• The Korean Journal of Nuclear Medicine
• /
• v.37 no.6
• /
• pp.382-392
• /
• 2003

Purpose: Uptakes of Tc-99m MIBI (MIBI) and Tc-99m tetrofosmin (tetrofosmin) in human non-small cell lung cancer A549, multidrug-resistance associated protein (MRP) expressing cell, were investigated in vitro and in vivo. Materials and Methods: Western blot analysis and immunohistochemistry were used for detection of MRP in A549 cells with anti-MRPr1 antibody. Cellular uptakes of two tracers were evaluated at $100{\mu}M$ of verapamil (Vrp), $50{\mu}M$ of cyclosporin A (CsA) and $25{\mu}M$ of butoxysulfoximide (BSO) after incubation with MIBI and tetrofosmin for 30 and 50 min at $37^{\circ}C$, using single cell suspensions at $1{\times}10^6cells/ml$. Radioactivities in supernatants and pellets were measured with gamma well counter. A549 cells were inoculated in each flanks of 24 nude mice. Group 1 (Gr1) and Gr3 mice were treated with only MIBI or tetrofosmin, and Gr2 and Gr4 mice were treated with 70mg/kg of CsA i.p. for 1 hour before injection of 370KBq of MIBI or tetrofosmin. Mice were sacrificed at 10, 60 and 240 min. Radioactivities of organs and tumors were expressed as percentage injected dose per gram of tissue (%ID/gm). Results: Western blot analysis of the A549 cells detected expression of MRPr1 (190 kDa) and immunohistochemical staining of tumor tissue for MRPr1 revealed brownish staining in cell membrane but not P-gp. Upon incubating A549 cells for 60 min with MIBI and tetrofosmin, cellular uptake of MIBI was higher than that of tetrofosmin. Coincubation with modulators resulted in an increase in cellular uptakes of MIBI and tetrofosmin. Percentage increase of MIBI was higher than that of tetrofosmin with Vrp by 623% and 427%, CsA by 753% and 629% and BSO by 219% and 140%, respectively. There was no significant difference in tumoral uptakes of MIBI and tetrofosmin between Gr1 and Gr3. Percentage increases in MIBI (114% at 10 min, 257% at 60 min, 396% at 240 min) and tetrofosmin uptake (110% at 10 min, 205% at 60 min, 410% at 240 min) were progressively higher by the time up to 240 min with CsA. Conclusion: These results indicate that MIBI and tetrofosmin are suitable tracers for imaging MRP-mediated drug resistance in A549 tumors. MIBI may be a better tracer than tetrofosmin for evaluating MRP reversal effect of modulators.

• Radiation Oncology Journal
• /
• v.17 no.2
• /
• pp.113-119
• /
• 1999

Purpose : To evaluate possible acute toxicity and early response of concurrent radiation therapy and low dose daily cisplatin as a radiosensitizer in patients with locally advanced uterine cervical carcinomas. Materials and Method : From December 1996 to January 1999, 38 previously untreated Patients with locally advanced squamous cell carcinoma of the uterine cervix (from stage IIB to stage IIIB) were treated at Inha University Hospital. All patients underwent standard pretreatment staging Procedures after the initial evaluation by gynecologists and radiation oncologists. Sixteen Patients with huge cervical mass (>4 cm) were submitted to the group treated with concurrent radiation therapy and low dose daily cisplatin while the remainder was treated with radiation therapy alone. Radiation therapy consisted of 4500 cGy external beam irradiation to whole pelvis (midline block after 3000 cGy), 900$\~$1000 cGy boost to involved parametrium, and high dose-rate intracavitary brachytherapy (a total dose of 3000$\~$3500 cGy/500 cGy per fraction to point A, twice per week). In the group treated with low dose cisplatin concurrently, 10 mg of daily intravenous cisplatin was given from the 1st day of radiation therapy to the 20th day of radiation therapy. Acute toxicity was measured according to expanded common toxicity criteria of the NCI (C) Clinical Trials. Early response data were analyzed at minimum 4 weeks' follow-up after completion of the treatment protocol. Results: Hematolgic toxici쇼 was more prominent in patients treated with radiation therapy and cisplatin. Six of 16 patients (37.5$\~$) treated with radiation therapy and cisplatin and one of 22 patients (4.5$\~$) treated with radiation therapy alone experienced grade 3 leukopenia. In Fisher's exact test, there was statistically significant difference between two groups regarding leukopenia (P=0.030). There was no apparent difference in the frequency of gastrointestinal and genitourinary toxicity between two groups (P=0.066). Three of 16 patients (18.7$\~$) treated with radiation therapy and cisplatin and two of 22 patients (9.1$\~$) treated with radiation therapy alone experienced more than 5 kg weight loss during the treatment. There was no statistically significant difference on weight loss between two groups (P=0.63). Two patients on each group were not evaluable for the early response because of incomplete treatment. The complete response rate at four weeks' follow-up was 80$\~$(16/20) for the radiation therapy alone group and 78$\~$ (11/14) for the radiation therapy and cisplatin group. There was no statistically significant difference in early response between two treatment groups (P=0.126). Conclusion : This study led to the conclusion that the hematologic toxicity from the treatment with concurrent radiation therapy and low dose daily cisplatin seems to be more prominent than that from the treatment of radiation therapy alone. There was no grade 4 hematologic toxicity or mortality in both groups. The hematologic toxicity in both treatment groups seems to be well managable modically. Since the risk factors were not balanced between two treatment groups, the direct comparison of early response of both groups was not possible. However, preliminary results regarding early response for patients with bulky cervical tumor mass treated with radiation therapy and low dose daily cisplatin was encouraging. Longer follow-up is necessary to evaluate the survival data. A phase III study is needed to evaluate the efficacy of concurrent daily low dose cisplatin with radiation therapy in bulky cervical cancer.

• Radiation Oncology Journal
• /
• v.22 no.3
• /
• pp.192-199
• /
• 2004

Purpose: To determine the patterns on evaluation and treatment in the patient with early breast cancer treated with conservative surgery and radiotherapy and to improve the radiotherapy techiniques, nationwide survey was peformed. Materials and Methods: A web-based database system for korean Patterns of Care Study (PCS) for 6 common cancers was developed. Two hundreds sixty-one randomly selected records of eligible patients treated between 1998$\~$1999 from 15 hospitals were reviewed. Results: The patients ages ranged from 24 to 85 years(median 45 years). Infiltrating ductal carcinoma was most common histologic type (88.9$\%$) followed by medullary carcinoma (4.2$\%$) and infiltrating lobular carcinoma (1.5$\%$). Pathologic T stage by AJCC was T1 in 59.7$\%$ of the casses, T2 in 29.5$\%$ of the cases, Tis in 8.8$\%$ of the cases. Axillary lymph node dissection was peformed I\in 91.2$\%$ of the cases and 69.7$\%$ were node negative. AJCC stage was 0 in 8.8$\%$ of the cases, stage I in 44.9$\%$ of the cases, stage IIa in 33.3$\%$ of the cases, and stage IIb in 8.4$\%$ of the cases. Estrogen and progesteron receptors were evaluated in 71.6$\%$, and 70.9$\%$ of the patients, respectively. Surgical methods of breast-conserving surgery was excision/lumpectomy in 37.2$\%$, wide excision in 11.5$\%$, quadrantectomy in 23$\%$ and partial mastectomy in 27.5$\%$ of the cases. A pathologically confirmed negative margin was obtained in 90.8$\%$ of the cases. Pathological margin was involved with tumor in 10 patients and margin was close (less than 2 mm) in 10 patients. All the patients except one recieved more than 90$\%$ of the planned radiotherapy dose. Radiotherapy volume was breast only In 88$\%$ of the cases, breast+supraclavicular fossa (SCL) in 5$\%$ of the cases, and breast+ SCL+ posterior axillary boost in 4.2%$\%$of the cases. Only one patient received isolated internal mammary lymph node irradiation. Used radiation beam was Co-60 in 8 cases, 4 MV X-ray in 115 cases, 6 MV X-ray in 125 cases, and 10 MV X-ray in 11 cases. The radiation dose to the whole breast was 45$\~$59.4 Gy (median 50.4) and boost dose was 8$\~$20 Gy (median 10 Gy). The total radiation dose delivered was 50.4$\~$70.4 Gy (median 60.4 Gy). Conclusion: There was no major deviation from current standard in the patterns of evaluation and treatment for the patients with early breast cancer treated with breast conservation method. Some varieties were identified in boost irradiation dose. Separate analysis for the datails of radiotherapy planning will be followed and the outcome of treatment is needed to evaluate the process.

• Radiation Oncology Journal
• /
• v.25 no.2
• /
• pp.79-92
• /
• 2007

[ $\underline{Purpose}$ ]: For the first time, a nationwide survey in the Republic of Korea was conducted to determine the basic parameters for the treatment of esophageal cancer and to offer a solid cooperative system for the Korean Pattern of Care Study database. $\underline{Materials\;and\;Methods}$: During $1998{\sim}1999$, biopsy-confirmed 246 esophageal cancer patients that received radiotherapy were enrolled from 23 different institutions in South Korea. Random sampling was based on power allocation method. Patient parameters and specific information regarding tumor characteristics and treatment methods were collected and registered through the web based PCS system. The data was analyzed by the use of the Chi-squared test. $\underline{Results}$: The median age of the collected patients was 62 years. The male to female ratio was about 91 to 9 with an absolute male predominance. The performance status ranged from ECOG 0 to 1 in 82.5% of the patients. Diagnostic procedures included an esophagogram (228 patients, 92.7%), endoscopy (226 patients, 91.9%), and a chest CT scan (238 patients, 96.7%). Squamous cell carcinoma was diagnosed in 96.3% of the patients; mid-thoracic esophageal cancer was most prevalent (110 patients, 44.7%) and 135 patients presented with clinical stage III disease. Fifty seven patients received radiotherapy alone and 37 patients received surgery with adjuvant postoperative radiotherapy. Half of the patients (123 patients) received chemotherapy together with RT and 70 patients (56.9%) received it as concurrent chemoradiotherapy. The most frequently used chemotherapeutic agent was a combination of cisplatin and 5-FU. Most patients received radiotherapy either with 6 MV (116 patients, 47.2%) or with 10 MV photons (87 patients, 35.4%). Radiotherapy was delivered through a conventional AP-PA field for 206 patients (83.7%) without using a CT plan and the median delivered dose was 3,600 cGy. The median total dose of postoperative radiotherapy was 5,040 cGy while for the non-operative patients the median total dose was 5,970 cGy. Thirty-four patients received intraluminal brachytherapy with high dose rate Iridium-192. Brachytherapy was delivered with a median dose of 300 cGy in each fraction and was typically delivered $3{\sim}4\;times$. The most frequently encountered complication during the radiotherapy treatment was esophagitis in 155 patients (63.0%). $\underline{Conclusion}$: For the evaluation and treatment of esophageal cancer patients at radiation facilities in Korea, this study will provide guidelines and benchmark data for the solid cooperative systems of the Korean PCS. Although some differences were noted between institutions, there was no major difference in the treatment modalities and RT techniques.

• Radiation Oncology Journal
• /
• v.22 no.1
• /
• pp.40-54
• /
• 2004

Purpose : Captopril (angiotension converting enzyme inhibitor) is known to have a radioproptective effect in the lungs, intestines and skin, but its effect in the heart is unclear. To investigate the radioprotectlve efiect and mechanism of captopril on the heart, the histopathological changes and immunohistochemical stains were compared with radiation alone, and radiation combined with captopril, in the rats. Materials and Methods : The histopathological changes and immunohistochemical stains ($TNF{\alpha}$, $TGF{\beta}1$, PDGF and FGF2) were examined in the radiation alone and the combined captopril and radiation groups, 2 and 8 weeks after irradiation. Each group consisted of 8 to 10 rats (Sprague-Dawley). Irradiation (12.5 Gy) was given to the left hemithorax in a single fraction. Captopril (50 mg/Kg/d) mixed with water, was given orally and continuously from the first week prior to, up to the 8th week of the experiment. Results : In the radiation alone group, the ventricle at 2 weeks after irradiation showed prominent edema (p=0.082) and fibrin deposit (p=0.018) compared to the control group. At 8 weeks, the edema was decreased and fibrosis increased compared to those at 2 weeks. The histopathological changes of the combined group were similar to those of the control group, due to the reduced radiation toxicity at 2 and 8 weeks. The endocardial fibrin deposit (p=0.047) in the atrium, and the interstitial fibrin deposit (p=0.019) and edema (p=0.042) of the ventricle were reduced significantly in the combined group compared to those in the radiation alone group at 2 weeks. The expressions of $TNF-{\alpha}$, $TGF-{\beta}1$, PDGF and FGF-2 in the radiation alone group were more increased than in the control group, especially in the pericardium and endocardium of the atrium at 2 weeks. At 8 weeks, the pericardial $TNF-{\alpha}$ and $TGF-{\beta}1$ in the radiation alone group continuously increased. The expressions of $TNF-{\alpha}$, $TGF-{\beta}1$ and PDGF were decreased in the combined group at 2 weeks. At 8 weeks, the expressions of $TNF-{\alpha}$ in the atrial and ventricular pericardia were markedly reduced (p=0.049, p=0.009). Conclusion : This study revealed that the early heart damage induced by radiation can be reduced by the addition of captopril in a rat model. The expressions of $TNF-{\alpha}$, $TGF-{\beta}1$ and PDGF were further decreased in the combined compared to the radiation alone group at both 2 and 8 weeks. From these results, it may be concluded that these cytokines probably play roles in the radioprotective mechanism of captopril from the radiation-induced heart toxicity, similarly to in other organs.

• Radiation Oncology Journal
• /
• v.14 no.3
• /
• pp.221-228
• /
• 1996

Purpose : We tried to evaluate the clinical characteristics, the treatment methods, the results of treatments, and the Patterns of failure in ovarian dysgerminoma retrospectively According to the results we would like to suggest the proper management guideline of stage la ovarian dysgerminoma patients who want to maintain fertility. Materials and Methods : Between 1975 and 1990, 34 patients with ovarian dysgerminoma were treated at the Yonsei University Hospital. The case records of these patients have been reviewed for presenting symptoms, treatment methods, local control and survival following treatment. Excluded from analysis were five patients with mixed ovarian germ cell tumors and gonadoblastomas (46,XY) Treatment results of the twenty nine patients were analysed by each treatment modality. Twenty one patients were treated with surgery and postoperative adjuvant radiotherapy (group 2). The other eight patients were treated with operation alone (group 2). The median age of twenty-nine patients was 23 years with a range of 8 to 39 years. Presenting symptoms were abdominal mass (20) pelvic discomfort or pain (5) et al. Radiotherapy was performed by 10MV LINAC or Co-60 teletherapy unit. The total radiation dose of the whole abdomen was 20-25 Gy/3weeks, 1-1.5 Gy/fraction with a boost to the whole pelvis 10-15 Gy/l-2weeks 1.8-2.0 Gy/fraction. Advanced stage disease (stage II or stage III) patients received prophylactic mediastinal and supraclavicular irradiation to a dose of 16-26 Gy. Median duration of follow-up of living patients was 80 months (range 13-201 months). Results : All of the twenty one patients of group 1 were alive without disease ($100\%$). Among the eight patients who were not treated with radiotherapy (group 2), six patients developed local recurrence. Four Patients referred with recurrent disease were treated with salvage radiotherapy. Three of four patients were salvaged and one Patient who had recurrent intra-abdominal disease died of progressed carcinomatosis at 11 months after salvage radiotherapy. The other two patients with recurrence were salvaged with chemotherapy (1 patient) or re-operation (1 Patient). Twenty eight patients remained alive without disease at last follow up, so the 5 year local control rate and 5 year overall survival rate for all groups were $96.6\%$ (28/29), respectively. Among thirteen patients with stage la unilateral tumors seven patients were treated with postoperative radiotherapy and the other six patients were treated with unilateral salpingo-oophorectomy alone. Five patients who did not received radiotherapy developed local failure but all of the recurrent ovarian dysgerminomas were salvaged with radiotherapy, chemotherapy or re-operation. So all the 13 patients with stage la ovarian dysgerminoma were free of disease from 20-201 months (median 80 months). Conclusion : The authors consider external irradiation to be an effective treatment as a complement to surgery in ovarian dysgerminoma. For those patients with disease presenting in stage la tumors who wish to maintain fertility, unilateral salpingo-oophorectomy alone may be curative and spare ovarian function considering excellent salvage rate of recurrent ovarian dysgerminoma in present study.

• Radiation Oncology Journal
• /
• v.20 no.4
• /
• pp.323-327
• /
• 2002

Purpose : To evaluate the outcome of early stage non-small cell lung cancer patients who were treated with radiation therapy alone and define the optimal radiotherapeutic regimen for these patients. Materials and Methods : A retrospective review was peformed on patients with sage I or II non-small cell carcinoma of the lung that were treated at our institution between June, 1987 and May, 2000. A total of 21 patients treated definitively with radiation therapy alone were included in this study. The age of the patients ranged from 53 to 81 years with a median of 66 years. All the patients were male. The medical reasons for inoperability were lack of pulmonary reserve, cardiovascular disease, poor performance status, old age, and patient refusal in the decreasing order. Pathological evidence was not adequate to characterize the non-small cell subtype in two patients. Of the remaining 19 patients, 16 had squamous cell carcinoma and 3 had adenocarcinoma. Treatment was given with conventional fractionation, once a day, five times a week. The doses to the primary site ranged from 56 Gy to 59 Gy. No patients were lost to follow-up. Results : The overall survival rates for the entire group at 2, 3 and 5 years were 41, 30 and $21\%$, respectively. The cause specific survivals at 2, 3 and 5 years were 55, 36 and $25\%$, respectively. An intercurrent disease was the cause of death in two patients. The cumulative local failure rate at 5 years was $43\%$. Nine of the 21 patients had treatment failures after the curative radiotherapy was attempted. Local recurrences as the first site of failure were documented in 7 patients. Therefore, local failure alone represented $78\%$ of the total failures. Those patients whose tumor sizes were less than 4 cm had a significantly better 5 year disease free survival than those with tumors greater than 4 cm $(0\%\;vs\;36\%)$. Those patients with a Karnofsky performance status less than 70 did not differ significantly with respect to actuarial survival when compared to those with a status greater than 70 $(25\%\;vs\;26\%,\;p>0.05)$. Conclusion : Radiation therapy 리one is an effective and safe treatment for early stage non-small ceil lung cancer patients who are medically inoperable or refuse surgery. Also we believe that a higher radiation dose to the primary site could improve the local control rate, and ultimately the overall survival rate.

• Tuberculosis and Respiratory Diseases
• /
• v.44 no.4
• /
• pp.871-888
• /
• 1997

Background : It is now thought that the earliest manifestation of idiopathic pulmonary fibrosis is alveolitis, that is, an accumulation of inflammatory and immune effector cells within alveolar walls and spaces. Inflammatory cells including alveolar macrophages and resident normal pulmonary tissue cells participate through the release of many variable mediators such as inflammatory growth factors and cytokines, which contribute to tissue damage and finally cause chronic pulmonary inflammation and fibrosis. This study was performed to investigate the source and distribution pattern of transforming growth factor-${\beta}_1$(TGF-${\beta}_1$), platelet derived growth factor(PDGF), basic fibroblast growth factor(bFGF), interleukin 1(IL-1), interleukin 6(IL-6), tumor necrosis factor-$\alpha$ (TNF-$\alpha$) and the role of these mediators on bleomycin(BLM)-induced pulmonary injury and fibrosis in rats. Method : Wistar rats were divided into three groups(control group, BLM treated group, BLM and vitamine E treated group). Animals were sacrificed periodically at 1, 2, 3, 4, 5, 7, 14, 21, 28 days after saline or BLM administration. The effects were compared to the results of bronchoalveolar lavage fluid analysis, light microscopic findings, immunohistochemical stains for six different mediators(TGF-${\beta}_1$, PDGF, bFGF, IL-1, IL-6 and TNF-$\alpha$) and mRNA in situ hybridization for TGF-${\beta}_1$. Results : IL-1 and IL-6 are maximally expressed at postbleomycin 1~7th day which are mainly produced by neutrophils and bronchiolar epithelium. It is thought that they induce recruitment of inflammatory cells at the injury site. The expression of IL-1 and IL-6 at the bronchiolar epithelium within 7th day is an indirect evidence of contribution of bronchiolar epithelial cells to promote and maintain the inflammatory and immune responses adjacent to the airways. TNF-$\alpha$ is mainly produced by neutrophils and bronchiolar epithelial cells during 1~5th day, alveolar macrophages during 7~28th day. At the earlier period, TNF-$\alpha$ causes recruitment of inflammatory cells at the injury site and later stimulates pulmonary fibrosis. The main secreting cells of TGF-${\beta}_1$ are alveolar macrophages and bronchiolar epithelium and the target is pulmonary fibroblasts and extracellular matrix. TGF-${\beta}_1$ and PDGF stimulate proliferation of pulmonary fibroblasts and TGF-${\beta}_1$ and bFGF incite the fibroblasts to produce extracellular matrix. The vitamine E and BLM treated group shows few positive cells(p<0.05). Conclusion : After endothelial and epithelial injury, the neutrophils and bronchiolar epithelium secrete IL-1, IL-6, TNF-$\alpha$ which induce infiltration of many neutrophils. It is thought that variable enzymes and $O_2$ radicals released by these neutrophils cause destruction of normal lung architecture and progression of pulmonary fibrosis. At the 7~28th day, TGF-${\beta}_1$, PDGF, bFGF, TNF-$\alpha$ secreted by alveolar macrophages sting pulmonary fibroblasts into proliferating with increased production of extracellular matrix and finally, they make progression of pulmonary fibrosis. TNF-$\alpha$ compares quite important with TGF-${\beta}_1$ to cause pulmonary fibrosis. Vitamine E seems to decrease the extent of BLM induced pulmonary fibrosis.

• Radiation Oncology Journal
• /
• v.17 no.2
• /
• pp.91-99
• /
• 1999

Propose : This study was performed to find out the prognostic factors affecting local control, survival and disease free survival rate in nasopharyngeal carcinomas treated with chemotherapy and radiation therapy. Materials and Methods : We analysed 47 patients of nasopharyngeal carcinomas, histologically confirmed and treated at Chonnam University Hospital between July 1986 and June 1996, retrospectively. Range of patients' age were from 16 to 80 years (median; 52 years). Thirty three (70$\%$) patients was male. Histological types were composed of 3 (6$\%$) keratinizing, 30 (64$\%$) nonkeratinizing squamous cell carcinoma and 13 (28$\%$) undifferentiated carcinoma. Histoiogicai type was not known in 1 patient (2$\%$). We restaged according to the staging system of 1997 American Joint Committee on Cancer Forty seven patients were recorded as follows: 71: 11 (23$\%$), T2a; 6 (13$\%$), T2b; 9 (19$\%$), 73; 7 (15$\%$), 74: 14 (30$\%$), and NO; 7 (15$\%$), Nl: 14 (30$\%$), N2; 21 (45%), N3: 5 (10%). Clinical staging was grouped as follows: Stage 1; 2 (4$\%$), IIA: 2 (4$\%$), IIB; 10 (21$\%$), III; 14 (30$\%$), IVA; 14 (30$\%$) and IVB; 5 (11$\%$). Radiation therapy was done using 6 MV and 10 MV X- ray of linear accelerator. Electron beam was used for the Iymph nodes of posterior neck after 4500 cGy. The range of total radiation dose delivered to the primary tumor was from 6120 to 7920 cGy (median; 7020 cGy). Neoadjuvant chemotherapy was performed with cisplatin +5-fluorouracil (25 patients) or cisplatin+pepleomycin (17 patients) with one to three cycles. Five patients did not received chemotherapy. Local control rate, survival and disease free suwival rate were calculated by Kaplan-Meier method. Generalized Wilcoxon test was used to evaluate the difference of survival rates between groups. multivariate analysis using Cox proportional hazard model was done for finding prognostic factors. Results: Local control rate was 81$\%$ in 5 year. Five year survival rate was 60$\%$ (median survival; 100 months). We included age, sex, cranial nerve deflicit, histologic type, stage group, chemotherapy, elapsed days between chemotherapy and radiotherapy, total radiation dose, period of radiotherapy as potential prognostic factors in multivariate analysis. As a result, cranial none deficit (P=0.004) had statistical significance in local control rate. Stage group and total radiation dose were significant prognostic factors in survival (P=0.000, P=0.012), and in disease free survival rates (P=0.003, P=0.008), respectively. Common complications were xerostomia, tooth and ear problems. Hypothyroidism was developed in 2 patients. Conclusion : In our study, cranial none deficit was a significant prognostic factor in local control rate, and stage group and total radiation dose were significant factors in both survival and disease free survival of nasopharyngeal carcinoma. We have concluded that chemotherapy and radiotherapy used in our patients were effective without any serious complication.

• Tuberculosis and Respiratory Diseases
• /
• v.44 no.2
• /
• pp.379-390
• /
• 1997

Background : It has long been suggested that neutrophils and their products are implicated as the central mediators of the acute lung injuries. Contrary to the dominant role of neutrophils in ARDS, many cases of ARDS has occurred in the setting of severe neutropenia without pulmonary neutrophil infiltration. Therefore it is certain that effector cell(s) other than neutrophil play an important role in the pathogenesis of ARDS. This experiment was performed to define the mechanism of ARDS in the setting of neutropenia, 1) by comparing the severity of endotoxin-induced lung injury, 2) by measurement of hydrogen peroxide production and cytokine concentration in the bronchoalveolar lavage cells and fluids obtained from different rats with and without cyclophosphamide-pretreatment. Method : The male Sprague-Dawleys were divided into the normal control (NC)-, endotoxin (ETX)-, and cyclophosphamide (CPA)-group in which neutropenia was induced by injecting cyclophosphamide intraperitoneally. Acute lung injury was evoked by injecting lipopolysaccharide (LPS) into a tail vein. The bronchoalveolar lavage (BAL) was performed at 3 and 6 hour after administration of LPS to measure the change of cell counts and concentrations of protein and cytokines, tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6). Hydrogen peroxide (HPO) production from BAL cells was measured at 6 hour after LPS administration by phenol red microassay with and without zymosan stimulation. Results : The results were as follows. A change of leukocyte counts in the peripheral blood after treatment with CPA : More than 95% of total leukocytes and neutrophils were reduced after CPA administration, resulting in severe neutropenia. A change of BAL cells : In the ETX-group, the number of total cells (p < 0.01) and of macrophage and neutrophil (p < 0.05) were increased at 3 and 6 hour after LPS administration compared to those of NC-group. In the CPA-group, the number of total leukocyte and macrophage were not changed after LPS administration, but neutrophil counts were significantly reduced and it took part in less than 0.1% of total BAL cells (p < 0.01 vs NC-group). BAL cells in this group were almost all macrophages (99.7%). A change of protein concentration in the BALF : In the ETX-group, protein concentration was increased at 3 hour and was more increased at 6 hour after LPS administration (p < 0.05 and < 0.01 vs NC-group, respectively). In the CPA-group, it was also significantly elevated at 3 hour after LPS administration (p < 0.05 vs NC-group), but the value was statistically not different from that of ETX-group. The value measured at 6 hour after LPS administration in the CPA-group became lower than that of ETX-group (p < 0.05), but showed still a higher value compared to that of NC-group (p < 0.05). A change of cytokine concentration in the BALF : TNF -alpha and IL-6 were elevated in the ETX - and CPA-group compared to those of NC-group at both time intervals. There was no statistical difference in the values of both cytokines between the ETX- and CPA-groups. Measurement of hydrogen peroxide production from BAL cells : There was no intergroup difference of HPO production from resting cells. HPO production after incubation with opsonized zymosan was significantly elevated in all groups. The percent increment of HPO production was highest in the ETX-group (89.0%, p < 0.0008 vs NC-group), and was 42.85 in the CPA-group (p = 0.003 vs NC-group ). Conclusion : Acute lung injury in the setting of neutropenia might be caused by functional activation of resident alveolar macrophages.