Lipid peroxidation inhibition by raxofelast improves angiogenesis and wound healing in experimental burn wounds.
We investigated the effects of raxofelast, a lipid peroxidation inhibitor, in an experimental model of burn wounds. C57BL/6 male mice of 25-30 g were immersed in 80 degrees C water for 10 seconds to achieve a partial-thickness scald burn. Animals received intraperitoneally either raxofelast (20 mg/kg/day for 14 days in 100 microL) or its vehicle alone (100 microL/day for 14 days). On day 14, burn areas were used for measuring conjugated dienes, reduced glutathione levels, histological damage, neoangiogenesis by immunohistochemistry and expression (Western blot) of the specific endothelial marker CD31 as well as quantification of microvessel density, VEGF wound content, endothelial and inducible nitric oxide synthase (eNOS and iNOS) expression and wound nitrite content. Raxofelast decreased tissue conjugated dienes (vehicle 6.1 +/- 1.4 DeltaABS/mg protein; raxofelast 3.7 +/- 0.8 DeltaABS/mg protein), prevented tissue glutathione consumption (vehicle 3.2 +/- 0.9 micromol/g protein; raxofelast 6.7 +/- 1.8 mumol/g protein), increased epithelial proliferation, extracellular matrix maturation, and augmented neoangiogenesis as suggested by the marked increase in microvessel density and by the robust expression of the specific endothelial marker CD31 (vehicle 9.4 +/- 1.1 integrated intensity; raxofelast 14.8 +/- 1.8 integrated intensity). Furthermore, raxofelast enhanced VEGF wound content (vehicle 1.4 +/- 0.4 pg/mg protein; raxofelast 2.4 +/- 0.6 pg/mg protein), caused a marked expression of eNOS (vehicle 16.1 +/- 3 integrated intensity; raxofelast 26.2 +/- 4 integrated intensity) and iNOS (vehicle 9.1 +/- 1.8 integrated intensity; raxofelast 16.2 +/- 3.5 integrated intensity) and increased wound nitrite content. Lipid peroxidation inhibition by raxofelast may be an effective therapeutic approach to improve clinical outcomes after thermal injury.
Department of Clinical and Experimental Medicine and Pharmacology, University of Messina, Messina, Italy.
Domenica
D
Altavilla
Mariarosaria
M
Galeano
Alessandra
A
Bitto
Letteria
L
Minutoli
Giovanni
G
Squadrito
Paolo
P
Seminara
Francesco S
FS
Venuti
Valerio
V
Torre
Margherita
M
Calò
Michele
M
Colonna
Patrizia
P
Lo Cascio
Giovanni
G
Giugliano
Nicolò
N
Scuderi
Chiara
C
Mioni
Sheila
S
Leone
Francesco
F
Squadrito
D000818:Animals; D001572:Benzofurans / Q000494:pharmacology* / Q000627:therapeutic use; D002056:Burns / Q000097:blood / Q000188:drug therapy*; D004195:Disease Models, Animal; D005978:Glutathione / Q000378:metabolism; D007150:Immunohistochemistry; D015227:Lipid Peroxidation / Q000187:drug effects*; D051379:Mice; D009569:Nitric Oxide / Q000032:analysis; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D009573:Nitrites / Q000378:metabolism; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000096:biosynthesis; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis; D014810:Vitamin E / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D014945:Wound Healing / Q000187:drug effects*
D001572:Benzofurans; D009573:Nitrites; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D014810:Vitamin E; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D005978:Glutathione; C071049:Raxofelast