Category: Other - Immunology and Inflammation
Introduction: Pulmonary fibrosis is a class of inflammatory lung diseases with poor prognosis. Recent studies have implicated Toll-like receptor 4 (TLR4) and damage-associated molecular patterns (DAMPs) in its pathogenesis. Extracellular cold-inducible RNA-binding protein (eCIRP) is a novel DAMP which exacerbates inflammation. eCIRP promotes inflammation through its binding to the TLR4/MD2 complex. We hypothesized that eCIRP enhances the fibrotic process in lungs by fibroblast activation.
Methods: Pulmonary fibrosis was induced in male 8-week old C57BL/6 WT and CIRP -/- mice through intratracheal (i.t.) instillation or subcutaneous (s.c.) injection of bleomycin and lung tissues were obtained and analyzed for hydroxyproline contents. To study the effect of eCIRP on fibroblasts, we preincubated mouse embryonic fibroblasts (MEF) cells with rmCIRP and the effects of transforming growth factor-β (TGF-β) in the expression of profibrotic genes were assessed by quantitative real-time PCR (qRT-PCR).
Results: Exposure of WT mice to bleomycin elicited significant changes in the lungs with substantial collagen accumulation as confirmed by increased hydroxyproline content as compared to the control WT mice (both i.t and s.c and p<0.05). Furthermore, pulmonary fibrosis showed substantial attenuation in CIRP KO mice (ANOVA, p<0.05). In MEF cells exposed to TGF-β, pre-incubation with rmCIRP significantly induced the expression of fibrotic genes compared to pre-incubation with PBS (Col1a2, α-SMA, MMP2, and MMP9, p<0.05).
Conclusion: eCIRP enhances TGF-β signaling in fibroblasts and induction of fibrotic process pulmonary tissue. The detailed mechanism by which this enhancement occurs is now under investigation. The results suggest a role for eCIRP in the pathogenesis of pulmonary fibrosis.
Siavash Bolourani– Elmezzi Scholar, The Feinstein Institute for Medical Research
Monowar Aziz– Assistant Professor, The Feinstein Institute for Medical Research
Max Brenner– Assistant Professor, The Feinstein Institute for Medical Research
Ping Wang– Chief Scientific Officer, The Feinstein Institute for Medical Research