Is adalimumab protective in ischemia-reperfusion injury in lung?

Document Type : Original Article


1 RecepTayyip Erdogan University, School of Medicine, Department of Thoracic Surgery, Rize, Turkey

2 RecepTayyip Erdogan University, School of Medicine, Department of Histology and Embryology, Rize, Turkey

3 RecepTayyip Erdogan University, School of Medicine, Department of Biochemistry, Rize, Turkey

4 RecepTayyip Erdogan University, School of Medicine, Department of Internal Medicine, Rize , Turkey

5 RecepTayyip Erdogan University, School of Medicine, Department of Pathology, Rize, Turkey


Objective(s): Increasing cytokines and reactive oxygen species (ROS) during ischemia reperfusion (I-R) leads to the lung damage. Adalimumab (Ada) is a potent tumor necrosis factor-alpha (TNF-α) inhibitor agent. We aimed to evaluate whether Ada would prevent the lung tissue from damage development over the I-R process.
Materials and Methods:Twenty seven Wistar albino male rats were divided into three groups (each group had 9 rats). To the control group, only laparotomy procedure was carried out. For I-R group, first infrarenal abdominal aorta was cross-clamped during 2 hr, and then reperfusion was performed for 2 hr. To I-R+Ada group, first a single dose of 50 mg/kg Ada was given intraperitoneally and 5 days later, same I-R procedure was carried out.
Results:Levels of TNF-α, malondialdehyde (MDA), myeloperoxidase (MPO), endothelin-1 (ET-1) and caspase-3 enzyme activity of I-R group were higher than that of both I-R+ Ada [TNF-α (P=0.021), MDA (P=0.029), MPO (P=0.012), ET-1 (P=0.036, caspase-3 (P=0.007), respectively] and control group [TNF- α (P=0.008), MDA (P<0.001), MPO (P=0.001), ET-1 (P<0.001), caspase-3 (P<0.001), respectively]. In I-R group, severe damage was detected by hematoxylin-eosin staining. This damage was found less severe in Ada treatment group.
Conclusion:The release of cytokines and ET-1 in a large proportion after I-R injury, and generating of ROS in excessive quantity could cause severe damage in the lung tissue. Ada could be considered as a protective agent for lung tissue during I-R process.


1. Ng CS, Wan S, Arifi AA, Yim AP. Inflammatory response to pulmonary ischemia- reperfusion injury. Surg Today 2006; 36:205-214.
2. Türüt H, Kurutas EB, Bulbuloglu E, Yasim A, Ozkaya M, Onder A, et al. Zinc aspartate  alleviates lung injury induced by intestinal ischemia-reperfusion in rats. J Surg Res  2009; 151:62-67.
3. Mao YF, Yu QH, Zheng XF, Liu K, Liang WQ, Wang YW, et al. Pre-treatment with Cobra venom factor alleviates acute lung injury induced by intestinal ischemia-reperfusion in rats. Eur Rev Med Pharmacol Sci 2013; 17:2207-2217.
4. Garbaisz D, Turoczi Z, Fulop A, Rosero O, Aranyi P, Onody P, et al. Therapeutic option for managing lung injury induced by infrarenal aortic cross-clamping. J Surg Res 2013; 185:469-476.
5. Faith M, Sukumaran A, Pulimood AB, Jacob M. How reliable an indicator of inflammation is myeloperoxi-dase activity? Clin Chim Acta 2008; 396:23-25.
6. Sato Y, Hogg JC, English D, van Eeden SF. Endothelin-1 changes polymorphonuclear leuko-cytes' deformability and CD11b expression and promotes their retention in the lung. Am J Respir Cell Mol Biol 2000; 23:404-410.
7. Helset E, Lindal S, Olsen R, Myklebust R, Jørgensen L. Endothelin-1 causes sequential trapping of platelets and neutrophils in pulmonary microcirculation in rats. Am J Physiol 1996; 271:L538-546.
8. Zhang A, Fu S, Chen L, Ren L, Qu S, Zhang Y, et al. Lacidipine attenuates apoptosis via   a caspase-3 dependent pathway in human kidney cells. Cell Physiol Biochem 2013; 32:1040-1049.
9. Chang CW, Wei SC, Chou JW, Hsu TC, Chuang CH, Lin CP, et al. Safety and efficacy of adalimumab for patients with moderate to severe crohn's disease: the taiwan society of inflammatory bowel disease (TSIBD) study. Intest Res 2014; 12:287-292.
10. Furst DE, Schiff MH, Fleischmann RM, Strand V, Birbara CA, Compagnone D, et al. Adalimumab, a fully human anti tumor necrosis factor-alpha monoclonal antibody, and concomitant standard antirheumatic therapy for the treatment of rheumatoid arthritis:results of STAR (Safety Trial of Adalimumab in Rheumatoid Arthritis). J Rheumatol 2003; 30:2563-2571.
11. Nakamizo S, Miyachi Y, Kabashima K. Addition of cyclosporine to adalimumab improved psoriasis and adalimumab-induced injection site reaction. Indian J Dermatol 2014; 59:522-523.
12. Shen C, Assche GV, Colpaert S, Maerten P, Geboes K, Rutgeerts P, et al. Adalimumab induces apoptosis of human monocytes: a comparative study with infliximab and etanercept. Aliment Pharmacol Ther 20051; 21:251-258.
13. Cure E, Cumhur Cure M, Tumkaya L, Kalkan Y, Aydin I, Kirbas A, et al. Adalimumab ameliorates abdominal aorta cross clamping which induced liver injury in rats. Biomed Res Int 2014; 2014:907915.
14. Yilmaz M, Tekekoglu S, Herek O, Ozmen O, Sahinduran S, Buyukoglu T. Ameliorative effect of adalimumab on experimentally induced acute pancreatitis in rats. Pancreas 2010; 39:1238-1242.
15. Oyar EÖ, Kiriş I, Gülmen S, Ceyhan BM, Cüre MC, Sütcü R, et al. Adrenomedullin attenuates aortic cross-clamping-induced myocardial injury in rats. Am J Surg 2011; 201:226-232.
16. Lowry OH, Rosebrough NJ, Farr AL, Randall RJ. Protein measurement with the folin phenol reagent. J Biol Chem 1951; 193:265–275.
17. Draper HH, Hadley M. Malondialdehyde determination as index of lipid peroxidation. Methods Enzymol 1990; 186:421-431.
18. Cure E, Cure MC, Tumkaya L, Kalkan Y, Aydin I, Kirbas A, et al. Topiramate  ameliorates abdominal aorta cross-clamping induced liver injury in rats. Saudi J Gastroenterol 2014; 20:297-303.
19. Nielsen F, Mikkelsen BB, Nielsen JB, Andersen HR, Grandjean P. Plasma malondialdehyde as biomarker for oxidative stress: reference interval and effects of life-style factors. Clin Chem 1997; 43:1209-1214.
20. Fu Z, Liu X, Geng B, Fang L, Tang C. Hydrogen sulfide protects rat lung from ischemia-reperfusion injury. Life Sci 2008; 82:1196-1202.
21. Cao QF, Qu MJ, Yang WQ, Wang DP, Zhang MH, Di SB. Ischemia postconditioning preventing lung ischemia-reperfusion injury. Gene 2015; 554:120-124.
22. Bayomy NA, Elshafhey SH, ElBakary RH, Abdelaziz EZ. Protective effect of hesperidin against lung injury induced by intestinal ischemia/reperfusion in adult albino rats:histological, immunohistochemical and biochemical study. Tissue Cell 2014; 46:304-310.
23. De Perrot M, Liu M, Waddell TK, Keshavjee S. Ischemia-reperfusion-induced lung injury. Am J Respir Crit Care Med 2003; 167:490-511.
24. Kotyla PJ, Owczarek A, Rakoczy J, Lewicki M, Kucharz EJ, Emery P. Infliximab treatment increases left ventricular ejection fraction in patients with rheumatoid arthritis:assessment of heart function by echocardiography, endothelin 1, interleukin 6, and NT-pro brain natriuretic peptide. J Rheumatol 2012; 39:701-706.