WS10.2 Hypoxic epithelial necrosis triggers neutrophilic inflammation via IL-1 receptor signaling in cystic fibrosis-like lung disease

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In many organs, hypoxic cell death triggers sterile neutrophilic inflammation via Interleukin-1 receptor (IL-1R) signaling. Although hypoxia is common in airways from patients with cystic fibrosis (CF), its role in neutrophilic inflammation remains unknown. We recently demonstrated that hypoxic epithelial necrosis due to airway mucus obstruction precedes neutrophilic inflammation in Scnn1b -transgenic ( Scnn1b -Tg) mice with CF-like lung disease. To determine the role of hypoxic epithelial necrosis and IL-1R signaling in the development of neutrophilic inflammation, mucus obstruction and structural lung damage in CF lung disease, we used genetic deletion and pharmacological inhibition of IL-1R in Scnn1b -Tg mice and studied effects on airway epithelial necrosis, levels of IL-1α, keratinocyte chemoattractant (KC), neutrophils in bronchoalveolar lavage and mortality, mucus obstruction and emphysema. We evaluated lung tissues from patients with CF and COPD and controls for airway epithelial necrosis and mucus obstruction. Lack of IL-1R abrogated airway neutrophilia and reduced mortality, mucus obstruction and emphysema in Scnn1b -Tg mice. Treatment with IL-1R antagonist anakinra in adult Scnn1b -Tg mice showed similar protective effects. Numbers of necrotic airway epithelial cells were elevated and correlated with mucus obstruction in patients with CF and COPD. Our results support an important role of hypoxic epithelial necrosis in the pathogenesis of neutrophilic airway inflammation independent of bacterial infection and suggest IL-1R as a novel target for antiinflammatory therapy in CF and potentially other muco-obstructive airway diseases. Supported by DFG (DFG MA 2081/3–2).