Lipopolysaccharid-induced neutrophilic inflammation in marmosets

Neutrophilic airway inflammation is a hallmark of chronic obstructive pulmonary disease (COPD), affecting 65 million people worldwide. Marmoset monkeys (Callithrix jacchus) are New World monkeys, frequently used in biomedical research (Mansfield 2003). A high sequence homology of immunity related genes (Kohu et al., 2008) enables an exceptional transferability of results obtained in preclinical studies. Furthermore, marmoset lung tissue shares physiological phenotypes with human tissue. More precisely, airways display a comparable response towards treatment with histamine, in contrast to rodents (Seehase et al., 2011).

Considering these advantages, we have introduced a model of lipopolysaccharide (LPS)-induced acute lung inflammation in marmoset monkeys (Seehase et al., 2012, Curths et al., 2014). LPS is an integral part of the gram-negative bacterial outer membrane. It is commonly used to model lung inflammation (Matute-Bello et al., 2008), accompanied by an upregulation of proinflammatory cytokines including TNF-α and MIP-1β. In in vitro and ex vivo trials, incubation of marmoset monkey whole blood as well as precision-cut lung slices with LPS revealed an increase of these cytokines. Additionally, in an in vivo trial, intrapulmonary administered LPS stimulated cytokine production which was analysed in bronchoalveolar lavage fluid (Seehase 2012). Besides increased cytokine levels, inflammatory cells, particularly neutrophils, displayed elevated numbers. Moreover, these LPS-induced changes were sensitive towards treatment with a glucocorticoid and a phosphodiesterase type 4 inhibitor, frequently used in human COPD treatment. In sum, this marmoset model provides an opportunity for pre-clinical efficacy testing of anti-inflammatory substances.

Species

Marmoset monkeys (Callithrix jacchus)

Field of application

  • Preclinical efficacy testing

Endpoints/Outcome parameter

  • Neutrophilic Airway Inflammation & Airway Hyperresponsiveness

Readout parameter

  • Bronchoalveolar lavage: cell count + differential cell count (incl. inflammatory cells), cytokine profiles
  • Lung function measurements e.g. airway hyperresponsiveness (AHR)
  • Blood analysis: cell count + differential cell count (incl. inflammatory cells), serology
  • Cytokine profiles (ELISA) of stimulated peripheral blood mononuclear cells
  • Histology: conventional staining and tissue pathohistology/ conventional microscopy (e.g. tissue cell infiltration), immunohistochemistry/fluorescence microscopy
  • Lung tissue analysis (RNA isolation, cytokine profiles)
  • Precision-cut lung slices

Quality management and validation

  • Internal quality management
  • Historical data available
  • Reference compounds e.g. dexamethasone, roflumilast
  • Accurate observance of EU directive 2010/63/EU on the protection of animals used for scientific purposes and of the German animal protection law

References

  • Curths C, Wichmann J, Dunker S, Windt H, Hoymann H G, Lauenstein H D, Hohlfeld J, Becker T, Kaup F J, Braun A, and Knauf S (2014). Airway hyper-responsiveness in lipopolysaccharide-challenged common marmosets (Callithrix jacchus). Clin Sci (Lond). 126(2): 155-162.

  • Seehase S, Schleputz M, Switalla S, Matz-Rensing K, Kaup F J, Zoller M, Schlumbohm C, Fuchs E, Lauenstein H D, Winkler C, Kuehl A R, Uhlig S, Braun A, Sewald K, and Martin C (2011). Bronchoconstriction in nonhuman primates: a species comparison. J Appl Physiol (1985). 111(3): 791-798.

  • Seehase S, Lauenstein H D, Schlumbohm C, Switalla S, Neuhaus V, Forster C, Fieguth H G, Pfennig O, Fuchs E, Kaup F J, Bleyer M, Hohlfeld J M, Braun A, Sewald K, and Knauf S (2012). LPS-induced lung inflammation in marmoset monkeys - an acute model for anti-inflammatory drug testing. PLoS One. 7(8): e43709.

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