Radiation damage to the lung: mitigation by angiotensin converting enzyme (ACE) inhibitors (original) (raw)

. Author manuscript; available in PMC: 2013 Jan 1.

Abstract

Concern regarding accidental overexposure to radiation has been raised after the devastating Tohuku earthquake and tsunami which initiated the Fukushima Daiichi nuclear disaster in Japan, in March 2011. Radiation exposure is toxic and can be fatal depending on the dose received. Injury to the lung is often reported as part of multi-organ failure in victims of accidental exposures. Doses of radiation >8 Gray to the chest can induce pneumonitis with right ventricular hypertrophy starting after ~2 months. Higher doses may be followed by pulmonary fibrosis that presents months to years after exposure. Though the exact mechanisms of radiation lung damage are not known, experimental animal models have been widely used to study this injury. Rodent models for pneumonitis and fibrosis exhibit vascular, parenchymal and pleural injuries to the lung. Inflammation is a part of the injuries suggesting involvement of the immune system. Researchers world-wide have tested a number of interventions to prevent or mitigate radiation lung injury. One of the first and most successful class of mitigators are inhibitors of angiotensin converting enzyme (ACE), an enzyme that is abundant in the lung. These results offer hope that lung injury from radiation accidents may be mitigated, since the ACE inhibitor captopril was effective when started up to one week after irradiation.

Keywords: captopril, lung fibrosis, mitigation, radiation pneumonitis, nuclear accident, radiological terrorism

INTRODUCTION

The purpose of this review is to summarize the known effects of accidental radiation overexposure of the lung as well as experimental investigations towards the mechanisms involved. Currently there are a number of interventions being developed to decrease radiation-induced lung damage, of which the first and one very promising class of mitigators areACE inhibitors.

EFFECTS OF ACCIDENTAL IRRADIATION TO THE LUNG

The lung is a radiosensitive organ and radiotherapy to the chest is limited by toxicity to healthy lung.1 Lung injury is reported in over 50% of victims after radiation accidents often in conjunction with multi-organ failure. Table 1 summarizes accidents since 1945 that have reported lung-related symptoms and damage.2–10 The lethal dose (LD50*) for a single-fraction exposure in humans is around 10 Gray§ (Gy).11,12 Classically, injury has been described in 2 phases, acute pneumonitis and late fibrosis.13 The radiation-induced pneumonitis manifests after approximately 2 months12 while the fibrosis presents months to years later.13 On the basis of several studies, a single dose of 8 Gy to both lungs will cause pneumonitis in about 30% of patients10 while a higher dose may be needed to observe fibrosis. The symptoms of pneumonitis include shortness of breath, dry cough, rales and mild fever. The signs can be complicated by preexisting lung diseases. Pain due to pleuritis can occur since radiation causes irritation of the pleura.13 Late developing pulmonary fibrosis is a scarring disease that can severely reduce lung function. Either pneumonitis or fibrosis can be fatal.

A brief summary of some examples of direct and indirect injury to the lungs due to accidental exposure are listed in the table. These events include criticality and other incidents at nuclear plants and overexposure from medical sources during radiotherapy, sterilization and other accidental exposures. Most accidents involved male workers though a few involved females and one included a child.4 Lung injuries resulted from total body or localized exposures and were often a part of multi-organ failure and not the single cause of death. Patients were often treated and the interventions may have affected the outcomes. The one case of lung fibrosis in the Shanghai accident may have resulted from treatment with oxygen.6

Date Accident Lung-related symptoms Estimated radiation dose Ref
1945–64 Los Alamos and Wood River, USA Edema, hemorrhage, aspiration pneumonia, focal atelactasis, focal emphysema, hydrothorax 5.1->100Gy* 2
1948–1958 Mayak, USSR Dyspnoea, tachypnea 7–46 Gy 3
1987 Goiania Severe hemorrhage, pneumonia, right ventricular hypertrophy, pleuritis, enlarged lungs, 4.5–6 Gy including internal contamination 4
1990 Israel Tachypnea, hypoxia, acidosis, infiltrate, severe RP§ and CMVΨ infection 10–20 Gy 5
1990 Shanghai, China Pneumonia, hemorrhage, ARDSς, decreased oxygen saturation, CMV infection, tachypnea, hypertrophy and dilatation of the right heart, severe pulmonary fibrosis 11–12 Gy 6
1997 Selected report from Chernobyl, USSR Hypoxemia, ARDS >10 Gy 7
1999 Tokai-mura, Japan Transient hypoxemia, interstitial edema >2 Gy 8
2000 Samut Prakarn, Thailand Tachypnea, septic shock, pneumonia, acidosis, pulmonary edema Not in report 9
2001 Bialystok, Poland Pleural effusion Not in report 10

Pathologically, pneumonitis is accompanied by vascular disease including narrowing of arterioles and capillaries. In addition, hyaline membranes form to line the alveolar walls.10 Epithelial cell morphology is altered and local cellularity is increased. Pleural effusions develop in severe cases. Late fibrotic lesions are accompanied by calcified plaques, atelactasis and volume loss.

Morphological radiation-induced injuries to the lung are followed non-invasively using computed tomography (CT).13 Functional imaging such as single-photon emission computed tomography (SPECT), positron emission tomography (PET) and magnetic resonance imaging (MRI) provide quantitative end points for metabolic activity, perfusion and contrast within the lung.14 More recently, hyperpolarized helium 3 (HP (3) He) MRI has been developed to focus on ventilation and diffusion-weighted imaging.15. Fibrotic changes are detected by CT, usually after doses of 60 Gy delivered over 6 weeks. Predicting the risk of radiation–induced lung injury is a challenge that has been pursued by many researchers. Dose-volume histograms are the most important factor used to guide radiotherapy though other variables have been identified.1,13,16–18 These include pulmonary function before exposure and smoking status.19 Surprisingly, smokers display a decreased inflammatory reaction and decreased symptoms of pneumonitis.20 More detailed effects on the lung, as determined by the use of animal models, are discussed next.

EXPERIMENTAL LUNG INJURY BY RADIATION

Rodent models of radiation lung injury have been extensively studied. The rat has larger lungs making it more amenable to pulmonary-function studies while mice have been utilized to monitor function as well as changes in cytokine and chemokines after radiation.21 Rodent lungs differ from human lungs with respect to lobularity and thickness of septa and pleura. The effects of radiation have many similarities including time and dose response, making rodent models a popular choice for researchers. Horse and pig lungs are more similar in structure to humans, while dog lungs are closer to those of rodents.22 For this review, rodent models will be discussed since they have been the most widely used for experimental and preclinical investigations.

Rodent lungs are sensitive to the volume as well as the region of irradiation. Similar volumes of radiation to the base of the lungs generate greater loss of function than corresponding exposure to the apex.12 In addition, DNA damage has been observed in cells that are out of the irradiation field23 suggesting a role for cytokines and chemokines. More recent studies describe waves of expression of these mediators. The best studied include interleukin-1B (IL-1B), interleukin 6,(IL-6) tumor necrosis factor (TNF-alpha) and transforming growth factor-Beta (TGF-beta).24–26 Markers may be different in younger animals.27 In spite of over a decade of research, no cytokine or chemokine profile has been generally accepted by researchers as reflecting or predicting radiation-related pulmonary injury. A cascade of molecular and cellular events are believed to occur after exposure that induces chronic oxidative stress and culminate in loss of pulmonary structure and function.28–30

Gross structural changes

Changes in gross structure down to the electron microscopy level have been described in detail.31,32 Focal patchy areas were observed on inspection 2 months after 20 Gy to the right lung of Sprague Dawley rats. The irradiated lung was shrunken, firm and resistant to inflation at 6 months with compensatory hypertrophy of the contralateral lung. Light microscopy revealed perivasculitis and perivascular edema31 which has also been reported in WAG/RijCmcr rats (an inbred Wistar strain) after 10 Gy.33 By 2 months exudative lesions were observed with proteinaceous fluid in the alveolar spaces.31 Cellular infiltrate was present accompanied by increasing cellularity by 3 months. Interstitial widening was evident but the most pronounced changes occurred in Type II pneumocytes.31 The cells became large, more granular and atypical. Focal remodeling was apparent with increased staining for reticulin which was deposited in the alveolar walls of affected areas.31 By 4–6 months the exudative lesion lessened but cellularity in the form of infiltrates, fibroblasts and Type II cell hypertrophy was increased. Atelactasis and denudation of epithelial cells in the alveolar walls were evident. Collagen was observed in focal areas becoming diffuse throughout the alveolar walls and pleura with time.31 Alveolar wall widening and atypical hypertrophy of the epithelial cells also increased with time.

Fibrin deposition with entrapped cells was observed by electron microscopy. At 6 months the lesions were multifocal and consolidated. The most pronounced change was the presence of mast cells in the alveolar walls, often associated with fibroblast-like cells.31

An ultrastructural quantitation of cells in the lungs at 12 and 26 weeks after radiation pointed out dynamic changes.32 For example, pulmonary mast cells in male Sprague-Dawley rats after unilateral thoracic irradiation with 30 Gy increased by 540-fold in the interstitium at 26 weeks.32 Other infiltrates or ‘plasma cells’ were increased 180-fold. Type 1 epthelial, Type 2 epithelial and endothelial cells were decreased 50–70% after 12 weeks at which time the total volume of intracapillary blood was decreased 75%. The density of interstitial cells was increased 3-fold.32 Whole thoracic irradiation of male WAG/RijCmcr rats did not show an increase in infiltrated lymphocytes or macrophages in the lungs at 8 weeks after 10 or 15 Gy.34 Neutrophils were modestly increased (~30%) by 15 but not 10 Gy while mast cells were dramatically increased (~16 fold) after 15 Gy.34

Functional changes

Functional injury in rodent models irradiated to the thorax have been followed predominantly by serial measurement of breathing rates.33,35,36 There is a sharp rise in this index in WAG/RijCmcr rats from 6 weeks after 10–15 Gy37 which returns to normal by 10 weeks.33 A second rise is observed during fibrosis depending on the strain.38 Some strains such as WAG/Rij suffer fibrosis over a year after exposure39 while Sprague Dawley rats exhibit a second peak in breathing rate after only 16 weeks following radiation.38 Mice demonstrate increased breathing rates due to pneumonitis at 10 weeks after 10–15 Gy. The severity of this phase of injury is strain-dependent with C3H/HeN21 and C57L40 displaying acute pneumonitis while C57BL/6 suffer predominantly the fibrotic (late) injury.21,40

Vascular changes

Structural and functional vascular injuries as well as changes in hemodynamics accompanying pneumonitis have been described in detail in female Fisher41 and WAG/RijCmcr rats.33,42 Isolated and perfused lungs ex vivo demonstrated a decrease in mean vascular surface area after 10 Gy to the thorax, as determined by measuring activity of the endothelial enzyme ACE.42 This was confirmed by reports of reduced arterial density in high resolution angiograms of the same lungs perfused with a contrast agent.42 In the same study, irradiated lungs had increased pulmonary vascular resistance with right ventricular hypertrophy at 8 weeks after 10 Gy to the thorax that resolved by 5 months when the pneumonitis had passed. Pulmonary vessels had decreased distensibility after radiation, which did not recover by 1 year.42 Reactivity of isolated arterial rings was also less during pneumonitis.33 Vessels from irradiated lungs were less reactive ex vivo to vasoconstrictors such as angiotensin II or the thromboxane mimetic U46619. These preconstricted vessels relaxed less in the presence of acetylcholine than unirradiated controls.33,37 In Fisher rats given 28 Gy to one lung, increase in oxidative stress, macrophages, cytokines such as transforming growth factor beta and vascular endothelial growth factor (VEGF) and biochemical evidence of hypoxia were observed.41 These results confirmed severe pulmonary vascular and endothelial dysfunction during pneumonitis.

Pleural and cardiac effusions

Another striking effect after whole-thoracic irradiation in rodent lungs is pleural effusion.40 This can be caused by occlusion of lymph vessels and/or other pulmonary injuries43–45 Pericardial effusion has also been reported but whether this is due to radiation to the heart or lung is difficult to assess as the heart is often in the field after whole thoracic irradiation. As seen in Table 1, pleural effusion has been observed in human lungs exposed to accidental radiation.10

ACE INHIBITORS AS MITIGATORS OF RADIATION LUNG INJURY

A number of investigators have identified countermeasures against radiation-induced lung injury including some that may be started after radiation.30,37,38,46–51 For countermeasure studies, agents given after exposure but before symptoms develop are termed mitigators.52 Mitigation is important for victims of nuclear accidents or radiological-terrorism events, when interventions cannot be given before or during irradiation.

One of the most successful and studied class of drugs for mitigation of radiation-induced lung injuries are suppressors of the renin-angiotensin system. These drugs were first tested against radiation pneumonitis and fibrosis in the 1980s using non-lethal models in which only one lung of an anesthetized rat was irradiated with a single dose of 10, 20 or 30 Gy.53,54 Drugs were started after irradiation and the experiments were terminated at fixed times up to 2 months following exposure.47,53,54,55 Lysates from the irradiated lung were used to measure 4 markers of vascular endothelial function, angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, prostacyclin (PGI2) production and thromboxane (TXA2) production. ACE and PLA activities decreased with increasing doses of 10, 20 and 30 Gy, while production of PGI2 and TXA2 production were increased. The ACE inhibitors captopril, CL242817 and CGS13945 spared the suppression of ACE and PLA activities.54 Captopril and CL242817 (both containing a thiol group) also spared the increase in PGI2 and TXA2.54 In addition, the ACE inhibitors captopril, CL242817, CL248817 and CGS13945 mitigated radiation-induced increase in hydroxyproline (a measure of fibrosis) 53,56 and inflammation56, while CGS13945 spared the inflammation but not the fibrosis.

A later study applied an injury model more relevant to a radiological accident or terrorism event.37 The whole volume of rat lungs were exposed to a single fraction of 10, 12 or 15 Gy in unanesthetized animals. Drugs were started immediately after radiation or 1 or 2 weeks later. There was considerable morbidity after 12 and 15 Gy and rats had to be euthanized according to regulations of the animal care committee at the institution where the experiments were being performed (Medical College of Wisconsin, Milwaukee, USA). Captopril improved survival at doses ranging from 34–56 mg/kg/day when given immediately after irradiation. These doses correspond to 145–345 mg/m2/day, which are in the range approved for clinical use.57 In addition, when given up to 1 week after irradiation, captopril mitigated the increase in breathing rate due to pneumonitis at 8 weeks as well as the drop in vascular reactivity of isolated pulmonary arteries. This included relaxation to acetylcholine in preconstricted pulmonary artery rings ex vivo. Histological studies confirmed there was less damage in lungs from irradiated rats treated with captopril than untreated, irradiated cohorts. While the ACE inhibitor captopril mitigated tachypnea when therapy is started 1 week following irradiation, the angiotensin receptor 1 (AT1) blocker losartan was not as effective.37 These results were different from the effects of the two drugs on radiation nephropathy, where both drugs were equally potent mitigators at these doses.58 One limitation of all the studies of ACE inhibitors against lung injury is that a single time point (often at the peak of pneumonitis) was used for analysis of experimental groups, so it is not clear whether ACE inhibition decreases the magnitude of the pneumonitis or merely delays it.

Captopril is FDA approved and has enjoyed widespread clinical use for a number of indications, the most popular being hypertension and heart disease. It is orally available and is well tolerated. A trial of captopril in lung cancer patients demonstrated the absence of enhanced toxicity when therapy started after irradiation.59 A trial of captopril in patients receiving total body irradiation for bone marrow transplantation demonstrated not only safety, but also efficacy against renal and pulmonary injury.60 In addition there is evidence that ACE inhibitors can mitigate a range of experimental radiation injuries other than radiation pneumonitis and fibrosis60–62 making them excellent candidates to test against multiple-organ failure that would result from accidental radiological events.

CONCLUSION AND FUTURE DIRECTIONS

The lung is a dose-limiting organ for radiation with the dose-volume relationship being the best known variable to predict injury. Much progress has recently been made in describing lung damage after radiation and in developing rodent models of injury, protection and mitigation. However much remains to be done. Molecular mechanisms of radiation injury to the lung are still poorly understood making targeted drug development a challenge. There are no accepted biomarkers that predict radiation pneumonitis or fibrosis, and the best therapies need to be compared in a scientific manner to focus on effective agents. The ACE inhibitor captopril is one of a few drugs that improves survival and lung function after a single dose of radiation to the thorax in a schedule that mimics exposure during a nuclear accident or terrorist event.

Acknowledgments

We thank Jayashree Narayanan for help with preparing the manuscript. Funding was provided by NIH/NIAID (USA) RC1 AI81294 & 01S1 and agreements U19 AI67734.

Footnotes

*

Dose that kills 50% of subjects tested

§

Gray is unit of absorbed dose of one joule of ionizing radiation by one kilogram of matter

References