Jkstro004 · 2005. 4. 25. · 대한방사선종양학회지 2004;22(1):40～54 방사선 조사 후 발생한 흰쥐 심장손상에서 Captopril의 방어역할과 기전 2003 12

대한방사선종양학회지 2004;22(1):40～54

방사선 조사 후 발생한 흰쥐 심장손상에서 Captopril의 방어역할과 기전

2003 12 8 2004 2 27.

: , Tel: 02)2127-5390, Fax: 02)2127-5383E-mail: [email protected]

장승희 외 2인: 방사선 조사 후 발생한 흰쥐 심장손상에서 Captopril의 방어역할과 기전

대한방사선종양학회지 2004;22(1):40～54


대한방사선종양학회지 2004;22(1):40～54


대한방사선종양학회지 2004;22(1):40～54

RT (2W) RT+C (2W) RT (8W) RT+C (8W)

3.0

0.0

2.5

2.0

1.5

0.5

1.0

Endocardial fibrin deposit (2W) / fibrosis (8W)Pericardial fibrin deposit (2W) / fibrosis (8W)

A

Perivascular edema (2W)Interstitial fibrin deposit (2W) / fibrosis (8W)

Inflammation (2W / 8W)Interstitial edema (2W) / Edema (8W)


3.0

0.0

2.5

2.0

1.5

0.5

1.0

Endocardial fibrin deposit (2W) / fibrosis (8W)Pericardial fibrin deposit (2W) / fibrosis (8W)

B

Perivascular fibrosis (8W)Interstitial fibrin deposit (2W) / fibrosis (8W)

Interstitial edema (2W) / Edema (8W)Perivascular edema (2W)

Inflammation (2W / 8W)


대한방사선종양학회지 2004;22(1):40～54

TGF- 1 PericadiumβTNF- Pericadiumα

A


3.0

0.0

2.5

2.0

1.5

0.5

1.0

FGF-2 PericadiumPDGF Pericadium

TGF- 1 Endocardiumβ TGF- 1 InterstitiumβTNF- Endocardiumα TNF- Interstitiumα

FGF-2 EndocardiumPDGF Endocardium PDGF Myocardium

B


3.0

0.0

2.5

2.0

1.5

0.5

1.0


대한방사선종양학회지 2004;22(1):40～54

Radiation-induced heart disease; an update. Prog Cardiovasc Dis 1984;27:173-194

Late cardiac, thyroid and pulmonary sequelae

of mantle radiotherapy for Hodgkin's disease. Int J Radiat Oncol Biol Phys 1985;11:1925-1931

Late effects after mantle radiotherapy in patients with Hodgkin's


disease. Ann Oncol 1990;1:355-363 Long-

term cardiac morbidity and mortality in a randomized trial of pre-and postoperative radiation therapy versus surgery alone in primary breast cancer. Radiother Oncol 1998;48(2): 185-190

Radiation-induced heart disease. A study of 25

patients. Radiology 1967;89:302-310 Radiation induced cardiomyopathy. 1. An electron

microscopic study of cardiac muscle cells. Am J Pathol 1973;73:131-146

Pathology of experimental radiation pancarditis. I. Observation on radiation-induced heart injuries following a single dose of X-ray irradiation to rabbit heart with special reference to its pathogenesis. Acta Pathol Jpn 1980;30: 59-78

Radi-ation injury to the heart. Int J Radiat Oncol Biol Phys 1995; 31(5):1205-1211

Response of swine skin microvasculature to acute single exposures of x-rays: Quantification of endothelial changes. Radiat Res 1984;98: 37-51

Pathogenesis of radiation in-duced myocardial fibrosis. Lab Invest 1973;29:244-257

The unique physiology of endothelial cells and its implications in radiobiology. Front Radiat Ther Oncol 1989;23:96-112

Endothelial alkaline phosphatase activity loss as an early stage in the development of radiation induced heart disease in rats. Radiat Res 1987;110:118-128

In vitro growth potential of fibroblast isolated from pigs with radiation-induced fibro-sis. Int J Radiat Biol 1986;49:821-828

Susceptibility of irradiated bo-vine aortic endothelial cells to injury. Am J Pathol 1988;133: 277-284

Captopril re-duces collagen and mast cell accumulation in irradiated rat lung. Int J Radiat Oncol Biol Phys 1990B;19:1405-1409

Temporal sequence of early alterations in rat lung follow-ing thoracic X-irradiation. Int J Radiat Biol 1991;59:657-677

Cardiac interstitium in health and disease. J Am Col Cardio 1989;13:1637-1652

Effect of capto-pril on changes in rats` hearts induced by long-term irradi-ation. Radiat Res 1993;133:187-197

Progressive cardiac fibrosis and myocyte injury in v-fps transgenic mice. Lab Invest 1991;64:457-462

Structural changes in the auricles of the rat heart after local ionizing irradiation. Radiother Oncol 2001;58(3):303-311

Radiation induced heart disease in rats. Int J Radiat Oncol Biol Phys 1985;11:801-808

Radiation-induced damage of the Wistar rat heart: biochemistry and function. Radiother Oncol 1993;27:216-222

Effects of single doses of radi-ation on cardiac function in the rat. Radiother Oncol 1985;3: 339-345

Endothelial cell proliferation in the rat heart following local heart irradiation. Int J Radiat Biol 1990; 57(5):1017-1030

Molecular biology mechanisms in the radiation induction of pulmonary injury syndromes: Interrelationship between the alveolar macro-phage and the septal fibroblast. Int J Radiat Oncol Biol Phys 1992;24:93-101

Cellular basis of radiation- induced fibrosis Radiother Oncol 1995;35:83-90

Mo-lecular and cellular basis of radiation fibrosis. Int J Radiat Biol 1998;73(4):401-408

Long-term overproduction of collagen in radiation- induced fibrosis. Radiat Res 1991;125:14-19

Latent-time estimation for late cutaneous and subcutaneous radiation reactions in a single-follow-up clinical study. Radiother Oncol 1989;15:267-274

Radiation hepatology of the rat: Parenchymal and nonparenchymal cell injury. Radiat Res 1993;136:205-213

Transforming growth factor beta stimulates mitogenically mouse NIH 3T3 fibroblasts and those cells transformed by the EJ-H-ras oncogene. Growth Factors 1992;6:265-275

Cytokines and pulmonary fibrosis. Thorax 1993;48:931-935

Temporal modulation of TGF- 1 and -actin gene expression in pig skin and muscular fibrosis after ionizing radiation. Radiat Res 1993;134:63-70

TGF- 1 and radiation fibrosis: A master switch and a specific therapeutic target? Int J Radiat Oncol Biol Phys 2000;47(2):277-290

Growth factors in skin wound healing. Eur J Cell Biol 1995;68:1-7

A perpetual cascade of cytokines post- irradiation leads to pulmonary fibrosis. Int J Radiat Oncol Biol Phys 1995;33:99-109

Early and persistent alteration in the expression of interleukin-1, interleukin-1 and TNF

대한방사선종양학회지 2004;22(1):40～54

mRNA levels in fibrosis-resistant and fibrosis-sensitive mice after thoracic irradiation. Radiat Res 1996;145:762-767

In-creased concentrations of tumor necrosis factor in cachetic patients with severe chronic heart failure. Br Heart J 1991; 66:356-358

Basic mechanisms in congesitive heart failure recognizing the role of proinflammatory cyto-kine. Chest 1994;105:891-904

Cytokines and cardiac contractile function. Circulation 1997;95:778-781

Production of 13-hydroxy- octadecadienoic acid and tumor necrosis factor- by mu-rine peritoneal macrophages in response to irradiation. Radiat Res 1994;139:103-108

The underlying cellular mechanism of fibrosis. Kidney Int 1996;Suppl 54:S32-36

Transforming growth factor (TGF- ) caused a persistent increase in steady state amounts of type I and type III collagen and fibronectin mRNAs in normal human fibroblasts. Biochem J 1987;247:597-604

Transforming growth factor stimulates the expression of -2-macroglobulin by cultured bovine adre-nocortical cells. J Biol Chem 1990;265:2881-2887

Expression of 72-kDa gelatinase, collagenase and tissue metalloproteinase inhibitor (TIMP) in primary pig skin fibro-blast cultures derived from radiation-induced skin fibrosis. J Invest Derma 1994;102:945-950

Changes in plasma transforming growth factor beta during radiotherapy and the risk of symptomatic radiation- induced pneumonitis. Int J Radiat Oncol Biol Phys 1997;37: 253-258

Trans-forming Growth Factor beta-1 in acute myocardial infraction in rats. Growth Factors 1988;1:91-99

Hypertrophic stimuli induce transforming growth factor-beta 1 expression in rat ventricular myocytes. J Clin Invest 1994;94(4):1470-1476

Transforming growth factor-beta in tissue fibrosis. N Engl J Med 1994;331(19):1286-1292

Control of radiation-induced and lung fibrosis by angiotensin-con-verting enzyme inhibitors and angiotensin II type 1 receptor blocker. Int J Radiat Biol 2000;76(4):523-532

Radiation- induced pulmonary endothelial dysfunction in rats: modifi-cation by an inhibitor of angiotensin converting enzyme. Int J Radiat Oncol Biol Phys 1988;15:135-140

Structure-

function analysis of angiotensin-converting enzyme inhibi-tors as modifiers of radiation-induced pulmonary endothelial dysfunction in rats. Br J Radiol 1989;62:348-354

The radioprotective effect and mechanism of captopril on radiation induced lung damage in rat. J Kor Ther Radio Oncol 2001;19(2):190-198

The effect of captopril on benign and malignant reactions in irradiated rat skin. Br J Radiol 1990;63:349-354

Radioprotective effect of captopril on the mouse jejunal mucosa. Int J Radiat Oncol Biol Phys 1994;30:873-878

Captopril preserves function and ultrastructure in experimental radiation nephropathy. Lab Invest 1996;75:349-367

Radiation nephropathy is treatable with an angiotensin converting enzyme inhibitor or an angiotensin II type 1 (AT1) receptor antagonist. Radiother Oncol 1998;46:307-315

Can angiotensin- converting enzyme inhibitors protect against symptomatic radiation pneumonitis? Radiat Res 2000;153:405-410

Angiotensin II induces apoptosis of human endothelial cells: Protective effect of nitric oxide. Cir Res 1997;81:970-976

Angiotensin II stimulates extracellular matrix protein synthesis through induction of transforming growth factor- expression in rat glomerular mesangial cells. J Clin Invest 1992;90:1-7

TGF-1 production in radiation nephropathy: Role of angiotensin II. Int J Radiat Biol 1999;75:473-479

Angiotensin II in renal fibrosis: Should TGF- rather than blood pressure be the target? Semin Nephrol 1997;17:455-466

Angiotensin-con-verting enzyme inhibition attenuates proteinuria and renal TGF- 1 mRNA expression in rats with chronic renal dis-ease. Pharmacology 1998;57:20-27

Pharmacologic control of angiotensin II ameliorates renal disease while reducing renal TGF- in experimental mesangioproliferative glomer-ulonephritis. Am J Kidney Dis 1998;31:453-463

Captopril is an inhibitor of angiogenesis that is able to slow growth of experimental tumors in rats. J Clin Invest 1996;98:671-679

Captopril inhibits apoptosis in human lung epithelial cells: a potential antifi-brotic mechanism. Am J Physiol 1998;275:1013-1017

Effect of angiotensin converting enzyme inhibition of pressure-induced left ventri-cular hypertrophy in rats. Circ Res 1991;69:609-617

Captopril inhibits the production of tumor necrosis factor- by human mononuclear cells in patients


with congestive heart failure. Clinica Chemica Acta 2001;304: 85-90

Angiotensin-con-verting-enzyme inhibitors suppress synthesis of tumor necrosis factor and interleukin 1 by human peripheral blood cells. Cytokine 1995;7:526

Protein A, avidin, and biotin in immuni-histochemistry. J Histochem Cytochem 1981;29(11):1349- 1353

Changes in transforming growth factor- (TGF- 1), procollagen types I and III mRNA in the rat heart after irradiation. Int J Radiat Biol 1999;75(11):1429-1436

Radiation pneumotoxicity in rats: modification by inhibitor of

angiotensin converting enzyme. Int J Radiat Oncol Biol Phys 1992;22:623-625

Captopril inhibits proliferation of human lung fibroblast in culture: a potential antifibrotic mechanism. Proc Soc Exp Biol Med 1994;205(1):80-84

Thiol regulation of the production of TNF- , IL-6 and IL-8 by human alveolar macrophages. Eur Respir J 1999;14:98-105

Free radical scavenging and copper chelation: A potentially beneficial action of captopril. Free Rad Res 2000;32(3):199-211

Does captopril attenuate reper-fusion-induced myocardial dysfunction by scavenging free radicals? Circulation 1998;Suppl I, 77:130-139

대한방사선종양학회지 2004;22(1):40～54

The R ad ioprotective E ffect and M echanism o f C aptopril onR adiation Induced-H eart D am age in R ats

Departments of Radiation Oncology and †Anatomic Pathology, Ewha Womans University, Seoul, Korea

Captopril (angiotension converting enzyme inhibitor) is known to have a radioprotective effect in the lungs, intestines and skin, but its effect in the heart is unclear. To investigate the radioprotective effect and mechanism of captopril in the heart, the histopathological changes and immunohistochemical stains were com-pared with radiation alone, and radiation combined with captopril, in the rats.

The histopathological changes and immunohistochemical stains (TNF , TGF 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.

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- , TGF- 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- and TGF- 1 in the radiation alone group continuously increased. The expressions of TNF- , TGF- 1 and PDGF were decreased in the combined group at 2 weeks. At 8 weeks, the expressions of TNF- in the atrial and ventricular pericardia were markedly reduced (p=0.049, p=0.009).

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- , TGF- 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.

Captopril, Radioprotector, Heart

Documents

Jkstro004 · 2005. 4. 25. · 대한방사선종양학회지 2004;22(1):40～54 방사선 조사 후 발생한 흰쥐 심장손상에서 Captopril의 방어역할과 기전 2003 12