Therapy with granulocyte colony-stimulating factor in the chronic stage, but not in the acute stage, improves experimental autoimmune myocarditis in rats via nitric oxide.
We systematically investigated serial efficacy of granulocyte colony-stimulating factor (G-CSF) therapy upon experimental autoimmune myocarditis (EAM) in rats treated with and without the inhibition of nitric oxide (NO) with the analyses of tissue regeneration. G-CSF could mobilize multipotent progenitor cells of bone marrow into the peripheral blood and may improve ventricular function. A rat model of porcine myosin-induced EAM was used. After the immunization of myosin, G-CSF (10 microg/kg/day) or saline was injected intraperitoneally on days 0-21 in experiment 1 and on days 21-42 in experiment 2. Additional myosin-immunized rats were orally given 25 mg/kg/day of N(G)-nitro-L-arginine methylester (L-NAME), an inhibitor of nitric oxide synthase (NOS), in each experiment (each group; n=8-21). Serum cytokines and peripheral blood cell counts were measured in each group. In experiment 1, G-CSF treatment aggravated cardiac pathology associated with increased macrophage inflammatory protein-2 (MIP-2) and interleukin-6 (IL-6) levels and enhanced superoxide production. In experiment 2, G-CSF treatment reduced the severity of myocarditis with increased capillary density and improved left ventricular ejection fraction. In the rats with EAM treated with G-CSF associated with oral L-NAME treatment in experiment 2, the severity of myocarditis was not reduced. Myocardial c-kit(+) cells were demonstrated only in G-CSF-treated group in experiment 2 but not in other groups. G-CSF has differential effects on EAM in rats associated with the modulation of cytokine network. The overwhelming superoxide production by G-CSF administration in the acute stage may worsen the disease. G-CSF therapy improved cardiac function via NO system in a rat model of myocarditis in the chronic stage, but not in the acute stage, possibly through the myocardial regeneration and acceleration of healing process.
Shimada
Kana
K
Department of Cardiovascular Medicine, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
Okabe
Taka-aki
TA
Mikami
Yu
Y
Hattori
Miki
M
Fujita
Masatoshi
M
Kishimoto
Chiharu
C
D000208:Acute Disease; D000818:Animals; D001327:Autoimmune Diseases / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D024722:Cardiac Myosins / Q000378:metabolism; D002908:Chronic Disease; D016207:Cytokines / Q000378:metabolism; D004452:Echocardiography; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007114:Immunization; D007124:Immunoenzyme Techniques; D009205:Myocarditis / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009389:Neovascularization, Pathologic; D009569:Nitric Oxide / Q000378:metabolism*; D051381:Rats; D011917:Rats, Inbred Lew; D011994:Recombinant Proteins; D013481:Superoxides / Q000378:metabolism; D013552:Swine
D016207:Cytokines; D004791:Enzyme Inhibitors; D011994:Recombinant Proteins; D013481:Superoxides; D016179:Granulocyte Colony-Stimulating Factor; D009569:Nitric Oxide; D024722:Cardiac Myosins; D019331:NG-Nitroarginine Methyl Ester