The murine model of cantharidin-induced ear inflammation was profiled in detail for its
alignment with the human model and to explore the mechanism of anti-inflammatory activity
of the macrolide antibiotics, clarithromycin and azithromycin. Ear swelling in CD1
mice persisted for 7 days, with peak intensity at 16 h after inflammation induction.
As in humans, cantharidin (12.5 μg/ear) generated macrophage-inflammatory protein
(MIP)-2, monocyte chemoattractant protein (MCP)-1, keratinocyte-derived chemokine
(KC), interleukin (IL)-6, IL-1β, and myeloperoxidase (MPO) production, as well as
neutrophil accumulation in mouse ear tissue. The tested macrolides, clarithromycin
and azithromycin, administered orally (2 × 150 mg/kg) 0.5 h before and 5 h after cantharidin
challenge, reduced MIP-2, MCP-1, KC, and MPO concentrations and thereby decreased
ear swelling. Our results suggest that cantharidin-induced acute inflammation represents
an excellent model for translational research of novel anti-inflammatories.
Abbreviations:
ELISA (enzyme-linked immunosorbent assay), ENA-78 (epithelial cell-derived neutrophil attractant-78), GM-CSF (granulocyte macrophage-colony stimulating factor), GRO-α (growth-related oncogene-α), IL (interleukin), KC (keratinocyte-derived chemokine), LPS (lipopolysaccharide), MCP-1 (monocyte chemoattractant protein-1), MIP-2 (macrophage-inflammatory protein-2), MPO (myeloperoxidase), OXA (oxazolone), PBS (phosphate buffered saline), TNF-α (tumor necrosis factor-α)To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Translational ResearchAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Animal models of asthma: value, limitations and opportunities for alternative approaches.Drug Discov Today. 2011; 16: 659-670
- Can animal models of disease reliably inform human studies?.PLoS Med. 2010; https://doi.org/10.1371/journal.pmed.1000245
- Translational research: understanding the continuum from bench to bedside.Transl Res. 2011; 157: 1-5
- The meaning of translational research and why it matters.JAMA. 2008; 299: 211-213
- Basic science and translational research in JAMA.JAMA. 2002; 287: 1728
- Impaired neutrophil chemotaxis in Chron’s disease relates to reduced production of chemokines and can be augmented by granulocyte-colony stimulating factor.Aliment Pharmacol Ther. 2006; 24: 651-660
- Cantharidin blisters: a technique for investigating leukocyte trafficking and cytokine production at sites of inflammation in humans.J Immunol Methods. 2001; 257: 213-220
- Effects of low-dose aspirin on acute inflammatory responses in humans.J Immunol. 2009; 183: 2089-2096
- Neutrophil function in inflammation and inflammatory diseases.Rheumatology. 2010; 49: 1618-1631
- MPO and neutrophils: a magnetic attraction.Blood. 2011; 117: 1103-1104
- Measurement of cutaneous inflammation: estimation of neutrophil content with an enzyme marker.J Invest Dermatol. 1982; 78: 206-209
- The mouse ear as a model for cutaneous irritation.J Toxicol. 2002; 21: 191-202
- Topical azithromycin and clarithromycin inhibit acute and chronic skin inflammation in sensitized mice, with apparent selectivity for Th2-mediated processes in delayed type hypersensitivity.Inflammation. 2011; 35: 192-205
- Pharmacological study of cantharidin-induced ear inflammation in mice.J Pharmacol Methods. 1984; 11: 271-277
- Comparison of croton oil and cantharidin induced inflammations of the mouse ear and their modification by topically applied drugs.Arch Int Pharmacodyn. 1981; 254: 168-176
- Anti-inflammatory effects of macrolides–an underappreciated benefit in the treatment of the community acquired respiratory tract infections and chronic inflammatory pulmonary conditions?.J Antimicrob Chemother. 2005; 55: 10-21
- Anti-inflammatory effects of macrolide antibiotics.Eur J Pharmacol. 2001; 429: 209-229
- Cellular uptake and efflux of azithromycin, erythromycin, clarithromycin, telithromycin and cethromycin.Antimicrob Agents Chemother. 2005; 49: 2372-2377
- Anti-inflammatory activity of macrolide antibiotics.J Pharmacol Exp Ther. 2000; 292: 156-163
- Suppressive activity of macrolide antibiotics on nitric oxide production by lipopolysaccharide stimulation in mice.Mediat Inflamm. 2003; 12: 195-202
- Macrolide antibiotics as anti-inflammatory agents: roxythromycin in unexpected role.Agents Actions. 1993; 38: 85-90
- Comparative anti-inflammatory effects of roxithromycin, azithromycin and clarithromycin.J Antimicrob Chemother. 1998; 41: 47-50
- Cutaneously applied erythromycin base reduces various types of inflammatory reactions in mouse ear.Int J Tiss Reac. 1987; 9: 77-85
- Models of acute inflammation in the ear.in: Winyard P.G. Willoughby D.A. Methods in molecular biology: inflammation protocols. Humana Press Inc., Totowa, NJ2003: 129-137
- Production and resolution of cantharidin-induced inflammatory blisters.Int J Antimicrob Agents. 2003; 22: 77-80
- In vivo pharmacological disease models for psoriasis and atopic dermatitis in drug discovery.Bas Clin Pharmacol Tox. 2006; 99: 104-115
- CXC-chemokines KC and macrophage inflammatory protein-2 (MIP-2) synergistically induce leukocyte recruitment to the central nervous system in rats.Immunol Lett. 2003; 85: 1-4
- Neutrophil chemoattractant genes KC and MIP-2 are expressed in different cell populations at sites of surgical injury.J Leukoc Biol. 2004; 75: 641-648
- Expression of CCR2 on monocytes and macrophages in chronically inflamed skin in atopic dermatitis and psoriasis.Acta DermVenereol. 2004; 84: 353-358
- Monocyte chemoattractant protein 1 acts as a T-lymphocyte chemoattractant.Proc Natl Acad Sci USA. 1994; 91: 3652-3656
- Azithromycin blocks neutrophil recruitment in Pseudomonas endobronchial infection.Am J Respir Crit Care Med. 2004; 170: 1331-1339
- Azithromycin and clarithromycin inhibit lipopolysaccharide-induced murine pulmonary neutrophilia mainly through effects on macrophage-derived granulocyte-macrophage colony-stimulating factor and interleukin-1β.JPET. 2009; 331: 104-113
- The anti-inflammatory activity of clarithromycin inhibits TNFα production and prolongs survival following lipopolysaccharide administration in mice.Int J Antimicrob Agents. 2008; 32: 195-196
- Anti-inflammatory activity of azithromycin attenuates the effects of lipopolysaccharide administration in mice.Eur J Pharmacol. 2006; 539: 131-138
- Immunomodulatory effects of azithromycin on serum amyloid A production in lipopolysaccharide induced endotoxemia in mice.J Antib. 2011; 64: 515-517
- Effect of macrolide antibiotics on human endothelial cells activated by Chlamydia pneumoniae infection and tumor necrosis factor-α.J Infect Diseases. 2002; 185: 1631-1636
Article info
Publication history
Published online: February 27, 2012
Accepted:
February 2,
2012
Received in revised form:
February 1,
2012
Received:
November 4,
2011
Footnotes
This work was supported by GlaxoSmithKline Research Centre Zagreb Ltd.
Conflict of interest: At the time of study, the authors were all employees of GlaxoSmithKline Research Centre Zagreb Ltd. All authors have read the journal's policy on disclosure of potential conflicts of interest.
Identification
Copyright
© 2012 Mosby, Inc. Published by Elsevier Inc. All rights reserved.
