METHODS: On 1st, 3rd 5th 7th 9th 12th and 14th days after various treatments bacteria were isolated from the intestine and nearby organs (mesenteric lymph node, spleen and liver) for further analysis. The jejunum part of all animals was processed for histological analysis. RESULTS: The group radiation + drug showed reduced susceptibility to radiation injury as well as microbiota related anomalies compared to the irradiated alone group. This was described by increased microflora in different parts of the GI tract in the radiation + drug group compared to the irradiated group and reduced histopathological damages in the jejunum. Also, a reduced percentage of translocated bacteria were found in different organs of radiation + drug group animals. CONCLUSION: TSA treatment post-irradiation could effectively control bacterial translocation as well as GI injury in mice.

Trichostatin A, an epigenetic modifier, mitigates radiation-induced androphysiological anomalies and metabolite changes in mice as evident from NMR-based metabolomics.

PURPOSE: Ionizing radiation is known to damage male reproductive system. Current study aims to study the mitigative effects of trichostatin A on male reproductive system and accompanying metabolite changes in testicular tissue of mice. MATERIALS AND METHODS: Eight-week-old male C57 Bl/6J mice were exposed to 2 Gy γ-radiation with or without trichostatin A administration. The animals were sacrificed at various time intervals for organ body weight index, sperm head abnormality assay, sperm mobility assay, and study of various metabolites in testicular tissue using NMR spectroscopy. RESULTS: Ionizing radiation induced no significant change in organ body weight index at any time points studied, however a significant increase in sperm head abnormality and significant decrease in sperm mobility was evident on fifth postirradiation week. trichostatin A administration, 1 and 24 h postirradiation, could efficiently mitigate radiation-induced changes studied. NMR metabolome profile also showed prominent changes associated with energy metabolism, osmolytes and membrane metabolism at 24 h postirradiation and some of these changes (choline, glycerolphosphoethanol amine, and glycine) were persistent till fifth postirradiation week. Trichostatin A administration resulted in reverting metabolic profile of the irradiated animals to normal level suggesting its mitigative role. CONCLUSION: Results obtained suggest that trichostatin A could restore normal metabolic profile of testicular tissue of irradiated male mice and also restored certain morphological and functional properties of sperms. Trichostatin A thus could further be exploited for its radio-mitigative properties.

Mitigation of radiation-induced gastro-intestinal injury by the polyphenolic acetate 7, 8-diacetoxy-4-methylthiocoumarin in mice.

Radiation-induced intestinal injury (RIII) constitutes a crucial clinical element of acute radiation syndrome with life-threatening implications posing challenges in devising effective medical countermeasures. Herein, we report the potential of 7, 8-diacetoxy-4-methylthiocoumarin (DAMTC) to mitigate RIII following total-body irradiation (TBI) in C57BL/6 mice and underlying mechanisms. Administration of DAMTC 24 hours post TBI facilitated structural reconstitution and restoration of functional absorption linked to alleviation of radiation-induced apoptotic death of intestinal crypt progenitor/stem (ICPS) and villus stromal cells through induction of Bcl-2 family-mediated anti-apoptotic signalling. Reduction in TBI-induced DNA damage accumulation coupled with inhibition of cell cycle arrest through stimulation of anti-p53- and anti-p21-dependent synergistic signalling protected ICPS cells from radiation injury. Enhanced proliferation of crypt stem cells, induction of anti-oxidant defence, subjugation of TBI-induced lipid peroxidation and phenotypic polarization of intestinal macrophages to anti-inflammatory M2 class underlie amelioration of RIII. Stimulation of multiple mitigative signalling processes by DAMTC appeared to be associated with enhanced protein acetylation, an important regulator of cellular responses to radiation damage. Our findings establish the mitigative potential of DAMTC against RIII by hyper-acetylation-mediated epigenetic regulation, which triggers axes of anti-apoptotic and pro-survival pathways, enabling proliferation and maintenance of ICPS cells leading to epithelial regeneration.

Induction and repairability of DNA damage caused by ultrasoft X-rays: role of core events.

PURPOSE: To investigate the severity of damage induced in plasmid DNA by ultrasoft X-rays at different energies, in order to unravel the correlation between the sharp increase in cell-killing efficiency of ultrasoft X-rays above versus below the carbon K-threshold and the induction of core events in DNA atoms. MATERIALS AND METHODS: Bluescript (pBS, tight packing) and pSP189 (pSP, loose packing) plasmids were exposed to ultrasoft X-rays at 250, 380 and 760 eV energies, respectively, above phosphorus L-, carbon K- and oxygen K-thresholds. Complex DNA lesions were assayed by the repair protein Formamidopyrimidine DNA glycosylase (Fpg) and by in vitro repair assay using whole cell-free extracts. RESULTS: Clustered damage, as revealed by Fpg-induced double strand breaks, was observed at low level, but at similar rate at the three energies. Damage induced at 380 eV may be slightly less efficiently repaired by cell extracts than those produced at 250 eV. 760 eV photons which yield longer range electrons than 250 and 380 eV photons, induced more total damages which were more efficiently repaired, and thus likely more dispersed. CONCLUSION: It is demonstrated that ultrasoft X-rays induce complex damage, which do not exhibit the same ability to be repaired, depending on the energy and on DNA packing.

Role of some epigenetic factors in DNA damage response pathway.

The current review gives a brief account of the DNA damage response pathway and involvement of various epigenetic mechanisms in DNA damage response pathway. The main focus is on histone modifications leading to structural alterations in chromatin since the compact chromatin structure poses a major limitation in the DNA repair process. Based on this hypothesis, our laboratory has also evaluated certain histone deacetylase inhibitors as potential radiomitigators and the same has been discussed in brief at the end of the review.

EGCG, a tea polyphenol, as a potential mitigator of hematopoietic radiation injury in mice.

Agents capable of providing protection, mitigation or therapy against radiation injuries have long been of interest of radiation biologists owing to the ever expanding application of radiation in our day to day life despite the well reported ill effects of exposure. The current study investigates radiomitigating potential of EGCG (epigallocatechin gallate), a tea polyphenol with known DNMT inhibitory property, in C57 Bl/6 mice model. Treatment with 0.1833mg/kg body weight EGCG, 1.5h post-irradiation to lethally whole body irradiated mice rendered 45% survival for 30days and also helped restoring the body weight of the animals. An early recovery of various hematological parameters was observed in EGCG treated animals compared to radiation alone group. Significant recovery in the number of bone marrow colony forming cells was observed in EGCG treated irradiated animals. EGCG reduced cytogenetic damage to bone marrow cells in radiation exposed mice significantly as studied by micronucleus assay without any significant affect on cell cycle distribution of the bone marrow cells. ELISA assay with bone marrow cell lysates showed EGCG as an inhibitor of HDAC activity and DNase accessibility assay showed EGCG treatment increased the accessibility of chromatin to the enzyme. The results suggest EGCG provides mitigation against radiation injury to the hemopoietic system of mice and also inhibits HDAC enzyme activity. However, further studies are required to understand its mechanism of action.

Immunological Aspect of Radiation-Induced Pneumonitis, Current Treatment Strategies, and Future Prospects.

Delivery of high doses of radiation to thoracic region, particularly with non-small cell lung cancer patients, becomes difficult due to subsequent complications arising in the lungs of the patient. Radiation-induced pneumonitis is an early event evident in most radiation exposed patients observed within 2-4 months of treatment and leading to fibrosis later. Several cytokines and inflammatory molecules interplay in the vicinity of the tissue developing radiation injury leading to pneumonitis and fibrosis. While certain cytokines may be exploited as biomarkers, they also appear to be a potent target of intervention at transcriptional level. Initiation and progression of pneumonitis and fibrosis thus are dynamic processes arising after few months to year after irradiation of the lung tissue. Currently, available treatment strategies are challenged by the major dose limiting complications that curtails success of the treatment as well as well being of the patient's future life. Several approaches have been in practice while many other are still being explored to overcome such complications. The current review gives a brief account of the immunological aspects, existing management practices, and suggests possible futuristic approaches.