银翘温胆汤干预大鼠放射性肺纤维化的初步实验研究

目的应用大鼠放射性肺纤维化模型观察银翘温胆汤对早期放射性肺炎和晚期肺纤维化的干预效果。探讨其在治疗放射性肺纤维化中的作用机制,以期为临床应用提供实验依据。方法将雄性大鼠45只随机分为对照组(0Gy+生理盐水)、照射组(20Gy+生理盐水)、银翘温胆汤组(20Gy+中药),单次6MV X线20Gy照射大鼠双肺,建立放射性肺纤维化模型。分别于2、4、6周时各处死5只大鼠取肺组织,进行HE染色观察肺组织病理变化,检测肺系数,用免疫组化法测转化生长因子-β1(TGF-β1)的表达。结果照射组大鼠肺损伤明显,肺系数、肺纤维化和TGF-β1的表达较对照组明显增高(P<0.05),而银翘温胆汤组大鼠比照射组的肺充血、出血、渗出性改变及肺泡壁增厚、肺纤维化程度减轻,且肺系数和TGF-β1的表达有一定程度的下降。结论银翘温胆汤对大鼠早期放射性肺炎和肺纤维化有一定程度的保护作用,其机制可能是通过抑制TGF-β1表达,使放射性肺炎及肺纤维化病变减轻。     

Elective whole lung irradiation.

Whole lung irradiation has been effective in 10 of 17 patients irradiated solely electively (no demonstrable metastatic nodules) who are alive and well 2 to 5 years. Of an additional 17 patients with only one or two demonstrable pulmonary metastases (treated with resection or boost therapy plus whole lung irradiation), 6 are alive and well 5 to 8 years. Only one patient developed clinically significant postirradiation pneumonitis and this case proved to be fatal. Elective whole lung irradiation, especially in conjunction with modern adjuvant chemotherapy, shows promise in improving the survival of patients with tumors having a high propensity for metastasizing to the lungs.     

Perfusion characteristics of radiation-injured lung on Gd-DTPA-enhanced dynamic magnetic resonance imaging

RATIONALE AND OBJECTIVES: A contrast-enhanced dynamic magnetic resonance (MR) study was performed experimentally and clinically to describe perfusion characteristics of radiation-injured lung according to pathologic phases. METHODS: The MR study was performed before and at 0.5, 1, 2, 3, 4, and 7 months after 40 Gy-dose irradiation to the right hemithorax in 8 dogs, and clinically in 12 lung lesions of 9 patients with acute or fibrotic radiation pneumonitis. Altered Gd-DTPA kinetics in the affected lungs was assessed by time-signal intensity curves. MR findings were correlated with lung histology and CT images. RESULTS: Within 1 month after irradiation, the irradiated animal lungs showed focal and persistent contrast enhancement relative to nonirradiated lungs. This abnormality was pronounced during the next 2 months. After 4 months, irradiated lungs conversely showed lower enhancement during the Gd-DTPA first-pass but were followed by persistently greater enhancement during Gd-DTPA redistribution phase. Similar differences in enhancement abnormalities between acute and fibrotic radiation pneumonitis were clinically observed. CONCLUSION: These findings indicate that Gd-DTPA kinetics can be altered according to the histopathologic change in early/acute radiation pneumonitis and radiation fibrosis and that the contrast-enhanced perfusion MRI may help differentiate the phases of radiation pneumonitis.     

Effects of IL-4 on pulmonary fibrosis and the accumulation and phenotype of macrophage subpopulations following thoracic irradiation

Purpose: Thoracic irradiation injures lung parenchyma, triggering inflammation and immune cell activation, leading to pneumonitis and fibrosis. Macrophage polarization contributes to these processes. Since IL-4 promotes pro-fibrotic macrophage activation, its role in radiation-induced lung injury was investigated.

Materials and methods: Lung macrophage subpopulations were characterized from 3–26 weeks following exposure of WT and IL-4?/? mice to 0 or 12.5 Gray single dose thoracic irradiation.

Results: Loss of IL-4 did not prevent fibrosis, but blunted macrophage accumulation within the parenchyma. At 3 weeks following exposure, cell numbers and expression of F4/80 and CD206, an alternative activation marker, decreased in alveolar macrophages but increased in infiltrating macrophages in WT mice. Loss of IL-4 impaired recovery of these markers in alveolar macrophages and blunted expansion of these populations in infiltrating macrophages. CD206+ cells were evident in fibrotic regions of WT mice only, however Arg-1+ cells increased in fibrotic regions in IL-4?/? mice only. Radiation-induced proinflammatory Ly6C expression was more apparent in alveolar and interstitial macrophages from IL-4?/? mice.

Conclusions: IL-4 loss did not prevent alternative macrophage activation and fibrosis in irradiated mice. Instead, a role is indicated for IL-4 in maintenance of macrophage populations in the lung following high single dose thoracic irradiation.     

Experimental studies on mechanisms and prevention of radiation pneumonitis

Radiation pneumonitis are well recognized as complications of radiotherapy for the thoracic malignancies. However, the pathogenesis of radiation pneumonitis has been poorly understood and prevention of it has not been developed. In this study, to define the mechanisms of radiation pneumonitis biologically, we measured lipid peroxides, the activities of glutathione peroxidase (GSH pex.), leukotriene C4 and D4 (LTC4 and LTD4) in the irradiated lungs of mice. Eight weeks old female ICR mice were sacrificed at various time periods (immediately after to 5 days) following the 10 Gy whole-body irradiation with 60Co gamma rays. The lipid peroxides and the activities of GSH pex. increased immediately after the irradiation, but returned to the control level 1 hour after the irradiation. And then, the lipid peroxides also increased from 1 day after the irradiation, while the activities of GSH pex. decreased below the control level. LTC4 and LTD4 in the irradiated lungs of mice were also significantly higher than those of non-irradiated controls. Furthermore, we investigated effects of Coenzyme Q10 and Azelastine for the prevention of radiation pneumonitis. Lungs of ICR mice after 10 Gy whole-thorax irradiation treated with those drugs were compared with the control lungs pathologically. Intraperitoneal administration of those drugs decreased the damages for endothelium, such as vacuole formation and stripping off the basement membrane which were recognized by electron microscope. Based on these results, it was strongly suggested that initial damage of irradiated lungs might be induced by lipid peroxides and leukotrienes, and that Coenzyme Q10 and Azelastine could reduce radiation pneumonitis.     

Volume and dose–response effects for severe symptomatic pneumonitis after fractionated irradiation of canine lung

Purpose : To study the dose-related incidence of severe symptomatic pneumonitis following fractionated irradiation applied to three different volumes of lung in normal beagle dogs. Materials and methods : A three-dimensional treatment planning system was used to design mediastinal fields of increasing width to irradiate 33%, 67% or 100% of both lungs combined in 128 normal beagle dogs. Total doses, ranging from 27 to 72 Gy, were delivered in 1.5Gy fractions over 6 weeks. Results : No dogs irradiated to 33% of their total lung volume developed severe symptomatic pneumonitis. In the 67% volume group, logistic fit of the data showed a dose–response curve with a 50% probability of developing severe symptomatic pneumonitis (ED50) after a total dose of 56.0 Gy (52.2–66.0 Gy, 95% confidence interval, CI). The more clinically relevant ED 5 for the first 6 months after irradiation of 67% of the lung was 48.1 Gy (18.5–52.0 Gy, 95% CI). The ED 50 and ED 5 values after irradiation of the whole lung (100%) were 44.1 Gy (41.2–53.5 Gy, 95% CI) and 39.1 Gy (8.8–41.8 Gy, 95% CI) respectively. Conclusion : Severe symptomatic pneumonitis proved to be a very informative volume-effect endpoint, clearly demonstrating that irradiated lung volume is a critical parameter to be considered in assigning thoracic radiotherapy treatment parameters. Volume effects in lung are dependent on the compensatory capacity of the nonirradiated lung. Underlying pathophysiology of irradiated tissue, as well as decreased compensatory capacity of nonirradiated tissue may have a strong effect on the dose-volume response.     

Treg分化对放射性肺损伤的影响

目的 探讨调节性T细胞（Treg）的分化对放射性肺损伤的影响及其作用机制。 方法 建立Treg抑制小鼠模型,按随机数字表法将C57BL/6小鼠分成4组：空白对照组、单纯照射组、照射+免疫球蛋白G（IgG）组和照射+CD25组,每组12只,除空白对照组外其余3组小鼠给予单次20 Gy X射线全胸照射,照射+IgG组和照射+CD25组小鼠每周腹腔注射IgG抗体和CD25抗体。分别于照射后第4周和第8周各处死小鼠6只,采用流式细胞术检测小鼠肺组织内CD25+Foxp3+Treg（Foxp3：叉头样转录因子3）的百分比以鉴定模型是否建立成功;采用Western blot法检测单纯照射组小鼠肺组织内神经纤毛蛋白1（NRP1）的表达;采用免疫荧光法检测每组小鼠肺组织内CD25+NRP1+Treg的百分比;拍照并观察每组小鼠皮肤的损伤情况,采用苏木精-伊红染色法检测小鼠肺组织的病理学改变;采用酶联免疫吸附测定法检测每组小鼠肺组织内转化生长因子β1（TGF-β1）、白细胞介素（IL）-17A、干扰素γ（IFN-γ）、IL-2和IL-4的水平变化。两组间比较采用独立样本t检验。 结果 流式细胞术检测结果显示,照射后第4周和第8周,单纯照射组小鼠肺组织内CD25+Foxp3+Treg百分比[（1.73±0.04）%、（2.13±0.15）%]均较空白对照组[（1.14±0.02）%、（1.70±0.06）%] 明显升高,差异均有统计学意义（t=−26.680、−4.545,P=0.000、0.010）,抑制Treg后,第4周和第8周时照射+CD25组小鼠肺组织内CD25+Foxp3+Treg百分比[（0.72±0.14）%、（0.27±0.02）%]均较单纯照射组明显降低,差异均有统计学意义（t=5.296、37.538,均P=0.000）。Western blot结果显示,照射后第4周和第8周,单纯照射组小鼠肺组织内NRP1蛋白表达水平均较空白对照组升高,差异均有统计学意义（t=−7.341、−9.127,均P=0.000）。免疫荧光法检测结果显示,照射后第4周和第8周,单纯照射组小鼠肺组织内CD25+NRP1+Treg的百分比均较空白对照组升高,而照射+CD25组CD25+NRP1+Treg百分比均较单纯照射组降低,且差异均有统计学意义（t=8.926、14.457,P=0.001、0.000）。观察小鼠皮肤损伤程度后发现,照射后第4周和第8周,单纯照射组小鼠皮肤损伤严重,而照射+CD25组小鼠照射后第4周时皮肤基本完好,第8周时出现脱毛脱皮。病理学结果显示,照射后第4周和第8周,与空白对照组相比,单纯照射组小鼠的肺组织结构破坏,肺泡壁增厚,细胞外基质增多,而照射+CD25组小鼠的肺组织结构完整,肺泡壁纤细。酶联免疫吸附测定结果显示,与空白对照组相比,照射后第4周,单纯照射组小鼠肺组织内IL-17A和IL-4的水平均升高,差异均有统计学意义（t=−8.492、−15.796,P=0.001、0.000）,照射后第8周,TGF-β1和IL-17A水平升高,差异均有统计学意义（t=−11.072、−7.167,P=0.000、0.002）,IL-2水平在第4周和第8周时均降低,IFN-γ水平在第4周时升高,差异有统计学意义（t=−27.393,P=0.000）,第8周时下降;与单纯照射组相比,照射+CD25组小鼠TGF-β1和IL-17A水平在第4周和第8周时均降低（t=6.037、4.524、5.496、4.772,均P=0.000）,IFN-γ水平升高（t=−7.006、−12.565,P=0.002、0.000）,差异均有统计学意义,而IL-2和IL-4水平在第4周时均降低,第8周时均明显升高,差异均有统计学意义（t=2.866、−9.090、8.833、−7.191,均P=0.000）。 结论 放射性肺损伤小鼠的肺组织中出现Treg分化,并增强分泌TGF-β1促炎因子,同时干扰辅助T细胞（Th1、Th2型）细胞因子的平衡来促进放射性肺损伤的发生。     

Hyaluronan reflects the pre-fibrotic inflammation in irradiated rat lung: concomitant analysis of parenchymal tissues and bronchoalveolar lavage

The pathogenesis of pulmonary fibrosis is a complicated chain of interactions between cells and molecules. During recent years bronchoalveolar lavage (BAL) in patients with various interstitial lung disorders has increased our knowledge of the fibrosis process and focused on new interesting interactions. Here we present an animal model which makes it possible to apply both morphological and immunohistochemical tissue staining to perform bronchoalveolar lavage in the same animal. Irradiation is an established method for experimentally evoking lung fibrosis in animals. Rats received irradiation (30 Gy) to the lower parts of both lungs. Bronchoalveolar lavage was performed in the right lung. The biochemical determination of lavage concentration of hyaluronan (HA) and cellular differential counts were compared with interstitial morphology. Animals were sacrificed and analysed 2, 4, 6, 8 and 10 weeks after irradiation. After 6 weeks a massive increase in connective tissue mast cells was seen in the peribronchial and alveolar-interstitial tissue. This mastocytosis was closely related to a marked increase in HA. It became obvious that, in this model, cellular analysis of BAL fluid did not correctly reflect the cellular changes in the lung interstitium. While BAL revealed a pronounced increase of neutrophils with no--or only very few--mast cells, a concomitant increase in mononuclear cells and mast cells was seen in the lung interstitium. In contrast an increase in HA in BAL correlated well with an increase in HA-deposition in the lung interstitium, indicating that measurement of a non-cellular component, such as HA, may better reflect the tissue inflammation.     

Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker

Purpose : This report summarizes our experiences on the protective effect of angiotensin-converting enzyme (ACE) inhibitors, especially captopril and an angiotensin II type 1 receptor blocker on radiation-induced pulmonary injury. Method : In the first series of experiments, adult male Sprague Dawley rats were given a single dose of either 20 or 30 Gy of gamma rays to a 35 cm 2 right hemithorax port, whilst shielding the left, contralateral, lung. Perfusion scans and autopsies were performed at intervals up to 12 months post-radiation. Three different ACE inhibitors, penicillamine and pentoxifylline were given as radiation protectors and their activity compared. A model of irradiation for total bone marrow transplant (BMT) was used for the second group of experiments. Male WAC/Rij/MCW rats received total-body irradiation and a regimen of cyclophosphamide (CTX) in preparation for bone marrow transplant. The modifiers were two ACE inhibitors, captopril and enalapril, and L-158,809, an angiotensin II (A II) type 1 receptor blocker. All drugs were administered in the rats? drinking water and all were well-tolerated. Results : In the irradiated rats, pulmonary damage progressed from the presence of blebs and detachment from basement membranes of endothelial cells a few days after injury, to severe arteritis and interstitial collagen deposition at 3 months, and then on to severe pneumonitis and extensive pulmonary fibrosis at 6 months. Marked increase of hydroxyproline was also found in the lungs at 6 months. These morphological changes were associated with significant decrease of ACE and plasminogen activator activity (PLA) and a marked increase of prostaglandins (PG12) and thromboxane (Txa2), substances considered as indicators of endothelial pulmonary damage. ACE inhibitors captopril, CL 24817, enalapril and CGS 13945 prevented the markers of endothelial dysfunction. Captopril and CL 24817, which contain a sulphydryl (-SH) radical in their moiety and the AII type 1 receptor blocker, L-158,809, were the most efficient in protecting the lung parenchyma from the inflammatory response and subsequent fibrosis. Penicillamine, an SH-containing compound with weak ACE inhibitory activity was also a strong antifibrotic agent but showed only modest anti-inflammatory properties. Additionally, in the irradiated rats, captopril also reduced the incidence of squamous cell skin carcinomas and subcutaneous sarcomas consequent to the highest doses of radiation. Conclusion : ACE inhibitors and one AII type 1 receptor blocker were effective in protecting lungs from radiation-induced pneumonitis and the development of lung fibrosis in two models of rat radiation injury. In the first series of experiments (unilateral irradiation), those ACE inhibitors containing a sulphydryl radical were more effective than those without it. This observation led to the question of whether this protective effect is related to inhibition of AII synthesis or rather to some of the collateral pharmacologic properties of these drugs, such as anti-oxidation or protease inhibition. The AII receptor blocker, however, was shown to be equally effective, if not better, in its antifibrotic capacity than any ACE inhibitor with or without an SH radical, reaffirming the role of AII in modulation of collagen synthesis.     

Control of radiation-induced pneumopathy and lung fibrosis by angiotensin-converting enzyme inhibitors and an angiotensin II type 1 receptor blocker

PURPOSE: This report summarizes our experiences on the protective effect of angiotensin-converting enzyme (ACE) inhibitors, especially captopril and an angiotensin II type 1 receptor blocker on radiation-induced pulmonary injury. METHOD: In the first series of experiments, adult male Sprague Dawley rats were given a single dose of either 20 or 30 Gy of gamma rays to a 35 cm2 right hemithorax port, whilst shielding the left, contralateral, lung. Perfusion scans and autopsies were performed at intervals up to 12 months post-radiation. Three different ACE inhibitors, penicillamine and pentoxifylline were given as radiation protectors and their activity compared. A model of irradiation for total bone marrow transplant (BMT) was used for the second group of experiments. Male WAC/Rij/MCW rats received total-body irradiation and a regimen of cyclophosphamide (CTX) in preparation for bone marrow transplant. The modifiers were two ACE inhibitors, captopril and enalapril, and L-158,809, an angiotensin II (A II) type 1 receptor blocker. All drugs were administered in the rats' drinking water and all were well-tolerated. RESULTS: In the irradiated rats, pulmonary damage progressed from the presence of blebs and detachment from basement membranes of endothelial cells a few days after injury, to severe arteritis and interstitial collagen deposition at 3 months, and then on to severe pneumonitis and extensive pulmonary fibrosis at 6 months. Marked increase of hydroxyproline was also found in the lungs at 6 months. These morphological changes were associated with significant decrease of ACE and plasminogen activator activity (PLA) and a marked increase of prostaglandins (PG12) and thromboxane (Txa2), substances considered as indicators of endothelial pulmonary damage. ACE inhibitors captopril, CL 24817, enalapril and CGS 13945 prevented the markers of endothelial dysfunction. Captopril and CL 24817, which contain a sulphydryl (-SH) radical in their moiety and the AII type 1 receptor blocker, L-158,809, were the most efficient in protecting the lung parenchyma from the inflammatory response and subsequent fibrosis. Penicillamine, an SH-containing compound with weak ACE inhibitory activity was also a strong antifibrotic agent but showed only modest anti-inflammatory properties. Additionally, in the irradiated rats, captopril also reduced the incidence of squamous cell skin carcinomas and subcutaneous sarcomas consequent to the highest doses of radiation. CONCLUSION: ACE inhibitors and one AII type 1 receptor blocker were effective in protecting lungs from radiation-induced pneumonitis and the development of lung fibrosis in two models of rat radiation injury. In the first series of experiments (unilateral irradiation), those ACE inhibitors containing a sulphydryl radical were more effective than those without it. This observation led to the question of whether this protective effect is related to inhibition of AII synthesis or rather to some of the collateral pharmacologic properties of these drugs, such as anti-oxidation or protease inhibition. The AII receptor blocker, however, was shown to be equally effective, if not better, in its antifibrotic capacity than any ACE inhibitor with or without an SH radical, reaffirming the role of AII in modulation of collagen synthesis.     

巨噬细胞金属蛋白酶-12在放射性肺损伤早期组织重建中的作用

目的 探讨巨噬细胞金属蛋白酶(MMP-12)在放射性肺损伤早期肺组织重建中的作用。方法 用20 Gy ⁶⁰Co γ射线对Wistar大鼠进行全胸照射,分别于照后1、2和4周进行肺组织取材,RT-PCR方法检测MMP-12基因表达,酶谱分析法检测MMP-2、MMP-9和MMP-12酶活性,组织特殊染色法检测弹力纤维降解,电镜观察Ⅱ型细胞与肺泡隔间质细胞间的"信息交流(cross talking)"现象,ELISA检测肺泡灌洗液中TGF-β1和TNF-α含量,免疫组化检测肺组织α-平滑肌肌动蛋白(α-SMA)表达。结果 照射后1、2和4周肺组织MMP-12基因表达增加,2~4周MMP-12酶活性增高;照射后1周肺泡基底膜弹力纤维出现降解断裂,4周时最为严重;电镜观察发现肺泡Ⅱ型细胞与间质细胞间发生Cross talking现象,肺泡灌洗液TGF-β1和TNF-α含量与α-SMA免疫组化阳性信号皆随照射后时间延长而增高。结论 照射后肺组织MMP-12表达增加,可能通过降解基底膜弹力纤维启动肺组织重建,导致肺损伤朝着纤维化方向发展。     

Migratory pneumonitis similar to bronchiolitis obliterans organizing pneumonia after conservative treatment of breast cancer: a case report]

We report the case of a 63-year-old woman who developed cough and fever with migratory lung infiltrates three months after completion of right breast irradiation following conservative surgery. Lung infiltrates were initially localized in the irradiated area, but later spread to unirradiated areas in both lungs. No cause of migratory pneumonitis other than irradiation was found, and we clinically diagnosed this case as radiation-induced migratory pneumonitis similar to BOOP, without lung biopsy. Steroid therapy resulted incomplete resolution of lung infiltrates. The reported case clearly differed from typical radiation pneumonitis. We suggest that lung irradiation might trigger the development of migratory pneumonitis with a clinical pattern similar to that of BOOP.     

Volume and dose-response effects for severe symptomatic pneumonitis after fractionated irradiation of canine lung

PURPOSE: To study the dose-related incidence of severe symptomatic pneumonitis following fractionated irradiation applied to three different volumes of lung in normal beagle dogs. MATERIALS AND METHODS: A three-dimensional treatment planning system was used to design mediastinal fields of increasing width to irradiate 33%, 67% or 100% of both lungs combined in 128 normal beagle dogs. Total doses, ranging from 27 to 72 Gy, were delivered in 1.5 Gy fractions over 6 weeks. RESULTS: No dogs irradiated to 33% of their total lung volume developed severe symptomatic pneumonitis. In the 67% volume group, logistic fit of the data showed a dose-response curve with a 50% probability of developing severe symptomatic pneumonitis (ED50) after a total dose of 56.0 Gy (52.2-66.0 Gy, 95% confidence interval, CI). The more clinically relevant ED5 for the first 6 months after irradiation of 67% of the lung was 48.1 Gy (18.5-52.0 Gy, 95% CI). The ED50 and ED5 values after irradiation of the whole lung (100%) were 44.1 Gy (41.2-53.5Gy, 95% CI) and 39.1 Gy (8.8-41.8 Gy, 95% CI) respectively. CONCLUSION: Severe symptomatic pneumonitis proved to be a very informative volume-effect endpoint, clearly demonstrating that irradiated lung volume is a critical parameter to be considered in assigning thoracic radiotherapy treatment parameters. Volume effects in lung are dependent on the compensatory capacity of the nonirradiated lung. Underlying pathophysiology of irradiated tissue, as well as decreased compensatory capacity of nonirradiated tissue may have a strong effect on the dose-volume response.     

CBLB502对放射性肺炎和肺纤维化的防护作用研究

目的研究CBLB502对放射性肺炎和放射性肺纤维化的防护作用，从而证实CBLB502作为临床抗放射药物的可行性。方法C57BIM6J小鼠20Gy单次照射后24h、1个月、3个月和5个月取肺组织用TUNEL方法对肺泡上皮细胞和血管内皮细胞的凋亡进行检测，HE染色观察纤维化病理变化，免疫组织化学方法检测特异性指标表达，以及受照部位皮毛和皮肤的病理变化。结果CBLB502抑制了照射后小鼠肺泡上皮细胞和血管内皮细胞的凋亡，减缓了肺纤维化进程，同时减少层黏连蛋白表达，维持表面活性蛋白B表达量，受照皮肤的炎症反应也明显减轻。结论CBLB502对照射后放射性肺炎和放射性肺纤维化的发生和进程有防护作用。     

Pulmonary radioreaction demonstrated by x-ray pictures (author's transl)

X-ray radiographs of the thorax of 119 patients suffering from Morbus Hodgkin (period of therapy VI/1974-III/1979) which have been taken during radiotherapy and at routine follow up examinations have been analysed with regard to temporal progress and extent of the pulmonary radioreaction after standardised mantle-field irradiation with a 4-MeV linear accelerator, extended-field satellite technique and tumor doses of 40-46 Gy. After a characteristic latency period without radio-morphological reaction the patients on average showed 12 weeks after beginning of irradiation signs of a beginning pneumonitis (phase I), after 15 weeks a florid pneumonitis (phase IIa), and after 20 weeks a florid pneumonitis with beginning shrinkage (phase IIb). After 5-9 months (average level 34 weeks) the pulmonary radioreaction was complete after having reached a steady paramediastinal lung fibrosis (phase IV). Classifying the radioreaction into 3 degrees of gravity a light pneumonitis was found in 44%, a medium one in 29%, and a severe pneumonitis in 16% of the cases. For clinical use it is important to know that after beginning shrinkage new expansion of mediastinum and/or of peripheral parenchymal shadows cannot be radioreactions. Primarily these new changes have to be interpreted as recurrence.     

血管内皮生长因子及其受体在博莱霉素诱发大鼠肺间质纤维化中表达的研究

 目的探讨血管内皮生长因子(Vascular endothdlial growthfactor,VEGF)及其受体(Flt-1,Flk-1)在博莱霉素致大鼠肺纤维化肺组织中的表达及意义.方法采用免疫组化方法结合图像分析处理系统,研究VEGF及其受体在博莱霉素致肺纤维化大鼠肺组织中的免疫反应.结果VEGF在正常对照组大鼠肺组织中呈弱表达,分布于肺泡Ⅱ型上皮细胞(ATEⅡ)、细支气管上皮细胞、肺泡巨噬细胞及少量的肺内间质.在实验组VEGF亦表达于上述细胞并呈高表达,两者差异有显著性意义(P＜0.05).Flt-1在正常对照组可分布于ATEⅡ、细支气管上皮细胞、血管内皮细胞,呈弱表达,实验组表达于上述细胞,其表达量在14 d组达高峰,两者比较有显著意义(P＜0.05).结论在博莱霉素致大鼠肺损伤中VEGF是肺纤维化重要的细胞因子之一,它的高表达ATEⅡ损害直接相关.     

Effects of Tobacco-smoke on Radiation-induced Pneumonitis in Rats

To investigate the effect of exposure to tobacco smoke (TS) on the development of irradiation-induced pneumonitis in rats, five groups of animals were investigated including controls (C), tobacco smoke exposed (S), irradiated (RNS) and irradiated and tobacco smoke exposed (RS). An additional group (RS/NS) was exposed to tobacco before irradiation but not afterwards. Rats were exposed to diluted mainstream cigarette smoke at a concentration of about 0·4 mg/l in a nose-only exposure system for 1/day, 5 days/week for 10 weeks. Exposure to TS started 3 weeks before irradiation in which the basal one-third of both lungs was exposed to a single dose of 28 Gy. In previous studies this dose had been shown to cause significant pneumonitis. All the animals were killed at 7 weeks after irradiation. Examination of the morphology of lung sections showed less pulmonary inflammation in the RS group than in the RNS group. This was also reflected in the results of broncoalveolar lavage (BAL) which showed a decline in cell recovery and a marked decrease in the numbers of mast cells and neutrophils in the RS rats compared with the RNS animals. The concentration of hyaluronan in lavage fluid was increased in the RNS and RS/NS group while no increase was found in the RS group. A marked increase in BAL protein was also seen in the RNS and RS/NS groups as compared with the RS group but all were significantly higher than in unirradiated controls. This indicates that smoking suppresses the radiation-induced inflammation but to a lesser degree affects the radiation-induced increase in membrane permeability as reflected by increased protein levels in BAL. Moreover, the marked effects on the numbers of mast cells and neutrophils in the RS group may indicate that these cells play an important role in the mechanism by which tobacco smoke modulates the effects of irradiation. When exposure to tobacco smoke was terminated immediately after irradiation (RS/NS), the inflammatory response was unaffected.     

The role of T-cells in radiation pneumonitis after bone marrow transplantation

Radiation pneumonitis is a frequent complication of bone marrow transplantation. In limiting the effective dose that can be given, it decreases the chances of cancer cell destruction and of graft acceptance. The incidence of radiation pneumonitis is increased if graft-versus-host disease or infection is present, presumably due to an interaction between T-cell-mediated and radiation-mediated damage. Even in the absence of graft-versus-host disease and infection, we have found that syngeneic T-cells can contribute to radiation pneumonitis in a bone marrow transplant setting. The incidence of radiation pneumonitis was higher after whole-body irradiation and bone marrow transplantation than after whole-thorax irradiation. In the former situation, but not the latter, prior thymectomy decreased the incidence of radiation pneumonitis. It is hypothesized that autoreactive T-cells escape induction of self-tolerance during regression of the immune system after whole-body irradiation and, because autoregulatory cells are eliminated, they can contribute to radiation pneumonitis. If this concept is correct, it provides another possible explanation for the sensitivity of the lung to post-transplant pneumonitis and suggests new strategies to limit the incidence of this serious transplant-related complication.