Abstract
Background
COPD exacerbations contribute to progressive disease by inducing acute on chronic inflammation. Leukocytes have traditionally been considered orchestrators of this inflammation. We hypothesise tissue injury and release of damage associated molecular patterns(DAMPs) such as IL-1α drive inflammation and dysfunctional repair in parenchymal lung fibroblasts.
Methods
Lung fibroblasts were cultured from control(n=6) and COPD(n=6 GOLD stage III/IV) lung tissue. Cells were stimulated with Interleukin- 1alpha(IL1α) or Tissue Growth Factor- beta(TGFβ). Smad2 phosporylation(ELISA) was measured at 1hr and pro-inflammatory cytokine concentrations(multiplex MSD) and MMP2 activity(zymography) in supernatants measured at 24hr.
Results
IL1α induced a dose dependent increase in inflammatory cytokines(IL6,IL8, IL1β, GM-CSF and TNFα) from both control and COPD fibroblasts. The COPD fibroblasts demonstrated a more dramatic response to IL1α than controls. Constitutive Smad2 phosphorylation was higher in control than COPD fibroblasts and increased further in response to TGFβ stimulation. This increase was attenuated in COPD fibroblasts. MMP2 activity was detected in both control and COPD fibroblasts with no additional response to either TGFβ or IL1α stimulation.
Conclusion
Lung fibroblasts respond to the DAMP IL1α, adopting a potent pro-inflammatory phenotype a response which is exaggerated in COPD. In addition, COPD fibroblasts have a blunted signalling response to TGFβ compared to controls. These preliminary observations suggest COPD fibroblasts adopt a pro-inflammatory phenotype with reduced repair capacity in response to tissue injury implicating them in the pathophysiology of the disease.
- © 2014 ERS
