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

Yıl 2023, Cilt: 30 Sayı: 3, 474 - 483, 23.09.2023

Esra Nurlu Temel Şerife Ağırca Taşan İlter İlhan

https://doi.org/10.17343/sdutfd.1341730

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

Teşekkür

I want to thank my esteemed professor Prof. Dr. Özlem Özmen, and the Department of Pharmacology for their support at all stages of my work.

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

Kaynakça

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