title: Anti-TNF-alpha therapy does not ameliorate disease in a model of acute virus-endotoxin mediated respiratory disease in pigs.
abstract: Tumour necrosis factor-alpha (TNF-alpha) has been shown to play a role in many inflammatory conditions. Currently anti-TNF-alpha drugs (e.g. etanercept) are used in humans for treatment of autoimmune diseases. In this study we aimed to elucidate the role of TNF-alpha in the development of virus-endotoxin-induced respiratory disease. Twenty-two caesarean derived colostrum deprived pigs were used. Initially, the availability in the lungs and circulation, and possible clinical and inflammatory effects of etanercept alone were assessed in 4 pigs after intratracheal and intraperitoneal administration of 0.5mg/per route/per pig. High anti-TNF-alpha activity was detected in bronchoalveolar lavage (BAL) fluids, peritoneal lavage fluids and serum of all animals for at least 8h post-inoculation (HPI). No clinical symptoms, lung lesions, lung cell infiltration or induction of IFN-alpha, IL-1, IL-6, IL-12 and TNF-alpha in BAL were detected. Subsequently, the ability of etanercept to block porcine TNF-alpha and its effect on the above mentioned parameters and on lung virus titres were assessed in 8 pigs. They were inoculated intratracheally with porcine respiratory coronavirus (PRCV) followed by lipopolysaccharide (LPS) 24h later. Etanercept was administered at the time of LPS inoculation via the same routes and dose as in the initial experiment. The parameters were compared with a control group (n=8), receiving only PRCV-LPS. Half of the animals from each group were euthanized at 4 and the rest at 8h after LPS inoculation. TNF-alpha was completely neutralized in 3 of the 4 animals euthanized at 4 HPI and significantly lower than in the PRCV-LPS group at all times. No significant differences in disease severity, lung lesions, virus replication, lung cell infiltration or levels of IFN-alpha, IL-1, IL-6 and IL-12/IL-23 were observed between the two groups. Blocking of TNF-alpha alone was not sufficient to ameliorate disease in the PRCV-LPS model of respiratory disease, possibly due to the redundancy in the proinflammatory cytokine cascade, or the involvement of other unidentified disease mediators.
authors.affiliation: Laboratory of Virology, Faculty of Veterinary Medicine, Ghent University, Salisburylaan 133, B-9820 Merelbeke, Belgium.
authors.forename: Kalina
authors.initials: K
authors.lastname: Atanasova
authors.forename: Steven
authors.initials: S
authors.lastname: Van Gucht
authors.forename: Kristien
authors.initials: K
authors.lastname: Van Reeth
mesh_terms: D000208:Acute Disease; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D004195:Disease Models, Animal; D000068800:Etanercept; D005260:Female; D007074:Immunoglobulin G / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity*; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000188:drug therapy* / Q000276:immunology; D019318:Porcine Reproductive and Respiratory Syndrome / Q000188:drug therapy* / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use*; D013552:Swine; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000037:antagonists & inhibitors*
chemical_list: D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000068800:Etanercept
references.citation: Microb Pathog. 1995 Sep;19(3):175-83
references.pmid: 8559046
references.citation: Shock. 2009 Mar;31(3):262-6
references.pmid: 18650784
references.citation: Dermatol Ther. 2007 Jul-Aug;20(4):251-64
references.pmid: 17970890
references.citation: Int J Med Sci. 2008 Jul 03;5(4):169-80
references.pmid: 18645606
references.citation: Respir Res. 2006 Oct 11;7:125
references.pmid: 17034639
references.citation: Vet Microbiol. 2002 Aug 2;88(1):1-12
references.pmid: 12119134
references.citation: J Clin Microbiol. 2003 Mar;41(3):960-6
references.pmid: 12624016
references.citation: Br J Pharmacol. 2007 Feb;150(3):286-97
references.pmid: 17200677
references.citation: Eur J Immunol. 1988 Oct;18(10):1535-40
references.pmid: 3263920
references.citation: Cytokine Growth Factor Rev. 2004 Oct;15(5):367-77
references.pmid: 15450252
references.citation: Microbes Infect. 2006 May;8(6):1492-501
references.pmid: 16697680
references.citation: J Interferon Cytokine Res. 2006 Sep;26(9):661-7
references.pmid: 16978070
references.citation: J Interferon Cytokine Res. 2009 Nov;29(11):749-58
references.pmid: 19642909
references.citation: Am J Vet Res. 1994 Sep;55(9):1275-81
references.pmid: 7802396
references.citation: Immunol Rev. 2004 Dec;202:139-56
references.pmid: 15546391
references.citation: J Med Microbiol. 2000 Jul;49(7):613-620
references.pmid: 10882086
references.citation: J Clin Invest. 2008 Feb;118(2):560-70
references.pmid: 18219394
references.citation: Chin Med J (Engl). 2008 Apr 5;121(7):597-601
references.pmid: 18466678
references.citation: Res Vet Sci. 1999 Aug;67(1):47-52
references.pmid: 10425240
references.citation: Microbes Infect. 2004 May;6(6):630-6
references.pmid: 15158199