Abstract
Introduction: Mitochondrial damage-associated molecular patterns (mtDAMPs) are emerging as potential mediators in cancer & lung disease. Formyl peptides (FP) are a major source of mtDAMPs, aside from mitochondrial CpG-rich DNA, are bound by three main receptors in humans (FPR1-3) & eight in mice
Hypothesis: Release of mtDAMPs & ligation of FPR1 may play an important role in driving a fibrogenic response in the lung after potent inflammatory injury
Methods: FPR1 KO and C57bl/6 (WT) mice were treated intratracheally with bleomycin sulphate 0.007U/saline control with day 5 & day 21 timepoints. Expression of pro-inflammatory chemokines & cytokines was measured using Meso-scale discovery mouse cytokine assay on lung lobe homogenates. Lung collagen content was measured using a hydroxyproline assay. Expression of extra-cellular matrix molecules was assessed by ELISA, real-time PCR & immunohistochemistry. Immune cell phenotyping was performed using flow cytometry to identify inflammatory infiltrate
Results: FPR1 KO mice exhibit a blunted pro-inflammatory chemokine & cytokine profile compared to WT mice at day 5. Collagen content & expression of α-smooth muscle actin & other extra-cellular matrix molecules were reduced at day 21 in FPR1 KO mice. Differences in macrophage activation were found between WT & KO injured mice after 21 days. Macrophages in WT mice exhibited an M2 phenotype, characterised by high levels of CD206/FIZZ-1 in contrast to FPR1 KO macrophages
Conclusion: FPR1 KO mice are protected against fibrosis in response to bleomycin treatment indicating FPR interactions are important in driving fibrogenesis in the lung after an inflammatory injury.
- © 2014 ERS