Deneysel sepsis modelinde artemisinin ve hidroksiklorokin'in proinflamatuar sitokin üretimi üzerine etkilerinin araştırılması
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Tarih
2021
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Selçuk Üniversitesi, Tıp Fakültesi
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Amaç: Sepsis, enfeksiyona karşı konağın anormal sistemik inflamatuar yanıtı sonucu ortaya çıkar. Enfeksiyonu tedavi eden antibiyotiklerin sistemik inflamasyonu kontrol edememesi sonucu enfeksiyondan bile daha tehlikeli olabilen bu inflamasyonun yıkıcı etkileri nedeniyle sepsis önemli bir klinik sorundur. Bu çalışmada ratlarda bakteriyel lipopolisakkarit (LPS) ile deneysel sepsis modellemesi oluşturarak, antiinflamatuar etkinliği bilinen artemisinin (ART) ve hidroksiklorokin (HCQ) ilaçlarının, sepsis patofizyolojisinde önemli yer tutan proinflamatuar sitokin üretimi ve salgılanması üzerine kısa süredeki etkilerini araştırmayı amaçladık. Yöntem: Wistar Albino türü 24 rat rastgele 4 gruba ayırıldı. Grup 1: Kontrol grubu; bu gruptaki ratlara deneyden bir gün önce ve deney günü steril %0.9 NaCl oral gavaj ile verildi. Deney günü gavaj uygulamasından 2 saat sonra steril %0.9 NaCl intraperitoneal olarak uygulandı. Grup 2: Sepsis grubu; bu gruptaki ratlara deneyden bir gün önce ve deney günü steril %0.9 NaCl oral gavaj ile verildi. Deney günü gavaj uygulamasından 2 saat sonra 5mg/kg dozda LPS intraperitoneal olarak uygulandı. Grup 3: ART grubu; bu gruptaki ratlara deneyden bir gün önce ve deney günü 33.33 mg/kg dozda ART oral gavaj ile verildi. Deney günü uygulanan ART' den yarım saat sonra 5 mg/kg dozda LPS intraperitoneal olarak uygulandı. Grup 4: HCQ grubu; bu gruptaki ratlara deneyden bir gün önce ve deney günü 33.33 mg/kg dozda HCQ oral gavaj ile verildi. Deney günü uygulanan HCQ' den 2 saat sonra 5 mg/kg dozda LPS intraperitoneal olarak uygulandı. LPS uygulamalarını takiben üçer saat sonra (grup 3'teki ratlardan deneyin üçüncü saat otuzuncu dakikasında diğer gruplardaki ratlardan deneyin beşinci saatinde) genel anestezi altında intrakardiyak yolla kan alındı ve sonrasında ratlar sakrifiye edildi. Tüm ratlardan IL-1, IL-6, IL-10 ve TNF-α bakıldı. Bulgular: Wistar Albino türü ratlarda intraperitoneal LPS verilerek oluşturulan deneysel sepsisin erken döneminde artan proinflamatuar sitokinlerden IL-1 ve IL-6 düzeyleri HCQ ön tedavisi ile anlamlı derecede azalma göstermektedir. Benzer şekilde ART ön tedavisi aynı modellemede artan IL-1 düzeyini anlamlı derecede azaltırken, IL-6 düzeyini ise istatiksel olarak anlamlı olmayan düzeyde azaltmaktadır. Artış gösteren TNF-α düzeyini ART ve HCQ, kontrol grubu değerlerine benzer olacak şekilde azaltmaktadır. Antiinflamatuar sitokinlerden IL-10 düzeylerinde ise çalışma süresi içinde gruplar arasında anlamlı artış veya azalma olmamıştır. Sonuç: Çalışmamızdan elde ettiğimiz sonuçlar ART ve HCQ'in konağın sepsise yanıtını regüle edebilecek potansiyele sahip ajanlar olarak değerlendirilebileceğini göstermektedir. İnsanlarda farklı endikasyonlarda kullanım onayı bulunan bu iki ajanın insanlarda sepsisin oluşturduğu inflamatuar yanıtlara etkinliğini, optimal uygulama yöntemini ve zamanını belirlemek için daha ileri çalışmalara ihtiyaç vardır.
Aim: Sepsis occurs as a result of the host's abnormal systemic inflammatory response to infection. Sepsis is a major clinical problem due to the devastating effects of this inflammation which can be even more dangerous than infection as a result of the inability of antibiotics treating the infection to control systemic inflammation. In this study, we aimed to investigate the short-term effects of artemisinin (ART) and hydroxychloroquine (HCQ) drugs whose antiinflammatory effectiveness is known on the production and secretion of proinflammatory cytokines which play an important role in the pathophysiology of sepsis by creating experimental modeling of sepsis with bacterial lipopolysaccharide (LPS) in rats. Methods: The Wistar Albino species 24 rats were randomly divided into 4 groups. Group 1: control group; rats in this group were given a sterile 0.9% NaCl by oral gavage the day before the experiment and on the day of the experiment. Sterile 0.9% NaCl was administered intraperitoneally 2 hours after gavaj administration on the day of the experiment. Group 2: sepsis group; rats in this group were given a sterile 0.9% NaCl by oral gavage the day before the experiment and on the day of the experiment. On the day of the experiment, 2 hours after gavaj administration, LPS was administered intraperitoneally at a dose of 5mg/kg. Group 3: ART group; rats in this group were given ART by oral gavage the day before the experiment and on the day of the experiment at a dose of 33.33 mg/kg. Half an hour after ART administration on the day of the experiment, LPS was administered intraperitoneally at a dose of 5 mg/kg. Group 4: HCQ group; rats in this group were given HCQ by oral gavage the day before the experiment and on the day of the experiment at a dose of 33.33 mg/kg. 2 hours after HCQ administraiton on the day of the experiment, LPS was administered intraperitoneally at a dose of 5 mg/kg. In all groups, three hours after of LPS administration (from rats in Group 3 at the thirtieth minute of the third hour of the experiment, from rats in other groups at the fifth hour of the experiment) blood samples were taken intracardiac under general anesthesia and then the rats were sacrified. IL-1, IL-6, IL-10 and TNF-α were examined from blood samples taken from all rats. Results: IL-1 and IL-6 levels, which were increased proinflammatory cytokines in the early period of experimental sepsis created by giving intraperitoneal LPS in Wistar Albino type rats, decreased significantly with HCQ pre-treatment. Similarly, ART pre-treatment significantly decreased the increased IL-1 level in the same model, while it decreased the IL-6 level at a statistically insignificant level. ART and HCQ decreased the increased TNF-α level, similar to the control group values. IL-10 levels, one of the anti-inflammatory cytokines, did not increase or decrease significantly among the groups during the study period. Conclusion: The results of our study show that ART and HCQ can be evaluated as agents with the potential to regulate the host's response to sepsis. Further studies are needed to determine the effectiveness, optimal administration method and timing of these two agents which have approval for use in humans for different indications to inflammatory responses caused by sepsis in humans.
Aim: Sepsis occurs as a result of the host's abnormal systemic inflammatory response to infection. Sepsis is a major clinical problem due to the devastating effects of this inflammation which can be even more dangerous than infection as a result of the inability of antibiotics treating the infection to control systemic inflammation. In this study, we aimed to investigate the short-term effects of artemisinin (ART) and hydroxychloroquine (HCQ) drugs whose antiinflammatory effectiveness is known on the production and secretion of proinflammatory cytokines which play an important role in the pathophysiology of sepsis by creating experimental modeling of sepsis with bacterial lipopolysaccharide (LPS) in rats. Methods: The Wistar Albino species 24 rats were randomly divided into 4 groups. Group 1: control group; rats in this group were given a sterile 0.9% NaCl by oral gavage the day before the experiment and on the day of the experiment. Sterile 0.9% NaCl was administered intraperitoneally 2 hours after gavaj administration on the day of the experiment. Group 2: sepsis group; rats in this group were given a sterile 0.9% NaCl by oral gavage the day before the experiment and on the day of the experiment. On the day of the experiment, 2 hours after gavaj administration, LPS was administered intraperitoneally at a dose of 5mg/kg. Group 3: ART group; rats in this group were given ART by oral gavage the day before the experiment and on the day of the experiment at a dose of 33.33 mg/kg. Half an hour after ART administration on the day of the experiment, LPS was administered intraperitoneally at a dose of 5 mg/kg. Group 4: HCQ group; rats in this group were given HCQ by oral gavage the day before the experiment and on the day of the experiment at a dose of 33.33 mg/kg. 2 hours after HCQ administraiton on the day of the experiment, LPS was administered intraperitoneally at a dose of 5 mg/kg. In all groups, three hours after of LPS administration (from rats in Group 3 at the thirtieth minute of the third hour of the experiment, from rats in other groups at the fifth hour of the experiment) blood samples were taken intracardiac under general anesthesia and then the rats were sacrified. IL-1, IL-6, IL-10 and TNF-α were examined from blood samples taken from all rats. Results: IL-1 and IL-6 levels, which were increased proinflammatory cytokines in the early period of experimental sepsis created by giving intraperitoneal LPS in Wistar Albino type rats, decreased significantly with HCQ pre-treatment. Similarly, ART pre-treatment significantly decreased the increased IL-1 level in the same model, while it decreased the IL-6 level at a statistically insignificant level. ART and HCQ decreased the increased TNF-α level, similar to the control group values. IL-10 levels, one of the anti-inflammatory cytokines, did not increase or decrease significantly among the groups during the study period. Conclusion: The results of our study show that ART and HCQ can be evaluated as agents with the potential to regulate the host's response to sepsis. Further studies are needed to determine the effectiveness, optimal administration method and timing of these two agents which have approval for use in humans for different indications to inflammatory responses caused by sepsis in humans.
Açıklama
Anahtar Kelimeler
Hidroksiklorokin, Artemisinin, Sepsis, Sitokin, İnflamasyon, Hydroxychloroquine, Cytokine, Inflammation
Kaynak
WoS Q Değeri
Scopus Q Değeri
Cilt
Sayı
Künye
Büyükcavlak, M. (2021). Deneysel sepsis modelinde artemisinin ve hidroksiklorokin'in proinflamatuar sitokin üretimi üzerine etkilerinin araştırılması. (Uzmanlık Tezi). Selçuk Üniversitesi, Tıp Fakültesi, Konya.
