The tyrosine kinase inhibitor tyrphostin AG126 reduces the development of acute and chronic inflammation.
Protein tyrosine kinases help to regulate the expression of many genes that play important roles in inflammation. Here we investigate the effects of the tyrosine kinase inhibitor tyrphostin AG126 in two animal models of acute and chronic inflammation, carrageenan-induced pleurisy and collagen-induced arthritis. We report here that tyrphostin AG126 (given at 1, 3, or 10 mg/kg i.p. in the pleurisy model or 5 mg/kg i.p. every 48 hours in the arthritis model) exerts potent anti-inflammatory effects in animal models of acute and chronic inflammation in vivo. These include the inhibition of pleural exudate formation and mononuclear cell infiltration (pleurisy model) and the development of clinical signs and tissue injury (arthritis model). Furthermore, tyrphostin AG126 reduced the staining for nitrotyrosine and poly (ADP-ribose) polymerase (by immunohistochemistry) and the expression of inducible nitric oxide synthase and cyclooxygenase-2 in the lungs of carrageenan-treated rats and in the joints from collagen-treated rats. Thus, we provide the first evidence that prevention of the activation of protein tyrosine kinases reduces the development of acute and chronic inflammation, and that inhibition of the activity of certain tyrosine kinases may represent a novel approach for the therapy of inflammation.
Cuzzocrea
S
S
Institute of Pharmacology, University of Messina, Italy. salvator@www.unime.it
McDonald
M C
MC
Mazzon
E
E
Siriwardena
D
D
Calabrò
G
G
Britti
D
D
Mazzullo
G
G
De Sarro
A
A
Caputi
A P
AP
Thiemermann
C
C
D000208:Acute Disease; D000818:Animals; D001168:Arthritis / Q000139:chemically induced / Q000517:prevention & control; D002351:Carrageenan; D002908:Chronic Disease; D003094:Collagen; D051546:Cyclooxygenase 2; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007249:Inflammation / Q000473:pathology / Q000517:prevention & control*; D007527:Isoenzymes / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D010998:Pleurisy / Q000139:chemically induced / Q000517:prevention & control; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D013643:Tarsus, Animal / Q000187:drug effects / Q000473:pathology; D013977:Tibia / Q000187:drug effects / Q000473:pathology; D020032:Tyrphostins / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D020032:Tyrphostins; C069028:AG 127; D002351:Carrageenan; D003094:Collagen; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D011505:Protein-Tyrosine Kinases