Immune Modulation by Ionizing Radiation: Implications for Inflammation and COVID-19

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Abstract: The 2006 report of the United Nations Scientific Committee on the Effects of Atomic Radiation Sources challenged the classical paradigm that ionizing radiation (IR) solely acts as an immunosuppressant. Instead, it proposed the notion that at low doses, IR may induce the appearance of anti-inflammatory biomarkers.

Considering radiation as an immune modulating agent, this report highlights the diverse ways in which IR can influence the innate immune system, contingent upon factors such as dose, dose rate, age, health status, comorbidity, genetic background, lifestyle, and environmental co-stressors like air pollution. Of the various sources of IR, background radiation presents the most significant risk to public health, closely followed by medical imaging.

Naturally occurring radionuclides, when inhaled and deposited in the lungs, continue to disintegrate and emit radiation, thereby linking radiation-induced inflammation to inflammatory issues associated with SARS-CoV-2 viral infection. This article conducts an extensive review, focusing on common anti-inflammatory biomarkers observed in elderly COVID-19 patients with acute respiratory distress syndrome (ARDS) and in healthy subjects exposed to natural low-level ionizing radiation in regions with elevated background values due to geographical characteristics.

Consequently, we hypothesize that radioactivity amplifies inflammatory biomarkers, which remarkably align with those induced by the virus, thereby exacerbating its detrimental effects. If this hypothesis is confirmed by further clinical studies beyond the scope of this paper, it raises the question of whether artificial radiation from medical X-ray imaging could elicit similar immune system effects at low doses. To investigate these matters, we employed a comprehensive search strategy utilizing PubMed databases and various relevant terms such as dose-response, hormesis, J-shaped, NLRP3 inflammasome, natural radioactivity, and LNT model.

The study

Radon is a radioactive gas that comes from the natural decay of uranium in soil, rocks, water and building materials. The amount of background radiation an individual is exposed to depends on many factors, such as home ventilation and altitude. The standard average is estimated at 3 milliSieverts (mSv) per year, a figure that could vary depending on the geographical coordinates.

Healthy population in locations on Earth with higher levels of natural radioactivity show higher amounts of autoimmune biomarkers. China, Iran, Brazil and India are among the countries with the highest natural background radioactivity [29]. It was notable, during the height of the COVID-19 pandemic in 2020, that these places experienced a clear excess in mortality rates (see Figure 1) following inflammatory conditions related to SARS-CoV-2- linked acute respiratory distress syndrome. The radiation-driven biomarkers were common to those exhibited by ARDS and therefore a summative effect could be assumed.

On the other hand, current medicine offers a variety of diagnostic methods and tools that include imaging techniques where patients are exposed to artificial ionizing radiation, such as X-rays, computed tomography (CT), positron emission tomography (PET), gammagraphy, mammography and others.

The use of CT has been steadily increasing over the last decades, representing today an indispensable tool in diagnostic X-ray medical imaging [73]. A consequence of this excessive increase, caused by so-called defensive medical decision making, especially in developed countries, is that radiographic studies are largely responsible for exposure to artificial sources of ionising radiation, even if averaged over the entire population of a given country.

In particular, pulmonary high-resolution computed tomography (HRCT) is a well-established technique for diagnosing and treat- ing pulmonary complications [71]. Recurrent examinations have highlighted that many patients with COVID-19 develop lung damage due to viral pneumonia and ARDS [72]. However, the exposure to ionizing radiation from HRCT scans may also have adverse effects on lung tissue and immune system function [74], potentially worsening the clinical outcome of COVID-19 patients.

Therefore, it is important to assess the risks and benefits of radon exposure in relation to COVID-19. While some studies have suggested that low doses of radiation may have beneficial effects on immune system regulation and anti-inflammatory response [75], others have warned that radon exposure may increase the susceptibility and severity of COVID-19 infection by damaging lung cells and impairing respiratory function [76]. Moreover, radon exposure may interact with other environmental factors, such as air pollution and climate drivers, that may also influence the transmission and progression of COVID-19 [77].

Inflammatory biomarkers due to abnormal low dose radiation levels

Natural background radiation, influenced by geological composition, varies globally, with a well-established limit of 20 mSv/year. However, certain regions experience significantly higher levels of background radiation, up to 10 to 15 times the accepted value. In areas such as Taleshmahaleh and Chaparsar in northern Iran, where background radiation exceeds normal levels, studies have shown a lower total serum antioxidant level and altered cytokine production in individuals exposed to high doses of ionizing radiation. The main radioactive elements contributing to natural human exposure include potassium (K), uranium (U), thorium (Th), radium (Ra), and radon (Rn). Radon, released during the decay of uranium, emits alpha radiation when inhaled and has been associated with biomarkers of inflammation and endothelial dysfunction.

In regions with high indoor concentrations of radon, such as uranium mines, long-term exposed individuals demonstrated up-regulation of pro-inflammatory cytokines. Cytokines play a crucial role in modulating immune cell function, and their interaction with low doses of radiation influences the immune response. The activation of the NLRP3 inflammasome by ionizing radiation induces the production of reactive oxygen species (ROS) and various inflammatory mediators, including NF-κB, IL-1, IL-2, IL-6, IL-8, IL-33, TNF-α, TGF-β, and IFN-γ.

Lead (Pb), a highly toxic element, also induces inflammatory responses and affects immune system cells and immunoglobulin secretion. Although leaded gasoline has been phased out in many countries, its compounds can still be found in aviation fuel, leading to the presence of unstable radioactive forms, such as Lead-214 (214Pb), in the air. Additionally, tobacco smoke contains α radioactivity, mainly derived from radionuclides such as 226Ra, 210Pb, 228Ra, and 137Cs from the Chernobyl disaster. Smokers are exposed to significantly higher radiation doses compared to natural sources, resulting in increased pro-inflammatory cytokine levels and exacerbation of inflammation in chronic obstructive pulmonary disease (COPD) patients.

Air pollution, which includes particulate matter and nitrogen dioxide (NO2), can also contribute to inflammation and affect immune response. High levels of air pollution, as observed in Northern Italy, have been associated with elevated SARS-CoV-2 mortality rates due to severe pulmonary inflammation. Studies have demonstrated a relationship between air pollution, specifically PM2.5 concentrations, and increased COVID-19 mortality rates. Furthermore, exposure to NO2 from burning fossil fuels has been linked to lung inflammation and potential complications from viral infections.

Understanding the complex interactions between natural radiation, environmental factors, inflammation, and immune response is crucial for assessing their impact on human health. Further research and clinical studies are warranted to explore the mechanisms underlying these associations and evaluate the potential risks posed by low-dose radiation exposure, air pollution, and other environmental factors in the context of inflammatory diseases and viral infections.

The Role of Inflammation and Immune Response in COVID-19-Related Lung Injury

COVID-19, caused by the novel coronavirus SARS-CoV-2, can lead to severe lung inflammation and respiratory complications, including acute respiratory distress syndrome (ARDS) and respiratory failure. This intense inflammatory reaction is characterized by the infiltration of immune cells, fibrin exudates, multi-nucleate giant cells, and thickened alveoli due to the proliferation of interstitial fibroblasts. Similar patterns of lung hyperinflammation were observed during previous coronavirus outbreaks, such as SARS-CoV in 2002 and MERS-CoV in 2012.

While most individuals infected with SARS-CoV-2 experience mild flu-like symptoms, approximately 5-10% develop severe cases with respiratory system involvement and life-threatening pneumonia. These severe cases have been associated with increased levels of pro-inflammatory cytokines in the bloodstream, leading to a phenomenon known as a cytokine storm. The activation of the NLRP3 inflammasome, an intracellular signaling complex, plays a crucial role in this inflammatory response. Macrophage activation syndrome (MAS), characterized by elevated levels of IL-1, TNF-α, and IL-6 produced by M1-type macrophages, has been identified as a potential complication of COVID-19.

Chronic activation of the NLRP3 inflammasome, observed in various autoinflammatory diseases such as obesity, type 2 diabetes, rheumatoid arthritis, systemic lupus erythematosus, osteoarthritis, atherosclerosis, Alzheimer’s disease, Parkinson’s disease, cancer, asthma, and chronic obstructive pulmonary disease (COPD), can lead to damaging responses. In the case of COVID-19, when the immune system encounters SARS-CoV-2, blood monocytes are recruited to the alveoli, where they differentiate into M1 macrophages and release cytokines to fight the infection. In a normal response, M2 macrophages with anti-inflammatory properties would eventually replace the inflammatory M1 macrophages. However, in cases of ARDS and certain autoimmune disorders, the inflammatory state persists, leading to lung damage and multi-organ failure.

Persistent infiltration of inflammatory neutrophils in the alveoli, along with increased concentrations of reactive oxygen species (ROS) and TNF, contribute to lung injury in COVID-19 patients. Activation of the inflammasome also triggers severe uncontrolled pulmonary fibrosis, characterized by increased NLRP3 caspase-1 activity and elevated levels of mature IL-1β and IL-18 in the elderly. Additionally, the presence of polluted air and its induction of reactive oxygen species production can further enhance the expression of angiotensin-converting enzyme 2 (ACE-2) in lung tissue. ACE-2 serves as the entry point for SARS-CoV-2 into human cells and facilitates its spread throughout the body. Similar observations were made during the SARS-CoV outbreak in 2003, where ACE-2 receptors played a crucial role in viral entry and infection.

Understanding the mechanisms underlying inflammation and immune response in COVID-19-related lung injury is essential for developing effective treatment strategies and mitigating the severe complications associated with the disease. Further research is needed to explore the interplay between viral infection, inflammasome activation, and lung damage to identify potential therapeutic targets and interventions.

Conclusion

Low-dose radiation (LDR) has primarily been associated with cancer-related risks, particularly based on studies conducted among Japanese survivors. However, recent research suggests that dose-response effects can also be linked to secondary effects such as inflammation. Understanding the potential consequences of LDR exposure, particularly in the hormetic zone, is crucial. As the lower dose interval represents a more relevant exposure scenario for the general population, given the common use of X-ray imaging in general diagnostics, the potential dangers of LDR should be considered and steps taken to limit unnecessary exposure, unless antioxidant supplements are prescribed.

The validity of the accepted linear no-threshold (LNT) model in the low-dose range lacks sufficient data. Thus, using dose as a surrogate for risk in X-ray imaging is inappropriate, rendering the classical “As Low As Reasonably Achievable” (ALARA) concept obsolete. Concerns have been raised regarding overuse of computed tomography (CT) scanning and inappropriate selection of protocol exams. While CT is essential for ARDS disease follow-up, estimation of equivalent doses in organs at risk, as outlined in the European Union’s Council Directive 2013/59/Euratom, is necessary to ensure basic safety standards for protection against the dangers of ionizing radiation.

The adaptive response known as hormesis, triggered by excessive CT scans on ICU-admitted patients with COVID-19, appears to dramatically enhance viral inflammation. Hormesis, although protective against cancer, may also play a crucial role in auto-inflammatory processes.

The interrelationship between the immune system and ionizing radiation is complex, multifactorial, and dependent on radiation dose and immune cell type. Higher radiation levels typically result in immune suppression, while low values modulate various immune responses that exhibit hormetic properties. However, early inflammatory effects can be challenging to isolate and study independently, often overshadowed or concealed by comorbidities.

Neutrophils, in addition to cytokine secretion, also produce reactive oxygen species (ROS). Supplementation with diet supplements like N-acetylcysteine (NAC), a potent scavenger of hydroxyl radicals, may effectively prevent cytokine storms, ROS-induced pulmonary edema, and respiratory failure.

In conclusion, excessive use of computed tomography among the elderly population raises concerns about the immune effects of artificial ionizing radiation. It is hypothesized that the immune effects of artificial radiation should be similar to those of natural radiation, given the similarity in individual doses in both scenarios. However, limited information is available on the effects of artificial radiation compared to the well-studied effects of natural background radiation. Further research is necessary to gain a comprehensive understanding of the immune response to low-dose radiation and its implications for medical imaging practices, particularly in the context of COVID-19.


reference link : https://www.preprints.org/manuscript/202305.0829/v1

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