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Mol Imaging Biol. 2019 Sep 3. doi: 10.1007/s11307-019-01412-8. [Epub ahead of print]

Temporal Dynamics of Reactive Oxygen and Nitrogen Species and NF-κB Activation During Acute and Chronic T Cell-Driven Inflammation.

Author information

1
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, 72076, Tübingen, Germany.
2
Department of Nuclear Medicine, Eberhard Karls University, 72076, Tübingen, Germany.
3
Department of Diagnostic and Interventional Radiology, Eberhard Karls University, 72076, Tübingen, Germany.
4
Interfaculty Institute of Biochemistry, Eberhard Karls University of Tübingen, Tübingen, Germany.
5
Department of Pathology, Eberhard Karls University, 72076, Tübingen, Germany.
6
Department of Pediatrics I, Eberhard Karls University, 72076, Tübingen, Germany.
7
German Cancer Consortium (DKTK) and German Cancer Research Center, 69120, Heidelberg, Germany.
8
Department of Dermatology, Venereology and Allergology, Charité - Universitätsmedizin Berlin, 10117, Berlin, Germany.
9
Department of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, 1432, Ås, Norway.
10
Department of Dermatology, Eberhard Karls University, 72076, Tübingen, Germany.
11
Werner Siemens Imaging Center, Department of Preclinical Imaging and Radiopharmacy, Eberhard Karls University, 72076, Tübingen, Germany. manfred.kneilling@med.uni-tuebingen.de.
12
Department of Dermatology, Eberhard Karls University, 72076, Tübingen, Germany. manfred.kneilling@med.uni-tuebingen.de.

Abstract

PURPOSE:

Reactive oxygen and nitrogen species (ROS/RNS) production and the NF-κB activation are critically involved in inflammatory responses, but knowledge about the temporal dynamics during acute and chronic inflammation is limited. Here, we present a comparative longitudinal in vivo study of both parameters in an experimental model of acute and chronic T cell-driven delayed-type hypersensitivity reaction (DTHR) using noninvasive optical imaging.

PROCEDURES:

Trinitrochlorobenzene (TNCB)-sensitized NF-κB-luciferase-reporter and wild-type mice were TNCB challenged on the right ear to elicit acute DTHR and then repetitively challenged (up to five times) to induce chronic DTHR. Mice were treated with the ROS-scavenging and NF-κB inhibiting molecule N-acetylcysteine (NAC) or underwent sham treatment. ROS/RNS production was noninvasively analyzed in vivo using the ROS-/RNS-sensitive chemiluminescent probe L-012, and NF-κB activation was measured using NF-κB-luciferase-reporter mice. H&E staining, CD3 and myeloperoxidase (MPO) immunohistochemistry (IHC), and quantitative PCR (qPCR) analyses were employed to investigate immune cell infiltration and expression of NF-κB- and ROS-/RNS-driven genes.

RESULTS:

In acute DTHR, we found strongly elevated ROS/RNS production and NF-κB activation 12 h after the 1st TNCB ear challenge, peaking at 24 h after the challenge. In chronic DTHR, ROS production peaked as early as 4 h after the 5th TNCB challenge, whereas NF-κB activity peaked after 12 h. The increase in ROS/RNS production in acute DTHR was higher than the increase in NF-κB activity but the relationship was inverse in chronic DTHR. Treatment with the ROS scavenger NAC had differential effects on ROS/RNS production and NF-κB activation during acute and chronic DTHR. Ex vivo cross-validation by histopathology and qPCR analysis correlated closely with the in vivo imaging results.

CONCLUSIONS:

Noninvasive in vivo imaging is capable of assessing the temporal dynamics of ROS/RNS production and NF-κB activation during progression from acute to chronic DTHR and enables monitoring of anti-inflammatory treatment responses.

KEYWORDS:

Anti-inflammatory effect; Contact allergy; Contact hypersensitivity reaction; Delayed-type hypersensitivity reaction; Inflammation; L-012; N-acetylcysteine; NF-κB; Optical imaging

PMID:
31482411
DOI:
10.1007/s11307-019-01412-8

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