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Carbon-nanoparticle-triggered acute lung inflammation and its resolution are not altered in PPARĪ³-defective (P465L) mice.


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Authors

Gƶtz, Alexander A 
Vidal-Puig, Antonio  ORCID logo  https://orcid.org/0000-0003-4220-9577
Rƶdel, Heiko G 
de Angelis, Martin HrabĆ© 
Stoeger, Tobias 

Abstract

BACKGROUND: The alveolar macrophage (AM) - first line of innate immune defence against pathogens and environmental irritants - constitutively expresses peroxisome-proliferator activated receptor Ī³ (PPARĪ³). PPARĪ³ ligand-induced activation keeps the AM quiescent, and thereby contributes to combat invaders and resolve inflammation by augmenting the phagocytosis of apoptotic neutrophils and inhibiting an excessive expression of inflammatory genes. Because of these presumed anti-inflammatory functions of PPARĪ³ we tested the hypothesis, whether reduced functional receptor availability in mutant mice resulted in increased cellular and molecular inflammatory response during acute inflammation and/or in an impairment of its resolution. METHODS: To address this hypothesis we examined the effects of a carbon-nanoparticle (CNP) lung challenge, as surrogate for non-infectious environmental irritants, in a murine model carrying a dominant-negative point mutation in the ligand-binding domain of PPARĪ³ (P465L/wt). Animals were instilled intratracheally with Printex 90 CNPs and bronchoalveolar lavage (BAL) was gained 24 h or 72 h after instillation to investigate its cellular and protein composition. RESULTS: Higher BAL cell numbers - due to higher macrophage counts - were found in mutants irrespective of treatment. Neutrophil numbers in contrast were slightly lower in mutants. Intratracheal CNP instillation resulted in a profound recruitment of inflammatory neutrophils into the alveolus, but genotype related differences at acute inflammation (24 h) and resolution (72 h) were not observed. There were no signs for increased alveolar-capillary membrane damage or necrotic cell death in mutants as determined by BAL protein and lactate-dehydrogenase content. Pro-inflammatory macrophage-derived cytokine osteopontin was higher, but galectin-3 lower in female mutants. CXCL5 and lipocalin-2 markers, attributed to epithelial cell stimulation did not differ. CONCLUSIONS: Despite general genotype-related differences, we had to reject our hypothesis of an increased CNP induced lung inflammation and an impairment of its resolution in PPARĪ³ defective mice. Although earlier studies showed ligand-induced activation of nuclear receptor PPARĪ³ to promote resolution of lung inflammation, its reduced activity did not provide signs of resolution impairment in the settings investigated here.

Description

Keywords

Acute Lung Injury, Animals, Biomarkers, Bronchoalveolar Lavage Fluid, Carbon, Enzyme-Linked Immunosorbent Assay, Female, Leukocytes, Macrophages, Alveolar, Male, Mice, Mice, Inbred C57BL, Mice, Mutant Strains, Nanoparticles, PPAR gamma, Point Mutation, Sex Factors

Journal Title

Part Fibre Toxicol

Conference Name

Journal ISSN

1743-8977
1743-8977

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (G0600717)
Medical Research Council (G0400192)