Farelerde lipopolisakkarit ile indüklenen solunum yolu inflamasyonunda mitokondriye hedeflendirilmiş yavaş hidrojen sülfür salıveren AP39'un ve nitrik oksit sentaz inhibitörü asimetrik dimetil arjinin (ADMA)'nın etkilerinin araştırılması
Karaman Kutluay, Yasemin
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In this study, the effects of mitochondria-targeted slow H2S releasing donor AP39 on lipopolysaccharide (LPS)-induced airway inflammation were investigated in in vitro and in vivo models. In in vitro model tracheal rings and lung tissues isolated from mice were incubated with LPS for four days in tissue culture. LPS incubation lead to an increase in 5-hydroxytrytamine- and bradykinin-induced contraction responses in tracheal rings and interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), IL-6 levels were enhanced in lung tissues incubated with LPS. AP39 incubation prevented tracheal 5-hydroxytrytamine hyperreactivity at 30 nM concentration and increase in TNF-α, IL-6 levels at 30 and 300 nM concentrations. In in vivo model LPS and AP39 was applied as intranasal. AP39 (250, 500 and 1000 nmol/kg) treatment prevented the LPS-induced bronchial hyperreactivity and increase in IL-6 levels in bronchoalveolar lavage fluid at all doses, the increase in neutrophil numbers at 1000 nmol/kg, the increase in TNF-α level at 250 and 500 nmol/kg and did not prevent parenchymal inflammation in lung tissue. AP39 at 500 nmol/kg dose prevented the LPS-induced glucose-6-phosphate and succinate accumulation and 250 nmol/kg dose inhibited the decrease in cysteine levels and increased glutathione and taurine levels. In this study, the role of an endogenous nitric oxide synthase inhibitor asymmetric dimethyl arginine (ADMA) in LPS-induced airway inflammation was also evaluated. In tissue culture ADMA (3μM) incubation lead to an increase in 5-hydroxytrytamine- and bradykinin induced contractions. On the other hand, ADMA (30 and 100 μM) prevented 5- hydroxytrytamine hyperreactivity in the presence of LPS. In LPS-induced in vivo airway inflammation ADMA application via intratracheal route as acutely or intranasally inhibited bronchial hyperreacivity and intranasal application also prevented the increase in neutrophil numbers in bronchoalveolar lavage fluid. Our results indicate that the mitochondria-targeted H2S releasing donor AP39 decrease airway inflammation and prevent bronchial hyperreactivity however, the dose to be administered appears to be critical. ADMA is involved in the regulation of airway functions by inhibiting inducible and constitutive nitric oxide synthase and is thought to have therapeutic potential in airway inflammation.
xmlui.dri2xhtml.METS-1.0.item-citationKaraman-Kutluay, Y. Farelerde Lipopolisakkarit ile İndüklenen Solunum Yolu İnflamasyonunda Mitokondriye Hedeflendirilmiş Yavaş Hidrojen Sülfür Salıveren AP39’un ve Nitrik Oksit Sentaz İnhibitörü Asimetrik Dimetil Arjinin (ADMA)’nın Etkilerinin Araştırılması. Hacettepe Üniversitesi Sağlık Bilimleri Enstitüsü Farmakoloji Programı Doktora Tezi, Ankara, 2019.
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