Alveolar macrophage heterogeneity in idiopathic pulmonary fibrosis

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Title: Alveolar macrophage heterogeneity in idiopathic pulmonary fibrosis
Authors: Luk, Sheung Fung Simon
Item Type: Thesis or dissertation
Abstract: Idiopathic Pulmonary Fibrosis (IPF) involves excess extracellular matrix (ECM) deposition within the lung interstitium, caused by non-resolving chronic inflammation and dysregulated repair. Alveolar macrophage (AMφ) may contribute to IPF through releasing various mediators by different subsets, investigated here in vitro, and ex vivo using a mouse model of bleomycin (BLM)-induced pulmonary fibrosis. The role of foamy AMφ in the reported increased susceptibility of Hermansky Pudlak Syndrome (HPS) 1 mice to BLM-induced pulmonary fibrosis was also assessed. Novel characterisation studies revealed that terminally differentiated AMφ are inducible into M1-like [nitric oxide synthase 2 (NOS2)hi interleukin (IL)-1βhi IL-12 p40 (total)hi major histocompatibility protein (MHC)-IIhi mannose receptor C, type 1 (MRC1)-] or M2-like [Arginase 1 (Arg1)hi Fibronectinhi IGF-1hi MHC-IIlo MRC1-/+] phenotypes following IFN-Υ or IL-13 priming respectively. Lipopolysccharide (LPS) altered these AMφ subset phenotypes. AMφ heterogeneity in a novel multiple oropharyngeal dose, BLM-induced pulmonary fibrosis was evaluated from days 7 to 21. Accumulation of M1-like AMφ at day 7, and M1/M2-hybrid AMφ [Arg1hi IL-12 p40 (total)hi fibronectinhi MHC-IIlo MRC1-/+] from days 7 to 21, may promote inflammation and fibrosis respectively. Toll-like Receptor (TLR) 9 messenger ribonucleic acid (mRNA) and TLR2 surface protein, and both TLRs2 and 9 ex vivo activities were increased in BLM-challenged mice from days 7 to 21, suggesting their roles in inflammation and fibrosis. Foamy AMφ accumulated in BLM-induced pulmonary fibrosis, and their potential role in the reported increased susceptibility to BLM-induced pulmonary fibrosis of HPS1 mice was evaluated. BLM-challenged HPS1 mice (days 7-21) had increased weight loss indicating reduced BLM tolerance from days 7 to 11, but little/no difference in collagen accumulation, suggesting that reduced BLM tolerance is not correlated with increased pulmonary fibrosis. In conclusion AMφ alter their phenotype in response to their environment that contributes to different stages of BLM-induced pulmonary fibrosis. Reduced BLM tolerance in HPS1 mice is not correlated with increased pulmonary fibrosis.
Content Version: Open Access
Issue Date: Jul-2015
Date Awarded: Jan-2016
Supervisor: Dallman, Maggie
Sponsor/Funder: Medical Research Council
Novartis Institute of Biomedical Research
Department: Life Sciences
Publisher: Imperial College London
Qualification Level: Doctoral
Qualification Name: Doctor of Philosophy (PhD)
Appears in Collections:Life Sciences PhD theses

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