Background The role of inflammation in the pathogenesis of idiopathic pulmonary fibrosis (IPF) remains controversial. While immune activation is evident in IPF lungs, immunosuppressive therapies have historically been associated with adverse outcomes. Investigating the transcriptional response of IPF lung tissue to inflammatory stimuli may help elucidate the contribution of dysregulated inflammatory pathways to the underlying disease mechanism. Methods To test the inflammatory response of IPF lung tissue, human precision-cut lung slices (PCLS) were generated from 3 different regions of IPF lungs: non-fibrotic (NF), transition (T), and dense fibrotic area (F). For control, we obtained PCLS from normal lung tissue (N). PCLS were incubated with or without 100 ng/ml of lipopolysaccharide (LPS) for 48 h. Bulk RNA sequencing was performed and evaluated by differential gene expression (DGE), gene ontology (GO), gene set enrichment analysis (GSEA) and network analysis. Cytokines levels in supernatants, such as tumour necrosis factor (TNF), interleukin (IL)-6 and IL-8, were quantified by ELISA. Results Our findings confirm metabolic reprograming, including suppression of fatty acid/cholesterol metabolism and ribosomal genes, as characteristic hallmark of all IPF regions compared to N tissues, with a fibrosis severity-dependent gradient. Interestingly, untreated NF- and T-IPF PCLS showed upregulated inflammatory genes associated with toll-like receptors (TLR), TNF and IL-6 signature when compared to N and F-IPF. However, when challenged with LPS, most of the inflammatory genes displayed attenuated activation in IPF tissues, such as markers for T cells activation (INF-γ and α, TNF via NF-κB, TLR). TNF release was greater in N tissue compared to NF- and T-IPF but less for IL-6 and IL-8 if compared to IPF tissue. Conclusion Our findings show steady inflammation in normal appearing and transitional areas of IPF lung tissue. These inflammatory markers equally participate in the pro-fibrotic signalling through signal transducers and transcription factors, which might result in dual pro-fibrotic and inflammatory effects during disease progression.
