Research Article: TNF-alpha inhibitor adalimumab attenuates endotoxin induced cardiac damage in rats 1

Date Published: April 3, 2020

Publisher: Sociedade Brasileira para o Desenvolvimento da Pesquisa em Cirurgia

Author(s): Selim Durmaz, Tünay Kurtoğlu, Emin Barbarus, Nükhet Eliyatkın, Mustafa Yılmaz.

http://doi.org/10.1590/s0102-865020200020000002

Abstract

To investigate the effects of adalimumab pretreatment on the lipopolysaccharide-mediated myocardial injury.

Twenty-eight Wistar rats were randomized into four groups (n=7). Control (C) group animals were injected once a day with intraperitoneal (i.p) 0.9 % saline for two days. In the Adalimumab (Ada) group, adalimumab was injected at a dose of 10 mg/kg/ day (i.p) for two days. Lipopolysaccharide (Lps) group rats were injected with a dose of 5 mg/kg (i.p) lipopolysaccharide. Lipopolysaccharide + Adalimumab (Lps+Ada) group rats received adalimumab before the administration of lipopolysaccharide. The animals were sacrificed 24 h after the last injection and blood samples were obtained for determination of biochemical cardiac injury markers and circulating levels of TNF-α and interleukin-6 (IL-6). Hearts were harvested for histological examination.

Endotoxin exposure resulted in significant increases in serum cardiac injury markers, serum cytokines and histological myocardial injury scores in the Lps group. The levels of circulating cytokines, cardiac injury markers and histological injury scores for myocardial necrosis, perivascular cell infiltration, and inflammation were significantly reduced in Lps+Ada as compared to Lps group (p<0.05). Adalimumab pretreatment reduces endotoxin-induced myocardial damage in rats. This beneficial effect is thought to be related to the reduction of cytokine release.

Partial Text

Systemic inflammatory response syndrome is a phenomenon in which various stimuli- such as severe trauma, sepsis, acute mesenteric ischemia and major surgery- induce a widespread activation of inflammatory cascades leading to multi-organ failure1 . Systemic inflammation may be triggered by lipopolysaccharide (Lps) components of gram negative bacterial wall which are commonly known as endotoxins2 . Human intestinal flora produces a considerable amount of endotoxins but the endothelial cell lining in intestines restrict the transfer of these endotoxins into circulation and prevent the systemic inflammation in normal conditions. In the course of major surgical procedures including cardiac surgery with cardiopulmonary bypass and aortic aneurysm repair, the disruption of endothelial cell barrier may permit the passage of endotoxins through the mucosal epithelium to the adjacent tissues or distal organs and provoke a systemic inflammatory response leading to increased postoperative complications3 .

The animal care was conducted in accordance with the National Institute of Health’s Guide for the Care and Use of Laboratory Animals. The animals used in the experiment were obtained from the Aydın Adnan Menderes University Experimental Animals Research and Production Laboratory. Adult female Wistar rats (170-270g) were fed a standard rat chow diet and water ad libitum and kept in cages in a temperature (22°C ± 2°C) and humidity (45-50%) controlled room with a 12-h dark-light cycle and acclimatized for a week before the study. The experimental design and protocol were approved by the Animal Care Committee of Adnan Menderes University (approval number: 64583101/2018/81). The study was performed in the Adnan Menderes University Faculty of Medicine, Experimental Animals Laboratory, Aydın, Turkey. A total of 28 animals were randomly allocated into one of the four following groups each consisting of seven animals: Control (C), Adalimumab (Ada), Lipopolysaccharide (Lps), Lipopolysaccharide + Adalimumab (Lps+Ada) groups.

In the present study, we used a model of lipopolysaccharide-induced experimental myocardial injury. Our findings indicate that adalimumab treatment significantly reduces circulating cytokines (TNF-α and IL-6), which are released as a response to lipopolysaccharide administration in rats. In animals that are subjected to lipopolysaccharide, adalimumab treatment resulted in a significant reduction in serum levels of cardiac injury markers and amelioration of histopathologic signs of myocardial injury. These findings suggest that TNF- α blocker adalimumab attenuates endotoxin-induced myocardial injury by suppression of cytokine release into the circulation. Furthermore, we also observed that the administration of adalimumab at the selected dose in rats did not cause any cardiac injury whilst slightly reducing the levels of circulating cytokines.

The results of this study showed that adalimumab pretreatment reduces endotoxin-induced myocardial damage in rats. The beneficial effect of adalimumab observed in this study is thought to be related to the reduction of cytokine release. However, further investigation is needed to determine the effect of adalimumab in acute inflammatory conditions that damage the heart and enlighten the possible cardio protective role of adalimumab.

 

Source:

http://doi.org/10.1590/s0102-865020200020000002

 

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