Role of the cholinergic anti-inflammatory pathway in endotoxemia-induced multi-organ damage in the rat

Year 2015, Volume: 5 Issue: 1, 21 - 30, 03.05.2015

Meltem Kolgazi Fatih Özgür Ömer Beyazoğlu Ali Kocagöz Mehmethan Çelik Merve Açıkel Elmas Meral Yüksel Feriha Ercan İnci Alican

Abstract

Objective: To investigate the role of the cholinergic anti-inflammatory pathway and interaction of inducible nitric oxide (iNOS) and cycloxygenase (COX)-2 in organ dysfunction in rat sepsis. 

Methods: Lipopolysaccharide (LPS) (10 mg/kg; intraperitoneally) was given to Sprague-Dawley rats to induce sepsis. Groups were treated with nicotine alone or with nicotinic receptor antagonist mecamylamine (3 mg/kg; subcutaneously), selective iNOS inhibitor aminoguanidine (8 mg/kg; intraperitoneally) or selective COX-2 inhibitor nimesulide (8 mg/kg; intraperitoneally). Six hours after LPS, liver, kidney and lung samples were obtained for malondialdehyde (MDA), glutathione (GSH), myeloperoxidase (MPO), chemiluminescence assays and microscopic evaluation and blood was obtained for alanine transaminase (ALT), aspartate aminotransferase (AST) and blood urea nitrogen (BUN) assays. 

Results: Sepsis increased ALT (p<0.05), AST (p<0.01) and BUN (p<0.001), tissue MDA (p<0.01 for liver and p<0.05, for kidney and lung), tissue MPO (p<0.01, for liver; p<0.05, for kidney; p<0.001, for lung) and chemiluminescence (luminol p<0.001, for all tissues; lucigenin p<0.001 for liver and p<0.01 for kidney and lung) while decreasing GSH (p<0.01, for liver and kidney) compared to control. Nicotine prevented the increase in ALT, AST and BUN (p<0.05, for each), increase in liver and renal MDA (p<0.05, for each), consumption of GSH (p<0.01, for liver and kidney), injury score (p<0.05, for liver and kidney) and increased MPO (p<0.05, for liver and p<0.01, for kidney and lung). Beneficial effects of nicotine seemed to persist in the presence of other therapies.

Conclusions: Nicotine in sepsis protects the tissues partially via activation of the cholinergic anti-inflammatory pathway independently of the iNOS and COX-2.

Keywords

Sepsis, rat, cholinergic anti-inflammatory pathway, nicotine, inflammation

Sıçanda endotoksemiye bağlı çoklu organ hasarında kolinerjik anti-inflamatuvar yolun rolü

Abstract

Amaç: Sıçanda sepsise bağlı çoklu organ hasarında kolinerjik anti-inflamatuvar yolun rolünü araştırmak ve patojenezde indüklenebilir nitrik oksit sentaz (iNOS) ve siklooksijenaz (COX)-2 enzimlerinin etkileşimini incelemektir.

Yöntemler: Sprague-Dawley sıçanlara lipopolisakkarid (LPS) (10 mg/kg; intraperitoneal) uygulanarak sepsis oluşturuldu. Tedavi gruplarına, LPS öncesi 3 gün süreyle nikotin (0.1 mg/kg; intraperitoneal) tek başına veya nikotinik reseptör antagonisti mekamilamin (3 mg/kg; subkutan), selektif iNOS inhibitörü aminoguanidin (8 mg/kg; intraperitoneal) veya selektif COX-2 inhibitörü nimesulid (8 mg/kg; intraperitoneal) ile birlikte uygulandı. LPS’den 6 saat sonra dekapite edilen sıçanların karaciğer, böbrek ve akciğer örneklerinde malondialdehid (MDA), glutatyon (GSH), myeloperoksidaz (MPO) aktivitesi, kemiluminisans ölçümleri ve hasar skorlaması yapıldı. Kanda alanin transaminaz (ALT), aspartat aminotransferaz (AST) ve üre azotu (BUN) ölçüldü. 

Bulgular: Sepsis kanda ALT (p<0.05), AST (p<0.01) ve BUN (p<0.001) düzeylerinde artışa, karaciğer, böbrek ve akciğerde MDA’da yükselmeye (sırası ile, p<0.01, p<0.05 ve p<0.05), MPO’da artışa (sırası ile, p<0.01, p<0.05 ve p<0.001), GSH’da azalmaya (karaciğer için p<0.01, böbrek için p<0.01) ve kemiluminisansta artışa (luminol her üç doku için p<0.001; lusigenin karaciğer için p<0.001, böbrek ve akciğer için p<0.01) neden oldu. Nikotin ALT, AST ve BUN düzeylerindeki yükselmeyi (her üç parametre için p<0.05), karaciğer ve böbrekte MDA artışını (sırası ile, p<0.05 ve p<0.05), GSH’daki azalmayı (sırası ile, p<0.01 ve p<0.01), doku hasarını (sırası ile, p<0.05 ve p<0.05) ve MPO artışını (karaciğer için p<0.05, böbrek için p<0.01 ve akciğer için p<0.01) engelledi. Nikotinin yararlı etkileri diğer tedaviler varlığında devam etme eğilimi gösterdi. 

Sonuç: Nikotin tedavisi sepsise bağlı karaciğer, böbrek ve akciğer hasarını olasılıkla iNOS ve COX-2 enzim sistemlerinden bağımsız mekanizmalarla korumaktadır.

Keywords

Sepsis, sıçan, kolinerjik anti-inflamatuvar yol, nikotin, inflamasyon

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