A74-25 Interleukin-17a Orchestrates Lung Injury and Remodeling Through P53 and Upa System Crosstalk

Abstract Rationale Pulmonary influx of inflammatory cells such as T-lymphocytes, macrophages, mast cells and increased interleukin 17A (IL-17A) levels promote lung injury. We postulated that IL-17A augments alveolar epithelial injury and fibrosing remodeling through induction of p53 and downstream changes in fibrinolysis through p53 interaction with the major components urokinase-type plasminogen activator (uPA) system cross-talk. Methods We conducted comprehensive in vitro and in vivo studies using primary alveolar epithelial cells (AECs), lung fibroblasts (Lfs), and lung homogenates, along with lung tissues from normal individuals, COPD and IPF patients, and from naïve mice and preclinical mouse models of chronic tobacco smoke exposure (TSE-), bleomycin (BLM)-, silica-, and thoracic radiation (TR)-induced lung injury and pulmonary fibrosis (PF). To compare the responsiveness of AECs and Lfs to recombinant IL-17A and caveolin-1 (Cav1) scaffolding domain peptide (CSP) or CSP7, anti-IL-17A- or anti-IL-17RA-antibody treatment, we used in vitro and in vivo models, including transgenic mice and archived human lung tissues. Results We found that IL-17A and its receptor, IL-17RA are induced during diverse types of lung injuries. IL-17A augments, IL-17RA, p53 and PAI-1 with a concurrent decrement of uPA and its receptor, uPAR in AECs. The coordinate changes in these molecules promote AEC apoptosis, worsen alveolar injury and fibrosis. In addition, IL-17RA is increased in IPF Lfs compared to that in Lfs from control (non-IPF) donors. Further, IL-17A caused a dose-dependent increase in IL-17RA and fibrotic markers and their mRNAs in Lfs, suggesting myofibroblast differentiation. We found that inhibition of IL-17A by CSP) or CSP7 inhibits AEC apoptosis, lung inflammation and prevents subsequent lung fibrosis. CSP7 treatment inhibits IL-17A induced fibrotic marker and their mRNA in human and mouse Lfs. Further treatment of mice having BLM-induced lung fibrosis with anti-IL-17A or anti-IL-17RA antibody or CSP7 attenuates total lung hydroxyproline and soluble collagen contents as well as fibrotic marker proteins and their mRNAs, suggesting inhibition of BLM-PF. Conclusions These observations collectively support the direct role of IL-17A/IL-17RA signaling axis in diverse types of lung injuries and subsequent remodeling. Further suggest that targeting IL-17A/IL-17RA signaling axis may mitigate lung injury and PF. This abstract is funded by: National Institute of Health grants HL151397-01A1 and ES025815 (SS).