The pathogenesis of diclofenac induced immunoallergic hepatitis in a canine model of liver injury
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Saravanakumar Selvaraj1,*, Jung-Hwa Oh2,*, Reinhard Spanel1,3, Florian Länger4, Hyoung-Yun Han2, Eun-Hee Lee2, Seokjoo Yoon2 and Jürgen Borlak1
1Centre for Pharmacology and Toxicology, Hannover Medical School, 30625 Hannover, Germany
2Department of Predictive Toxicology, Korea Institute of Toxicology, 34114 Gajeong-ro, Yuseong, Daejeon, Republic of Korea
3Institute of Pathology, 41747 Viersen, Germany
4Institute of Pathology, Hannover Medical School, 30625 Hannover, Germany
*Contributed equally as first author
Jürgen Borlak, email: firstname.lastname@example.org
Keywords: diclofenac; immunogenomics; complement system; classical and alternate pathway; CARPA
Received: June 26, 2017 Accepted: July 31, 2017 Published: September 23, 2017
Hypersensitivity to non-steroidal anti-inflammatory drugs is a common adverse drug reaction and may result in serious inflammatory reactions of the liver. To investigate mechanism of immunoallergic hepatitis beagle dogs were given 1 or 3 mg/kg/day (HD) oral diclofenac for 28 days. HD diclofenac treatment caused liver function test abnormalities, reduced haematocrit and haemoglobin but induced reticulocyte, WBC, platelet, neutrophil and eosinophil counts. Histopathology evidenced hepatic steatosis and glycogen depletion, apoptosis, acute lobular hepatitis, granulomas and mastocytosis. Whole genome scans revealed 663 significantly regulated genes of which 82, 47 and 25 code for stress, immune response and inflammation. Immunopathology confirmed strong induction of IgM, the complement factors C3&B, SAA, SERPING1 and others of the classical and alternate pathway. Alike, marked expression of CD205 and CD74 in Kupffer cells and lymphocytes facilitate antigen presentation and B-cell differentiation. The highly induced HIF1A and KLF6 protein expression in mast cells and macrophages sustain inflammation. Furthermore, immunogenomics discovered 24, 17, 6 and 11 significantly regulated marker genes to hallmark M1/M2 polarized macrophages, lymphocytic and granulocytic infiltrates; note, the latter was confirmed by CAE staining. Other highly regulated genes included alpha-2-macroglobulin, CRP, hepcidin, IL1R1, S100A8 and CCL20. Diclofenac treatment caused unprecedented induction of myeloperoxidase in macrophages and oxidative stress as shown by SOD1/SOD2 immunohistochemistry. Lastly, bioinformatics defined molecular circuits of inflammation and consisted of 161 regulated genes.
Altogether, the mechanism of diclofenac induced liver hypersensitivity reactions involved oxidative stress, macrophage polarization, mastocytosis, complement activation and an erroneous programming of the innate and adaptive immune system.
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