İRBESARTAN LİPOPOLİSAKARİT TARAFINDAN İNDÜKLENEN KARACİĞER HASARINI, TOPLAM OKSİDAN DURUMU, İNTERLÖKİN-1B VE KASPAZ-3 SEVİYELERİNİN İNHİBİSYONU YOLUYLA AZALTIR

Öz

Amaç Septik koşullarda hiperinflamatuar yanıta ve hepatotoksisiteye; oksidatif stres, inflamasyon ve apoptoz neden olur. Bir adrenerjik reseptör blokeri olan irbesartan (IB), antiinflamatuar ve antioksidan özelliklere sahiptir. Bu çalışmada, IB'nin lipopolisakkarit (LPS) kaynaklı akut hepatotoksisite üzerindeki koruyucu etkisinin araştırılması amaçlandı. Gereç ve Yöntem Üç grupta toplam sekiz sıçan kullanıldı; kontrol grubu, LPS grubu [5 mg/kg, intraperitoneal (IP)]; ve LPS + IB grubu [5 mg/kg LPS (IP) + 50 mg/kg IB (oral)]. Sakrifikasyondan sonra interlökin-1 beta (IL-1β), kaspaz- 3 (Cas-3) alanin aminotransferaz (ALT), aspartat aminotransferaz (AST), oksidatif stres indeksi (OSI), toplam oksidan durumu (TOS) ve toplam antioksidan durumu (TAS) gibi immünohistokimyasal ve biyokimyasal değerlendirmeler için karaciğer ve kandan dokular alındı. Bulgular Kontrol grubuyla karşılaştırıldığında kanda AST ve ALT düzeylerinde artış, biyokimyasal olarak dokuda TOS ve OSI düzeyinde artış ve TAS düzeyinde azalma, immünohistokimyasal olarak IL-1β, Cas-3 düzeyinde artış tespit edildi. Ayrıca LPS grubunda karaciğer dokusunda histopatolojik olarak hiperemi, kanama, vakuolizasyon ve belirgin nötrofil infiltrasyonu saptandı. IB tüm bu bulguları tersine çevirdi. IB uygulaması ile TAS seviyeleri yükselirken, TOS ve OSI seviyeleri azaldı (p = 0.001). IB ayrıca AST ve ALT değerlerini de düşürdü (p = 0.001). IB grubunda, Cas-3 ve IL-1β seviyeleri, IB uygulamasıyla önemli ölçüde azaldı (p = 0.001). Ek olarak, IB, artmış hiperemi, kanama, vakuolizasyon ve önemli nötrofilik lökosit infiltrasyon gibi histopatolojik bulguları iyileştirdi (p = 0.001). IB tedavisi, antioksidan, antienflamatuar ve antiapoptotik özellikleriyle LPS'nin neden olduğu hepatotoksisiteyi zayıflattı. Sonuç Karaciğer hasarını hafifletmek ve karaciğer fonksiyonunu eski haline getirmek sepsisli hastalarda morbi- dite ve mortalite oranlarını düşürür. IB, antioksidan, antiinflamatuar ve antiapoptotik özellikleri sayesinde karaciğer dokusunu LPS'nin neden olduğu hepatotoksisiteden korur. Karaciğerin sepsisteki rolünün daha fazla araştırılması, yeni terapötik hedeflerin ve stratejilerin geliştirilmesine yol açabilir. IB, sepsis sırasında akut hepatotoksisitenin önlenmesi için alternatif bir terapötik ajan olabilir.

Anahtar Kelimeler

• Sepsis
• irbesartan
• inflamasyon
• hepatotoksisite
• oksidatif stres
• apoptoz

IRBESARTAN REDUCES LIVER DAMAGE INDUCED BY LIPOPOLYSACCHARIDE VIA INHIBITION OF TOTAL OXIDANT STATUS, INTERLEUKIN-1B AND CASPASE-3 LEVELS

Öz

Objective In septic conditions, hyperinflammatory response and hepatotoxicity are caused by oxidative stress, inflammation, and apoptosis. Irbesartan (IB), an adrenergic receptor blocker, has anti-inflammatory and antioxidant properties. This study aimed to investigate the protective effect of IB on lipopolysaccharide (LPS)- induced acute hepatotoxicity. Material and Method A total of eight rats were used in three groups; a control group; LPS group [5 mg/kg, intraperitoneally (IP)]; and LPS + IB group [5 mg/kg LPS (IP) + 50 mg/kg IB (orally)]. After sacrification, tissues from the liver and blood were obtained for immunohistochemical and biochemical evaluations, such as interleukin-1 beta (IL-1β), caspase-3 (Cas-3) alanine aminotransferase (ALT), aspartate aminotransferase (AST), oxidative stress index (OSI), total oxidant status (TOS), and total antioxidant status (TAS). Results Compared with the control group, increased AST and ALT levels in the blood, biochemically increased TOS and OSI and decreased TAS levels in the tissue, immunohistochemically increased IL-1β, Cas- 3, detected. Also, in liver tissue, histopathologically hyperemia, hemorrhage, vacuolization, and significant neutrophilia infiltration were found in the LPS group. IB administration significantly reversed all these parameters. TAS levels were increased by IB administration, whereas TOS and OSI levels were decreased (p = 0.001). IB also decreased AST and ALT values (p = 0.001). In the IB group, Cas-3 and IL-1β levels were significantly decreased by IB administration (p = 0.001). In addition, the IB ameliorated histopathological findings showed enhanced hyperaemia, haemorrhages, vacuolisation and significant neutrophilic leukocyte infiltration (p = 0.001). IB treatment attenuated LPS-induced hepatotoxicity by its antioxidant, anti-inflammatory and antiapoptotic properties. Conclusion Attenuating liver injury and restoring liver function lowers morbidity and mortality rates in patients with sepsis. IB protects liver tissue from hepatotoxicity caused by LPS thanks to its antioxidant, anti-inflammatory, and anti-apoptotic properties. Further investigation of the liver’s role in sepsis may lead to the development of new therapeutic targets and strategies. IB may be an alternative therapeutic agent for the prevention of acute hepatotoxicity during sepsis.

Anahtar Kelimeler

• Apoptosis
• Hepatotoxicity
• Irbesartan
• Inflammation
• Oxidative stress
• Sepsis

Kaynakça

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