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Thorax 67:A60-A61 doi:10.1136/thoraxjnl-2012-202678.131
  • Spoken sessions
  • Novel mechanisms in lung fibrogenesis

S126 Interleukin-1 Alpha (IL-1α) Released from Injured Lung Epithelium is a Critical Alarmin Driving Activation of a Potent Inflammatory Phenotype in Lung Fibroblasts

  1. AJ Fisher1
  1. 1Tissue Fibrosis and Repair Group, Institute of Cellular Medicine, Newcastle University, United Kingdom
  2. 2Immunopathogenesis Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
  3. 3Respiratory therapy area, GlaxoSmithKline, Stevenage, United Kingdom

Abstract

Background Activation of the innate immune system plays a key role in exacerbations of chronic lung disease. Myeloid cells are classically considered to drive innate immune responses yet the potential of fibroblasts to act as immune cells has been postulated. We hypothesized that alarmins released from lung epithelium during environmental insults such as oxidant injury and viral infection might induce innate immune responses in lung fibroblasts.

Methods Human bronchial epithelial cells (BECs) and human lung fibroblasts (HLFs) were cultured from brushings taken from lung transplant recipients and resected lung tissue respectively. Cytokine concentrations were measured by ELISA or multiplex platform (MSD). Gene expression was assessed by qRT-PCR. Wild-type and Il1a-/- mice were infected with Influenza (PR8). Data were analysed using t-Student or Mann-Whitney U Test. Correlations were assessed using Spearman rank correlation coefficient.

Results Conditioned media from PBECs subjected to oxidant injury contained elevated levels of alarmins. Treatment of HLFs with conditioned media significantly upregulated proinflammatory cytokine expression. Anti-IL-1α or IL-1Ra significantly reduced induction of IL-8 (93% and 95%), IL-6 (90% and 91%), MCP-1 (92% and 93%) and GM-CSF (95% and 94%). Anti-IL-1β had no effect. Co-stimulation with Poly I:C significantly accentuated the IL-1α induced inflammatory phenotype in HLFs. Bronchoalveolar lavage (BAL) form Influenza infected wild-type mice contains elevated levels of IL-1α and activates innate immune signalling in wild-type murine lung fibroblasts (MLFs) but not Il1r1-/- MLFs. BAL from Il1a-/- mice had no effect on MLFs and demonstrated a blunted neutrophilic response to Influenza. Clinically we show that IL-1α is increased in BAL of lung transplant recipients with infections and within 3 months of developing bronchiolitis obliterans syndrome (BOS) (p<0.001) and that IL-1α levels positively correlated with elevated IL-8 (p<0.001) and neutrophil counts (p<0.001).

Conclusions We propose a new paradigm of innate immune signalling in exacerbations of lung disease, where epithelial damage triggers a potent inflammatory phenotype in resident fibroblasts. The pivotal role of IL-1α in this process is accentuated in the presence of viral infection. This novel pathway warrants further evaluation of its therapeutic potential to limit the repeated cycles of injury and exacerbation in chronic lung diseases.