In-field and out-of-field effects in partial volume lung irradiation in rodents: possible correlation between early dna damage and functional endpoints

Purpose: Recent observations have shown that there are regional variations in radiation response in mouse lung as measured by functional assays. Furthermore, there are both in-field and out-of-field effects in radiation-induced lung damage as observed by DNA assay in rats. The purpose of this work is: (a) to examine mice lethality data following partial volume lung irradiation to assess the possibility of directional or regional effects, (b) to evaluate the correlation between mice lethality data and DNA damage assayed by micronuclei production in rat lung, and (c) to re-interpret mice lethality considering the existence of directional effects in lung cellular response to partial volume irradiation.

Methods and Materials: The lethality data for mice, generated at the M. D. Anderson Cancer Center, Houston, and micronuclei yield data for rats obtained at Princess Margaret Hospital, Toronto, were used. A radiobiological model that allows for out-of-field and in-field effects for lung cell damage and lung response was developed. This model is based on the observation of DNA damage in shielded parts of rat lung that was assumed relevant to cell lethality and consequently overall lung response.

Results: While the experimental data indicated directional or regional volume effects, the applicability of dose and volume as sole predictors of lung response to radiation was found to be unreliable for lower lung (base) irradiation in mice. This conforms well to rat lung response where micronuclei were observed in shielded apical parts of lung following base irradiation. The radiobiological model, which was specifically developed to account for the lung response outside of primary irradiated volume, provides a good fit to mice lethality data, using parameters inferred from rat micronuclei data.

Conclusion: Response to lung irradiation in rodents, in particular, elevated sensitivity to base irradiation, can be interpreted with a hypothesis of in-field and out-of-field effects for cellular response. If the existence of these effects for lung is subsequently proven in humans, it will require the incorporation of geometrical and directional information in normal tissue complication probability calculations for lung. These considerations are ignored in present approaches based only on conventional dose-volume histograms.     

Optimum dose range for the amelioration of long term radiation-induced hyposalivation using prophylactic pilocarpine treatment.

BACKGROUND: To determine dose and time dependency of pilocarpine pre-treatment protection from late damage after unilateral irradiation of the rat parotid gland. METHODS AND MATERIALS: The right parotid gland of saline (1mg/ml) or pilocarpine (4 mg/kg) pre-treated rats was irradiated with 10, 15 and 20 Gy. Saliva was collected from the irradiated and shielded parotid before, 30, 60, 120 and 240 days after irradiation. The number of acinar cells/gland was determined 30, 120 and 240 days after irradiation by histological examination. RESULTS: Pilocarpine pre-treated rats, protection of parotid gland function was seen in the early-intermediate phase (0-120 days) after 15 Gy and in the late phase (>120 days) after 10 and 15 Gy. Although no protection was observed after 20 Gy, a stimulatory effect of pilocarpine on the non-irradiated gland resulted in a significant increase in total saliva secretion. The increase in function after pilocarpine treatment was paralleled by a significant increase in the number of acinar cells in both the irradiated and shielded glands. CONCLUSIONS: Pre-irradiation treatment with pilocarpine induces compensatory response, at lower doses, in the irradiated and at higher doses in the non-irradiated gland reducing late damage, due to stimulation of unirradiated or surviving cells to divide.     

Effects of genistein following fractionated lung irradiation in mice

Background and purpose

This study investigated protection of lung injury by genistein following fractionated doses of radiation and its effect on tumor response.

Material and methods

C3H/HeJ mice were irradiated (100 kVp X-rays) with 9 fractions of 3.1 Gy over 30 days (approximately equivalent to 10 Gy single dose) and were maintained on a genistein diet (∼10 mg/kg). Damage was assessed over 28 weeks in lung cells by a cytokinesis block micronucleus (MN) assay and by changes in breathing rate and histology. Tumor protection was assessed using a colony assay to determine cell survival following in situ irradiation of small lung nodules (KHT fibrosarcoma).

Results

Genistein caused about a 50% reduction in the MN damage observed during the fractionated radiation treatment and this damage continued to decrease at later times to background levels by 16 weeks. In mice not receiving Genistein MN levels remained well above background out to 28 weeks after irradiation. Genistein reduced macrophage accumulation by 22% and reduced collagen deposition by 28%. There was minimal protection against increases in breathing rate or severe morbidity during pneumonitis. No tumor protection by genistein treatment was observed.

Conclusions

Genistein at the dose levels used in this study partially reduced the extent of fibrosis developing in mouse lung caused by irradiation but gave minimal protection against pneumonitis. There was no evidence that genistein caused protection of small tumors growing in the lung.     

Post-irradiation lung density changes measured by computerized tomography

To investigate the possibility of using computerized tomography (CT) as a prognostic indicator of radiation induced lung toxicity, a series of CT scans were performed on one patient. These scans suggested an increase in lung density at day 73 after an upper half body irradiation. Because of the difficulty in lung density follow-up in patients irradiated for palliation, further studies were performed with LAF1 mice. Serial scans were taken on three groups of mice: (1) control group, (2) irradiated to 11.0 Gy and (3) irradiated to 14.0 Gy. Lung density increases between 10 and 15 were observed in the two irradiated groups. The time course was dependent on dose with an earlier onset for the high dose group (14 weeks) than for the low dose group (24 weeks). These density changes were observed only a few weeks prior to the death of the animals, indicating that small animals such as mice will not likely be useful for assessing CT scanning as an early predictor of radiation damage to lungs.     

Outcome and prognostic factors for patients with non-small-cell lung cancer and severe radiation pneumonitis

PURPOSE: Radiation pneumonitis is a serious complication that develops after thoracic irradiation. The purpose of this study was to identify prognostic factors for severe radiation pneumonitis in patients with non-small-cell lung cancer. METHODS AND MATERIALS: The medical records of patients with non-small-cell lung cancer and severe radiation pneumonitis were reviewed. Variables were analyzed by univariate and stepwise multivariate analysis using the Cox regression model. RESULTS: Among the 31 patients, the mortality rate approached 50% in the first 2 months after the onset of radiation pneumonitis. The variables significantly associated with survival in the univariate analysis were tumor histologic feature, grade and extent (out-of-field or in-field) of radiation pneumonitis, oxygenation index, and serum albumin (<35 g/L or >or=35 g/L), and uric acid levels at the onset of radiation pneumonitis. Only the extent of radiation pneumonitis and serum albumin level were independently associated with survival in the multivariate analysis. CONCLUSION: The mortality rate of non-small-cell lung cancer patients with severe radiation pneumonitis is extremely high, and survival is much shorter in patients with out-of-field radiation pneumonitis or a low serum albumin level at the onset. Additional studies to investigate the factors precipitating out-of-field radiation pneumonitis should improve the management of irradiation complications.     

Low dose out-of-field radiotherapy,part 3: Qualitative and quantitative impact of scattered out-of-field radiation on MDA-MB-231 cell lines

Purpose

Patients who undergo external beam radiotherapy are at risk of developing second tumours due to scattered radiation outside the path of the primary beam. The aim of this study was to experimentally determine the in vitro radiobiological effects of scattered radiation in cells located outside the primary photon beam and to compare this to the effects that occur in cells inside the primary beam. The comparison was performed by assessing cell viability, DNA damage, and apoptosis.

Residual radiation damage in murine lung assessed by pneumonitis

The amount of radiation damage remaining in mouse lung has been assessed by retreatment from 1 to 6 months after a range of first doses. Pneumonitis at 196 days after retreatment was used as the endpoint. Lungs were first irradiated with a range of single doses (6-10 Gy). Ten Gy was the highest dose that, on its own, produced no changes in breathing rate or deaths due to pneumonitis. One to 6 months later lungs were retreated with a full range of single doses. Isoeffect doses were calculated for lethality for all retreatment times after each priming dose. The amount of residual damage remaining in the lung has been calculated as both a proportion of first doses and as the effect equivalent of remembered dose. Following a 10 Gy first dose, there was evidence of remembered irradiation injury at all retreatment intervals. After a 6 Gy priming dose, the lungs could be retreated to tolerance. The amount of residual damage was proportional to the size of first dose and was highest at 1 month (27% after 6 Gy and 70% after 10 Gy) and lowest after 3 months (0% after 6 Gy and 46% after 10 Gy). This partial recovery of lung function between 1 and 3 months was followed by an increase in amount of damage "remembered"; that is, a reduction in the retreatment dose that could be delivered. The proportion of residual damage after 10 Gy was never less than 25%. The data suggest an early target cell depletion and regeneration in the lung (within 3 months), the extent of which is dependent on the size of initial injury.     

Damage and morbidity from pneumonitis after irradiation of partial volumes of mouse lung

: The aims of this study were to: (a) define the relationship of dose and volume irradiated to damage and morbidity in mouse lung; (b) determine the threshold volume for morbidity after partial lung irradiation; and (c) determine whether the response to radiation of mouse lung is independent of the region irradiated.

: C3Hf/Kam female mice were used in this study. The fractional volume of the lung to be irradiated was determined by two methods, weights and computed tomography (CT) scanning. Two experiments were performed to define the volume effect and to determine whether the response of the mouse lung to radiation was homogeneous. In the first experiment, single doses of x-rays ranging from 12 to 20 Gy were given to partial volumes of 84%, 70%, and 40% including the base, 50%, 33%, and 17% including the apex, to 43% in the middle, and to the sum of 57% as 17% in the apex and 40% in the base. In the second experiment, the same volumes of 50% and 70–75% in the apex and base of the lung were irradiated with single doses ranging from 12–19.25 Gy. Morbidity from radiation pneumonitis was quantitated by two end points, breathing rate and lethality between 12 and 32 weeks after irradiation. Damage was assessed by histophological evidence of pneumonitis.

: Clear well-difined dose-response curves were obtained fro bot breathing rate and lethality after all volumes irradiated. There was a clear volume-dependent shift of the dose-reponse curves for breathing rate and lethality at 28 weeks after irradiation, the end of the pheumonitis phase of damage, to higher doses compared with these data after whole-lung irradiation. In addition, the slopes of teh dose-response curves for irradiation of partial lung volumes were more shallow compared to those after whole-lung irradiation. Increases in breathing rate correlated with lethality when the volume irradiated was equal to or greater than 50% of the reference volume. However, after irradiation of volumes smaller than 40%, breathing rate increases were not accompanied by death. A heterogeneous response of the mouse lung to radiation was observed in the first experiment and confirmed by the second experiment. For a given volume irradiated, the isoeffect dose was always less for the base than for the apex of the lung. The threshold volume for breathing rate changes was less than 17 and 40% when the irradiated volumes involved the apex and base, respectively. For lethality, the threshold volume was between 40 and 70% for the base and greater than 50% for the apex of the lung. Finally, damage as assessed by histological evidence of pneumonitis was observed in the irradiated area only.

: (a) The volume effect was resolve in mice, (b) the volume effect in mouse lung exhibits a clear threshold for morbidity, (c) the threshold volume for morbidity is dependent on the end point, (d) the response of mouse lung is heterogeneous, dependent on the site irradiated, and is always greater for the same volumes irradiated in the base than the apex, and, (e) histopathological damage does not always produce observable morbidity.     

Biologic and anatomic problems of lung shielding in whole-body irradiation

Lung shielding by lead blocks for reducing the dose to the lungs in whole-body irradiation results in relative protection of the leukemia cell population. The consequence is acceptable if the dose reduction is moderate (from 10 to 8 Gy) and if the shielded volume amounts to a small fraction (5%) of the body weight. The suggestion was made that certain limits should be put on the extent of shielding, so that the shielded lung fraction represents only 60% of the total lung volume.     

Partial volume rat lung irradiation: the protective/mitigating effects of Eukarion-189, a superoxide dismutase-catalase mimetic.

BACKGROUND AND PURPOSE: The purpose of the current study was to elucidate the protective/mitigating effects of a SOD-catalase mimetic, Eukarion-189 (EUK-189), on DNA damage in rat lung following irradiation. The particular focus of these studies was the efficacy of EUK-189 when given after irradiation (mitigation). PATIENTS AND METHODS: We exposed whole or lower lungs of female Sprague-Dawley rats to doses ranging from 10 to 20.5 Gray (Gy) of (60)Co gamma rays. Animals in the EUK-189 treated groups received 2 or 30 mg/kg intraperitoneally (i.p.) at various times postirradiation (PI). A micronucleus assay was used to examine DNA damage at various times up to 16 weeks PI. RESULTS: Our results indicated that EUK-189 administration after irradiation is effective at reducing micronucleus formation in lung fibroblasts at various times following radiation exposure. Treatment with EUK-189 in the first 3 days after thoracic irradiation did not, however, modify the dose required to cause severe morbidity at 2-3 months after irradiation. CONCLUSIONS: The protection produced when Eukarion-189 was given shortly after irradiation suggests that DNA damage observed in the lung may be caused by chronic production of ROS induced by a chronic inflammatory response initiated by the radiation treatment. We speculate that our failure to observe protection against severe morbidity at 2-3 months may be because our treatment regime only blocked the initial wave of ROS production and that treatment needs to be more prolonged to suppress the effects of a chronic inflammatory response.     

Hematological effects in dogs after irradiation of the lower part of the body with a single myeloablative dose

The lower body of dogs, containing approximately 30% of the total bone marrow, was exposed to 300 kV X-rays with a single myeloablative dose of 11.7 Gy, whereas the upper body was shielded by a lead box. The results of the present study are discussed in connection with recently published results obtained after irradiation of the upper body (UBI), containing approximately 70% of the total bone marrow mass. The main findings are as follows: (1) the nadir in the blood concentration of thrombocytes, lymphocytes, and granulocytes strongly depends on the volume of irradiated bone marrow; (2) apart from some quantitative differences, the time-related pattern of changes in the concentration of granulocyte/macrophage progenitor cells (GM-CFC) in irradiated and shielded bone marrow sites is very similar after irradiation of the lower part of the body (LBI) and UBI, i.e. is apparently independent of the relative amount of damaged bone marrow at volumes applied in the present models; (3) the concentration of GM-CFC in the blood after LBI shows a transient increase during the first phase of most rapid bone marrow GM-CFC regeneration, i.e. between day 7 and day 23; the magnitude of this transient increase obviously depends on the fraction of irradiated bone marrow.     

Radiobiological effect of 99mTechnetium-MIBI in human peripheral blood lymphocytes: ex vivo study using micronucleus/FISH assay

99mTc-MIBI is currently used, for cardiac investigations, for parathyroid thyroid imaging and evaluation of various tumours. It has been demonstrated that 99mTc-MIBI is specifically taken up by the human peripheral blood lymphocytes (HPBL), cells which are known to be highly radiosensitive. To evaluate the possible chromosomal damage induced on HPBL by their in vitro exposure to increasing activities of 99mTc-MIBI and also to establish whether HPBL undergo apoptosis or necrosis after in vitro exposure to 99mTc-MIBI. Blood from two healthy donors were irradiated, incubated in vitro with increasing activities of 99mTc-MIBI corresponding to absorbed doses ranging from 1 microGy, 100 microGy, 1 cGy, 10 cGy, 50 cGy to 1 Gy. The cytokinesis block micronucleus (MN) assay was used and the frequency of binucleated cells (BN) with MN (MNBN) was analyzed in cultured HPBL (in either the G0- or G1- and S1-phase of the cell cycle). The fluorescence in situ hybridization (FISH) with pancentromeric probes was also applied to study the MN regarding whole chromosomes or acentric fragments. Apoptosis induction by 0.1 Gy of 99mTc-MIBI in HPBL was quantified using annexin-V test. The frequencies of MNBC were similar in control cultures and in HBPL cultures exposed to 1 microGy, 100 microGy and 1 cGy. However, they were significantly higher (P<0.05 versus controls and lower doses) after one treatment exposure to 0.25 mCi of 99mTc-MIBI (corresponding to 10 cGy) or more but the percentages of MNBN with 10 cGy, 50 cGy and 1 Gy did not differ significantly. The increase of MNBN was more pronounced (P<0.05) for cells irradiated during G1 phase than for those irradiated during G0 or S1. Using FISH, 80-90% of the MN were centromere negative. Although small, the absolute number of MN positive for centromeric signal and presumably containing whole chromosomes increased with doses. There is a statistically significant (P=0.001 and 0.006) increase of both apoptotic cells and necrosis, respectively, as compared to control cells in two times studied (24 and 36 h). Chromosomic damages can thus be demonstrated in HPBL after in vitro exposure of blood to at least 0.25 mCi of 99mTc-MIBI corresponding to one absorbed dose of 10 cGy, and for this dose, apoptosis and necrosis phenomenons were detected.     

No change in repair capacity of mouse lung irradiated three months after a single dose of cyclophosphamide.

The repair capacity of mouse lung was determined at 3 months after a single i.p. injection of cyclophosphamide (Cy) at a maximally tolerated dose of 275 mg/kg. Mice were irradiated to the whole thorax only with 1, 2, 9, or 15 fractions of X-rays using doses/fraction ranging from 1.2 to 11 Gy. Breathing rate (breaths per minute), histology and pulmonary mortality were used to assess lung damage. Raw breathing rate data were converted to quantal response data by scoring the number of mice in each dose group in each fractionation schedule with a breathing rate 1.3 times the breathing rate of control mice. Dose-response curves of mortality and the converted breathing rate data were constructed at 15 weeks after irradiation (approximately 28 weeks after drug treatment) fitted by logit analysis and 50% effective doses with 95% confidence limits obtained. Values of alpha/beta were obtained by using the direct analysis method of H. D. Thames et al. (Int. J. Radiat. Biol., 49:999-1009, 1986). The alpha/beta for mice given Cy 3 months before radiation was 3.69 Gy (95% confidence limits, 2.83, 4.69 Gy) and 3.06 Gy (95% confidence limits, 2.31, 3.99 Gy) for the lethality data and breathing rate data, respectively. These alpha/beta values are in good agreement with the previously published ranges of alpha/beta of 3 to 4 Gy for mouse lung not given Cy previously. Because the repair capacity of the target cells of a tissue govern the fractionation response and choice of fractionation regimen in clinical radiotherapy, these data indicate that the fractionation regimen used can remain the same as that used in non-drug-treated lungs when the lung is irradiated 3 months after exposure to Cy.     

Selective mediastinal node irradiation based on FDG-PET scan data in patients with non-small-cell lung cancer: a prospective clinical study

PURPOSE: To evaluate the patterns of recurrence when selective mediastinal node irradiation based on FDG-PET scan data is used in patients with non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: A prospective Phase I/II study was undertaken on 44 patients with NSCLC without detectable distant metastases on CT and FDG-PET scan, delivering either 61.2 Gy in 34 fractions over 23 days or 64.8 Gy in 36 fractions over 24 days (1.8 Gy b.i.d. with 8-h interval). Only the primary tumor and the positive mediastinal areas on the pretreatment FDG-PET scan were irradiated. Isolated nodal failure was defined as recurrence in the regional nodes outside of the clinical target volume, in the absence of in-field failure. RESULTS: The CT and FDG-PET stage distribution was as follows: Stage I: 8 patients (18%) and 13 patients (29%); Stage II: 6 patients (14%) and 10 patients (23%); Stage IIIA: 15 patients (34%) and 7 patients (16%); Stage IIIB: 15 patients (34%) and 14 patients (32%), respectively. After a median follow-up time of 16 months (95% confidence interval [CI], 11-21 months) postradiotherapy, 11 patients (25%) developed a local recurrence. Only 1 patient (crude rate, 2.3%; upper bound of 95% CI, 10.3%), with a Stage II tumor on both CT and PET, developed an isolated nodal failure. The median actuarial overall survival was 21 months (95% CI, 14-28 months), and the median actuarial progression-free survival was 18 months (95% CI, 12-24 months). CONCLUSIONS: Selective mediastinal node irradiation based on FDG-PET scan data in patients with NSCLC results in low isolated nodal failure rates. In the Phase I component of this trial, radiation dose escalation up to 64.8 Gy in 36 fractions over 24 days is feasible.     

The density of mouse lung in vivo following X irradiation

The lungs of mice were irradiated with single X radiation doses of 5 to 14 Gy. Six weeks after irradiation, computed tomographic (CT) scans of the mice were performed at two-week intervals. Beyond 14 weeks after irradiation, the animals were scanned at 1-week intervals. The mice irradiated to 5 and 7 Gy exhibited no change in lung density, in comparison with the unirradiated lungs of control mice up to times of 48 weeks. The mice irradiated to doses of greater than 10 Gy exhibited marked increases in lung density at 15 weeks after irradiation. Increases in density followed a similar time course for these doses, but the magnitude of the density increase was dependent on the radiation dose. An interpretation of these findings in terms of radiation pneumonitis is presented, and the possibility of using Or to monitor lung density in radiotherapy patients is discussed.     

Long-term administration of a small molecular weight catalytic metalloporphyrin antioxidant, AEOL 10150, protects lungs from radiation-induced injury

PURPOSE: To determine whether administration of a catalytic antioxidant, Mn(III) tetrakis(N,N'-diethylimidazolium-2-yl) porphyrin, AEOL 10150, with superoxide dismutase (SOD) mimetic properties, reduces the severity of radiation-induced injury to the lung from single-dose irradiation (RT) of 28 Gy. METHODS AND MATERIALS: Rats were randomly divided into four different dose groups (0, 1, 10, and 30 mg/kg/day of AEOL 10150), receiving either short-term (1 week) or long-term (10 weeks) drug administration via osmotic pumps. Rats received single-dose irradiation (RT) of 28 Gy to the right hemithorax. Breathing rates, body weights, blood samples, histopathology, and immunohistochemistry were used to assess lung damage. RESULTS: There was no significant difference in any of the study endpoints between the irradiated controls and the three groups receiving RT and short-term administration of AEOL 10150. For the long-term administration, functional determinants of lung damage 20 weeks postradiation were significantly worse for RT + phosphate-buffered saline (PBS) and RT + 1 mg/kg/day of AEOL 10150 as compared with the irradiated groups treated with higher doses of AEOL 10150 (10 or 30 mg/kg/day). Lung histology at 20 weeks revealed a significant decrease in structural damage and collagen deposition in rats receiving 10 or 30 mg/kg/day after radiation in comparison to the RT + PBS and 1 mg/kg/day groups. Immunohistochemistry demonstrated a significant reduction in macrophage accumulation, oxidative stress, and hypoxia in rats receiving AEOL 10150 (10 or 30 mg/kg/day) after lung irradiation compared with the RT + PBS and 1 mg/kg/day groups. CONCLUSIONS: The chronic administration of a novel catalytic antioxidant, AEOL 10150, demonstrates a significant protective effect from radiation-induced lung injury. AEOL 10150 has its primary impact on the cascade of events after irradiation, and adding the drug before irradiation and its short-term administration have no significant additional benefits.     

Overexpression of manganese superoxide dismutase (MnSOD) in whole lung or alveolar type II cells of MnSOD transgenic mice does not provide intrinsic lung irradiation protection

Intratracheal (IT) injection of the transgene for human manganese superoxide dismutase in plasmid/liposome (SOD2-PL) complex prior to irradiation protects C57BL/6J mice from whole lung irradiation-induced organizing alveolitis/fibrosis. Transgene mRNA was detected in alveolar type II (AT-II) and tracheobronchial tree cells explanted to culture 48 hours after gene therapy. To determine whether constitutive overexpression of murine MnSOD (Sod2) in whole lung or surfactant promoter-restricted AT-II cells (SP1)-SOD2 mice would provide intrinsic radioresistance, transgenic mice of two strains were compared with age-matched controls. Other groups of surfactant promoter-restricted (SP1)-SOD2 transgenic mice or control FeVB/NHsd mice received IT SOD2-PL gene therapy prior to irradiation. There was no significant intrinsic lung protection in either strain of MnSOD transgenic mice. The SP1-SOD2 transgenic mice were protected from lung damage by IT injection of the human SOD2-PL complex 24 hours prior to irradiation. Thus, overexpression of either human SOD2 or murine Sod2 in the lungs of transgenic mice does not provide intrinsic lung irradiation protection. The overexpression of SOD2 in the SP1-SOD2 mice may have made the mice more sensitive to irradiation.     

Lung toxicity following chest irradiation in patients with lung cancer.

Classical radiation pneumonitis has been described after single dose whole lung irradiation in experimental animals where above a threshold dose of irradiation, there is a sigmoid dose response curve with increasing morbidity and mortality. After clinical fractionated irradiation, however, acute radiation pneumonitis consisting of cough shortness of breath and patchy radiological changes, occurs in <10% of patients, has dyspnoea out of proportion to the volume of lung irradiated and usually resolves completely without long-term effects. There is increasing evidence that this represents a bilateral lymphocytic alveolitis or hypersensitivity pneumonitis and has been termed sporadic pneumonitis. Late radiation toxicity results in pulmonary fibrosis. This is a consequence of repair, which is initiated by tissue injury within the radiation portal. It follows release of chemotactic factors for fibroblasts including transforming growth factor-beta, fibronectin and platelet derived growth factor. Radiation fibrosis is the clinically more significant syndrome for patients. It may result in progressive dyspnoea and mortality in patients. The most predictable change in laboratory lung function tests is a decrease in transfer factor due to damage at the capillary-alveolar level. It also results in decreased lung compliance, which will affect the total lung capacity and the forced vital capacity. The forced expiratory volume in 1 s is less affected, although this seems to depend on the volume of lung irradiated. There is also a decrease in perfusion in the irradiated lung. Radiation fibrosis seems to depend, amongst other factors, on the volume of lung, which is irradiated above a threshold of 20-30 Gy. The morbidity of radiation fibrosis may therefore be minimized by the use of dose volume histogram to minimize the volume of normal lung irradiated in patients at high risk, e.g., patients with who present with poor lung function. The importance of the baseline perfusion in the irradiated areas continues to be studied.     

Gamma irradiation induces acetylcholine-evoked, endothelium-independent relaxation and activates K-channels of isolated pulmonary artery of rats

PURPOSE: To test the effects of irradiation (R*) on the pulmonary artery (PA). METHODS AND MATERIALS: Isolated PA rings were submitted to gamma irradiation (cesium, 8 Gy/min(-1)) at doses of 20 Gy-140 Gy. Rings were placed in an organ chamber, contracted with serotonin (10(-4) M 5-hydroxytryptamine [5-HT]), then exposed to acetylcholine (ACh) in incremental concentrations. Smooth muscle cell (SMC) membrane potential was measured with microelectrodes. RESULTS: A high dose of irradiation (60 Gy) increased 5HT contraction by 20%, whereas lower (20 Gy) doses slightly decreased it compared with control. In the absence of the endothelium, 5-HT precontracted rings exposed to 20 Gy irradiation developed a dose-dependent relaxation induced by acetylcholine (EI-ACh) with maximal relaxation of 60 +/- 17% (n = 13). This was totally blocked by L-NAME (10(-4) M), partly by 7-nitro indazole; it was abolished by hypoxia and iberiotoxin, decreased by tetra-ethyl-ammonium, and not affected by free radical scavengers. In irradiated rings, hypoxia induced a slight contraction which was never observed in control rings. No differences in SMC membrane potential were observed between irradiated and nonirradiated PA rings. CONCLUSION: Irradiation mediates endothelium independent relaxation by a mechanism involving the nitric oxide pathway and K-channels.