Fibrinolytic Pathways In Interleukin-17A-induced lung Injury
Monday, March 5, 2018
South Hall A2 (Convention Center)
Sreerama Shetty, Venkadesa Perumal, Nivedita Tiwari, Amarnath Marudamuthu, Shwetha Kumari, Seong Park, Rashmi Shetty
RATIONALE: Accumulation of inflammatory cells and elevated interleukin-17A levels contributes to chronic inflammation, which results in the narrowing of small airways and alveolar wall destruction. Interleukin-17A is produced by T-lymphocytes, macrophages and mast cells, and augments lung inflammation. We hypothesized that interleukin-17A-mediated induction of plasminogen activator inhibitor-1 (PAI-1) expression leads to abnormal fibrin turnover and death of airway and alveolar epithelial cells (AECs) during lung injury.

METHODS: Wild-type and interleukin-17A-deficient mice were exposed to 20 weeks of environmental tobacco smoke (ETS) to induce lung injury. We analyzed lung tissues of patients with severe (stage III and IV) COPD and mice exposed to 20 weeks of ETS for elaboration of interleukin-17A, inflammatory cytokines and chemokines, PAI-1 and AEC apoptosis to test the hypothesis. This was further confirmed using primary human and mouse AECs treated with interleukin-17A in vitro, and lung tissues and AECs isolated from wild-type and PAI-1-deficient mice exposed to interleukin-17A in vivo.

RESULTS: We found elevated levels of T-lymphocytes, macrophages and neutrophils, and interleukin-17A in the lungs of patients with COPD and in wild-type mice exposed to ETS for 20 weeks. ETS and interleukin-17A exposure caused significant increase in PAI-1 and lung injury in wild-type mice. Mice deficient in interleukin-17A expression resisted ETS-induced lung injury, while those lacking PAI-1 expression resisted both ETS and interleukin-17A-induced lung injury.

CONCLUSIONS: Induction of PAI-1 expression due to increased interleukin-17A is associated with lung inflammation, AEC apoptosis and worsening of lung injury. Inhibition of this feedforward induction mitigates AEC apoptosis, inflammation and severity of lung injury.